Tricyclic compounds and their uses

Abstract

The present application provides a compound represented by formula (I) or a pharma- ceutically acceptable salt thereof, a pharmaceutical composition thereof, a method for preparing the same, and a use thereof as a MAT2A inhibitor. 1 , X 2 , L and R 1 is as defined in the specification. [Formula 1] JPEG2024502097000169.jpg5150

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a Chinese patent application filed with the State Intellectual Property Office of the People's Republic of China on December 31, 2020, with application number 202011637193.3 and titled "Tricyclic compounds and their use", filed with the State Intellectual Property Office of the People's Republic of China on February 26, 2021, with application number 202110213607.8 and titled "Tricyclic compounds and their use", filed with the State Intellectual Property Office of the People's Republic of China on April 29, 2021, with application number 20211047713 6.1, entitled "Tricyclic Compounds and Uses Thereof," and the Chinese patent application filed with the State Intellectual Property Office of China on July 9, 2021, bearing application number 202110780130.1, entitled "Tricyclic Compounds and Uses Thereof," and the Chinese patent application filed with the State Intellectual Property Office of China on August 27, 2021, bearing application number 202110998242.4, entitled "Tricyclic Compounds and Uses Thereof." The above patent applications are incorporated herein by reference in their entireties. [Background technology]

[0002] The present application belongs to the pharmaceutical field, and specifically relates to novel tricyclic compounds or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, and their use as MAT2A inhibitors.

[0003] Methionine adenosyltransferase (MAT), also known as S-adenosylmethionine synthase, is an enzyme that catalyzes the reaction of methionine (Met) with ATP to produce S-adenosylmethionine (SAM). SAM is the main methyl donor for methyltransferases in the body, and through methyl group transfer, it regulates gene expression, transcription, and translation, and can have important effects on cell growth, death, and differentiation. Protein arginine N-methyltransferase 5 (PRMT5) is a methyltransferase that uses SAM as a substrate and plays an important regulatory role in tumor cell proliferation and other processes.

[0004] There are three main subtypes of MAT enzymes: MAT1A, MAT2A, and MAT2B. MAT1A is primarily present in normal hepatocytes, whereas MAT2A is widely distributed in extrahepatic cells. These two subtypes differ in catalytic efficiency and regulatory mode. MAT2B is unable to catalyze SAM synthesis and, as a regulatory subunit of MAT2A, regulates the catalytic activity of MAT2A after forming a complex with MAT2A.

[0005] Studies have shown that cancer cell lines deficient in methylthioadenosine phosphorylase (MTAP) are sensitive to MAT2A inhibition (Cell Reports 15(3)(2016)574-587). MTAP is widely expressed in normal tissue cells. This enzyme catalyzes the conversion of 5'-methylthioadenosine (MTA) to 5-methylthioribose-1-phosphate and adenine. This process is also an important compensatory pathway for methionine in the human body. MTAP deficiency inhibits the MTA metabolic pathway, leading to the accumulation of large amounts of MTA in the body. The accumulation of MTA partially inhibits the activity of PRMT5, thereby increasing the sensitivity of PRMT5 to changes in SAM levels in the body. Therefore, in MTAP-deficient tumors, inhibiting MAT2A to reduce SAM levels in the body further inhibits PRMT5 activity, resulting in synthetic lethality.

[0006] The gene encoding human MTAP is located on chromosome 9p21 (chr9p21), and its homozygous deletion frequency in all tumors is approximately 15%, and the deletion frequency varies depending on the tumor. Tumor types with relatively high deletion frequencies include glioma, mesothelioma, melanoma, gastric cancer, esophageal cancer, bladder cancer, pancreatic cancer, non-small cell lung cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, and non-Hodgkin's lymphoma.

[0007] The human chromosome 9p21 region contains not only the gene encoding MTAP, but also the tumor suppressor genes p16INK4A (also known as CDKN2A) and p15INK4B. In 80% to 90% of CDKN2A-deficient tumors, MTAP is also deleted.

[0008] Considering that MAT2A expression levels are abnormally elevated in many types of tumors, including gastric cancer, colon cancer, liver cancer, and pancreatic cancer, and that selective inhibition of MAT2A can reduce the proliferation activity of MTAP-deficient cancer cells, selective inhibition of MAT2A can be used as an effective tumor treatment. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] WO2018039972 [Patent Document 2] WO2018045071 [Patent Document 3] WO2019191470 [Patent Document 4] WO2020123395

[0010] Patent documents such as US Pat. No. 5,629,299, ... and US Pat. No. 5,629,299 disclose heterocyclic MAT2A inhibitors for the treatment of tumors. Summary of the Invention

[0011] The present application provides a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, [ka] Among them, L is selected from a chemical bond, NH or O; R 1 is a halogen or optionally R 1a C1~C replaced by 10 Alkyl groups, C3-C 10 selected from a cycloalkyl group and a 3- to 10-membered heterocyclyl group; X1 and X2 are each independently selected from N or CH; Ring A is C6-C 10 an aryl group, a 5- to 10-membered heteroaryl group, or a 4- to 7-membered heterocyclyl group,10 The aryl group, 5- to 10-membered heteroaryl group, or 4- to 7-membered heterocyclyl group is optionally R 2 is replaced by

[0012] X and Y are ring atoms of ring A, and X and Y are each independently selected from a C atom or an N atom, and when at least one of X and Y is selected from an N atom, X and Y are linked by a single bond, and when both X and Y are selected from C atoms, X and Y may be linked by a single bond or a double bond;

[0013] R 2 is halogen, ═O, OH, CN, or optionally R 2a NH2, C1-C substituted by 10 Alkyl groups, C3-C 10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C1-C 10 Alkoxy group, C3-C 10 selected from a cycloalkyloxy group and a 3- to 10-membered heterocyclyloxy group;

[0014] Ring Q is C6 to C 10 an aryl group, or a 5- to 10-membered heteroaryl group, 10 The aryl group or 5- to 10-membered heteroaryl group is optionally R 3 is replaced by

[0015] R 3 is halogen, =O, OH, CN, NO2 or optionally R 3a Substituted by SH, NH2, C2~C 10 Alkenyl groups, C2-C 10 Alkynyl groups, C1-C 10 Alkyl groups, C3-C 10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C1-C 10 Alkoxy group, C3-C 10 selected from a cycloalkyloxy group and a 3- to 10-membered heterocyclyloxy group;

[0016] Each R 1a , R 2a , R3a are independently a deuterium atom, F, Cl, Br, I, OH, CN, ═O, or optionally R b selected from NH2, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a 4- to 7-membered heterocyclyl group, a 5- to 6-membered heteroaryl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyloxy group, and a 4- to 7-membered heterocyclyloxy group, each of which is substituted by

[0017] Each R b are independently selected from F, Cl, Br, I, OH, CN, ═O, NH2, SH, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, or a 4- to 7-membered heterocyclyl group.

[0018] In some embodiments, R 3 is halogen, ═O, OH, CN, or optionally R 3a NH2, C2 to C substituted by 10 Alkenyl groups, C2-C 10 Alkynyl groups, C1-C 10 Alkyl groups, C3-C 10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C1-C 10 Alkoxy group, C3-C 10 a cycloalkyloxy group, and a 3- to 10-membered heterocyclyloxy group, and each R 1a , R 2a , R 3a are independently a deuterium atom, F, Cl, Br, I, OH, CN, ═O, or optionally R b NH2, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a 4- to 7-membered heterocyclyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyloxy group, and a 4- to 7-membered heterocyclyloxy group substituted with each R b are independently selected from F, Cl, Br, I, OH, CN, ═O, NH2, SH, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, or a 4- to 7-membered heterocyclyl group.

[0019] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (Ia), or a pharmaceutically acceptable salt thereof: [ka] Among them, L is selected from a chemical bond, NH or O; R 1 is a halogen or optionally R 1a C1~C replaced by 10 Alkyl groups, C3-C 10 selected from a cycloalkyl group and a 3- to 10-membered heterocyclyl group; X1 and X2 are each independently selected from N or CH;

[0020] Ring A is C6-C 10 an aryl group, a 5- to 10-membered heteroaryl group, or a 4- to 7-membered heterocyclyl group, 10 The aryl group, 5- to 10-membered heteroaryl group, or 4- to 7-membered heterocyclyl group is optionally R 2 is replaced by

[0021] R 2 is halogen, ═O, OH, CN, or optionally R 2a NH2, C1-C substituted by 10 Alkyl groups, C3-C 10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C1-C 10 Alkoxy group, C3-C 10 selected from a cycloalkyloxy group and a 3- to 10-membered heterocyclyloxy group;

[0022] Ring Q is C6 to C 10 an aryl group, or a 5- to 10-membered heteroaryl group, 10 The aryl group or 5- to 10-membered heteroaryl group is optionally R 3 is replaced by

[0023] R 3 is halogen, ═O, OH, CN, or optionally R 3a NH2, C2 to C substituted by 10 Alkenyl groups, C2-C 10 Alkynyl groups, C1-C10 Alkyl groups, C3-C 10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C1-C 10 Alkoxy group, C3-C 10 selected from a cycloalkyloxy group and a 3- to 10-membered heterocyclyloxy group;

[0024] Each R 1a , R 2a , R 3a are independently F, Cl, Br, I, OH, CN, ═O, or optionally R b NH2, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a 4- to 7-membered heterocyclyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyloxy group, and a 4- to 7-membered heterocyclyloxy group, each of which is substituted with

[0025] Each R b are independently selected from F, Cl, Br, I, OH, CN, ═O, NH2, SH, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, or a 4- to 7-membered heterocyclyl group.

[0026] In some embodiments, the 3- to 10-membered heterocyclyl group contains 1 to 3 or 1 to 5 heteroatoms or heteroatomic groups, which are independently selected from N, O, S, P, B, -S(=O)2-, -S(=O)-, -P(=O)2-, -P(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH-, or -NHC(=O)NH-.

[0027] In some embodiments, the 3- to 10-membered heterocyclyl group contains 1 to 3 heteroatoms or heteroatomic groups, each independently selected from N, O, S, -S(=O)2-, or -NH-. In some embodiments, the 4- to 7-membered heterocyclyl group contains 1 to 3 heteroatoms or heteroatomic groups, each independently selected from N, O, S, -S(=O)2-, or -NH-. In some embodiments, the 4- to 7-membered heterocyclyl group contains 1, 2, or 3 heteroatoms, each independently selected from N, O, or S.

[0028] In some embodiments, the 5- to 10-membered heteroaryl group contains 1 to 3 or 1 to 5 heteroatoms, which are independently selected from N, O, and S. In some embodiments, the 5- to 6-membered heteroaryl group contains 1 to 3 heteroatoms, which are independently selected from N, O, and S.

[0029] In some embodiments, X and Y are ring atoms, and both X and Y are C and X and Y are connected by a single or double bond, or one of X and Y is C and the other is N and X and Y are connected by a single bond.

[0030] In some embodiments, X and Y are both C, X and Y are linked by a single or double bond, X1 is N, and X2 is CH or N, or X1 and X2 are both CH. In some embodiments, X and Y are both C, X and Y are linked by a double bond, X1 is N, and X2 is CH, or X1 and X2 are both CH, or X1 and X2 are both N.

[0031] In some embodiments, L is selected from NH and R 1 is selected from a C1-C6 alkyl group, a C3-C6 cycloalkyl group, or a 4- to 7-membered heterocyclyl group, and the C1-C6 alkyl group, C3-C6 cycloalkyl group, or 4- to 7-membered heterocyclyl group is optionally substituted by F, Cl, Br, I, OH, CN, ═O, NH2, NH(C1-C3 alkyl group), N(C1-C3 alkyl group)2, a C1-C3 alkyl group, or a C1-C3 alkoxy group.

[0032] In some embodiments, L is selected from NH and R 1 is selected from C1 to C6 alkyl groups. In some embodiments, L is selected from NH, X1 is selected from N, and X2 is selected from CH.

[0033] In some embodiments, L is selected from a chemical bond or O. In some embodiments, L is selected from a chemical bond. In some embodiments, L is selected from O.

[0034] In some embodiments, R 1 is a halogen or optionally R 1a and a C1-C3 alkyl group, a C3-C6 cycloalkyl group, and a 4- to 7-membered heterocyclyl group substituted by

[0035] In some embodiments, R 1 is a halogen or optionally R 1a and a 4- to 7-membered heterocyclyl group substituted with In some embodiments, R 1 is a halogen or optionally R 1a is selected from C1-C3 alkyl groups substituted with In some embodiments, R 1 is a halogen or optionally R 1a The alkyl group is selected from the group consisting of a methyl group, an ethyl group, and an oxetanyl group substituted with

[0036] In some embodiments, R 1 is a halogen or optionally R 1a and methyl and ethyl groups substituted by: In some embodiments, R 1 is optionally R 1a substituted methyl groups.

[0037] In some embodiments, each R 1a are independently F, Cl, Br, I, OH, CN, ═O, or optionally R b is selected from NH2 substituted by, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a 4- to 7-membered heterocyclyl group, and a C1-C6 alkoxy group.

[0038] In some embodiments, each R1a are independently selected from F, Cl, Br, and I. In some embodiments, each R 1a are independently chosen from F.

[0039] In some embodiments, R 1 is selected from Cl, CH3, CF3, an ethyl group, or an oxetanyl group. In some embodiments, R 1 is selected from CF3, an ethyl group, or an oxetanyl group. In some embodiments, R 1 is selected from Cl, CH3, CF3, or an ethyl group. In some embodiments, R 1 is selected from Cl, CF3, or an ethyl group.

[0040] In some embodiments, R 1 is selected from CF3 or an ethyl group. In some embodiments, R 1 is selected from CF3. In some embodiments, L is a chemical bond and R 1 is selected from halogen, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, or a 4- to 7-membered heterocyclyl group, and the C1-C6 alkyl group, C3-C6 cycloalkyl group, or 4- to 7-membered heterocyclyl group is optionally substituted by F, Cl, Br, I, OH, CN, ═O, NH2, NH(C1-C3 alkyl group), N(C1-C3 alkyl group)2, a C1-C3 alkyl group, and a C1-C3 alkoxy group.

[0041] In some embodiments, L is a chemical bond and R 1 is a halogen or optionally R 1a C1-C3 alkyl groups substituted with 1a are independently selected from F, Cl, Br, and I.

[0042] In some embodiments, L is O and R 1is selected from a C1-C6 alkyl group, a C3-C6 cycloalkyl group, or a 4- to 7-membered heterocyclyl group, and the C1-C6 alkyl group, C3-C6 cycloalkyl group, or 4- to 7-membered heterocyclyl group is optionally substituted by F, Cl, Br, I, OH, CN, ═O, NH2, NH(C1-C3 alkyl group), N(C1-C3 alkyl group)2, a C1-C3 alkyl group, and a C1-C3 alkoxy group.

[0043] In some embodiments, L is O and R 1 is selected from a C1 to C6 alkyl group or a 4 to 7 membered heterocyclyl group.

[0044] [ka]

[0045] In some embodiments, X 1 is selected from N. In some embodiments, X1 is selected from CH. In some embodiments, X2 is selected from CH. In some embodiments, X1 is N and X2 is CH. In some embodiments, X1 and X2 are both CH. In some embodiments, X1 and X2 are both N.

[0046] In some embodiments, X1 is selected from N or CH and X2 is selected from CH. In some embodiments, ring A is selected from a 5- to 6-membered heteroaryl group or a 4- to 7-membered heterocyclyl group, and the 5- to 6-membered heteroaryl group or the 4- to 7-membered heterocyclyl group is optionally selected from R 2 is replaced by

[0047] In some embodiments, ring A is selected from a 5- to 6-membered heteroaryl group or a 5- to 7-membered heterocyclyl group, wherein the ring atoms of the 5- to 6-membered heteroaryl group or the 5- to 7-membered heterocyclyl group contain at least one heteroatom or heteroatom group selected from N, O, S, and S(O)2, and the 5- to 6-membered heteroaryl group or the 5- to 7-membered heterocyclyl group optionally contains R 2 is replaced by

[0048] In some embodiments, ring A is optionally R 2 a pyrrolyl group, a pyrazolyl group, an imidazolyl group, an oxazolyl group, an isoxazolyl group, a triazolyl group substituted by [ka]

[0049] In some embodiments, ring A is optionally R 2 a pyrrolyl group, a pyrazolyl group, an imidazolyl group, an oxazolyl group, an isoxazolyl group, a triazolyl group substituted by [ka]

[0050] In some embodiments, ring A is optionally R 2 replaced by [ka]

[0051] In some embodiments, ring A is an imidazolyl group, an oxazolyl group, [ka]

[0052] In some embodiments, ring A is a pyrrolyl group, a pyrazolyl group, an imidazolyl group, an oxazolyl group, [ka] Optionally, R 2 is replaced by

[0053] In some embodiments, ring A is optionally R 2 replaced by [ka]

[0054] In some embodiments, ring A is selected from an imidazolyl group or a pyrazolyl group, wherein the imidazolyl group or the pyrazolyl group is optionally selected from R 2 is replaced by In some embodiments, R 2 is =O or optionally R 2a is selected from NH2 substituted by, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, and a C1-C6 alkoxy group.

[0055] In some embodiments, R 2 is =O or optionally R 2a and C1 to C6 alkoxy groups substituted with In some embodiments, R 2 is =O or optionally R 2a is selected from C1-C3 alkyl groups substituted with

[0056] In some embodiments, R 2a is selected from a deuterium atom, F, Cl, Br, I, OH, a C1-C3 alkyl group, NH2 optionally substituted with a C1-C3 alkyl group, or a 5- to 6-membered heteroaryl group optionally substituted with a C1-C3 alkyl group.

[0057] In some embodiments, R 2a is selected from a deuterium atom, F, Cl, Br, I, OH, a C1-C3 alkyl group, an NH2 optionally substituted with a C1-C3 alkyl group, or a pyrazolyl group optionally substituted with a C1-C3 alkyl group.

[0058] In some embodiments, R 2a is selected from a deuterium atom, F, Cl, Br, I, a C1-C3 alkyl group, or NH2 optionally substituted with a C1-C3 alkyl group. In some embodiments, R 2a is selected from NH2 optionally substituted with a C1-C3 alkyl group.

[0059] In some embodiments, R 2a is selected from a deuterium atom, a methyl group, F, or N(CH3)2. In some embodiments, R 2a is selected from N(CH3)2.

[0060] In some embodiments, R 2 is ═O, a methyl group, an ethyl group, CD3, CH2CH2N(CH3)2, CH2CH2OH, CH2CH2NH(CH3), CH2CH2NH2, OCH3, NHCH3, CHF2, CF3, a cyclopropyl group or [ka]

[0061] In some embodiments, R 2 is selected from =O, a methyl group, CD3, CH2CH2N(CH3)2, OCH3, NHCH3, CF3 or a cyclopropyl group. In some embodiments, R 2 is selected from =O, a methyl group, CD3, or OCH3.

[0062] In some embodiments, R 2 is selected from =O, a methyl group, or CH2CH2N(CH3)2. In some embodiments, R 2 is selected from ═O, a methyl group, or a methoxy group.

[0063] In some embodiments, ring A is optionally R 2replaced by [ka] Selected from R 2 is selected from =O, a methyl group, CD3, OCH3 or CF3.

[0064] In some embodiments, ring A is optionally R 2 replaced by [ka] Selected from R 2 is ═O, a methyl group, an ethyl group, CD3, CH2CH2N(CH3)2, CH2CH2OH, CH2CH2NH(CH3), CH2CH2NH2, OCH3, NHCH3, CHF2, CF3, a cyclopropyl group or [ka]

[0065] In some embodiments, ring A is [ka]

[0066] In some embodiments, ring A is [ka]

[0067] In some embodiments, ring A is [ka]

[0068] In some embodiments, ring A is [ka]

[0069] In some embodiments, ring A is [ka]

[0070] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka]

[0071] In some embodiments, ring A is [ka]

[0072] In some embodiments, ring A is [ka]

[0073] In some embodiments, ring A is [ka]

[0074] In some embodiments, ring Q is selected from a phenyl group or a 5- to 6-membered heteroaryl group, and the phenyl group or the 5- to 6-membered heteroaryl group is optionally selected from R 3 is replaced by

[0075] In some embodiments, ring Q is selected from a phenyl group, a pyridyl group, a pyrazolyl group, a pyrimidinyl group, or a pyrazinyl group, wherein the phenyl group, the pyridyl group, the pyrazolyl group, the pyrimidinyl group, or the pyrazinyl group is optionally selected from R 3 is replaced by

[0076] In some embodiments, ring Q is selected from a phenyl group or a pyridyl group, and the phenyl group or pyridyl group is optionally selected from R 3 is replaced by In some embodiments, ring Q is selected from a phenyl group, and the phenyl group is optionally selected from R 3 is replaced by

[0077] In some embodiments, R 3 is halogen, ═O, OH, CN, or optionally R 3a and is selected from SH substituted by, a C2-C3 alkynyl group, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, and a C3-C6 cycloalkyloxy group.

[0078] In some embodiments, R 3 is halogen, ═O, OH, CN, or optionally R 3a and a C2-C3 alkynyl group, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, or a C1-C6 alkoxy group substituted with

[0079] In some embodiments, R 3 is halogen, ═O, OH, CN, or optionally R 3a and is selected from an ethynyl group substituted with, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, and a C3-C6 cycloalkyloxy group.

[0080] In some embodiments, R 3 is halogen, ═O, OH, CN, or optionally R 3a is selected from a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, and a C3-C6 cycloalkyloxy group substituted by In some embodiments, R 3a is selected from halogen, CN, or a C1 to C3 alkyl group.

[0081] In some embodiments, R 3a is selected from halogens such as F. In some embodiments, R 3a is chosen from F. In some embodiments, R 3 is selected from halogen, CN, a C3 to C6 cycloalkyl group, a C2 to C3 alkynyl group, a C1 to C6 alkyl group optionally substituted with halogen, or a C1 to C6 alkoxy group optionally substituted with halogen.

[0082] In some embodiments, R 3 is selected from halogen, CN, a C3 to C6 cycloalkyl group, a C1 to C6 alkyl group optionally substituted with halogen, or a C1 to C6 alkoxy group optionally substituted with halogen. In some embodiments, R 3 is selected from halogen, CN, a C1-C6 alkyl group, or a C1-C6 alkoxy group optionally substituted with halogen.

[0083] In some embodiments, R 3 is selected from halogen, CN, a C1-C3 alkyl group, or a C1-C3 alkoxy group optionally substituted by halogen. In some embodiments, R 3 is selected from halogen or a C1-C6 alkoxy group optionally substituted by halogen. In some embodiments, R 3 is selected from halogen, CN, an isopropyl group, a cyclopropyl group, a methyl group optionally substituted with a halogen, or a methoxy group optionally substituted with a halogen.

[0084] In some embodiments, R 3 is selected from halogen, CN, a methyl group, an isopropyl group, or a methoxy group optionally substituted by a halogen. In some embodiments, R 3 is selected from halogen, CN, a methyl group, or a methoxy group optionally substituted by a halogen. In some embodiments, R3 is selected from halogen or a methoxy group optionally substituted by halogen.

[0085] In some embodiments, R 3 is selected from halogen, CN, an isopropyl group, a cyclopropyl group, a methyl group optionally substituted with F, or a methoxy group optionally substituted with F. In some embodiments, R 3 is selected from halogen, CN, a methyl group, or a methoxy group optionally substituted by F.

[0086] In some embodiments, R 3 is selected from halogen or a methoxy group optionally substituted by F. In some embodiments, R 3 is selected from F, Cl, Br, CN, SH, an isopropyl group, a cyclopropyl group, a methyl group, an ethyl group, a trifluoromethyl group, an ethynyl group, OCHF2, a methoxy group, and a methylthio group.

[0087] In some embodiments, R 3 is selected from F, Cl, Br, CN, an isopropyl group, a cyclopropyl group, a methyl group, an ethyl group, a trifluoromethyl group, an ethynyl group, OCHF2, or a methoxy group. In some embodiments, R 3 is selected from F, Cl, Br, CN, an isopropyl group, a cyclopropyl group, a methyl group, a trifluoromethyl group, OCHF2, or a methoxy group.

[0088] In some embodiments, R 3 is selected from F, Cl, Br, CN, a methyl group, an isopropyl group, OCHF2, or a methoxy group. In some embodiments, R 3 is selected from F, Cl, a methyl group, an isopropyl group, OCHF2, or a methoxy group.

[0089] In some embodiments, R 3is selected from Cl, Br, CN, a methyl group, OCHF2 or a methoxy group. In some embodiments, R 3 is selected from Cl or OCHF2.

[0090] In some embodiments, ring Q is selected from a phenyl group or a pyridyl group, and the phenyl group or pyridyl group is optionally selected from R 3 Each R is replaced by 3 are independently selected from halogen, CN, an isopropyl group, a cyclopropyl group, a methyl group optionally substituted with a halogen (e.g., F), or a methoxy group optionally substituted with a halogen (e.g., F).

[0091] In some embodiments, ring Q is selected from a phenyl group or a pyridyl group, and the phenyl group or pyridyl group is optionally selected from R 3 Each R is replaced by 3 are independently selected from F, Cl, Br, CN, an isopropyl group, a cyclopropyl group, a methyl group, a trifluoromethyl group, OCHF2, or a methoxy group.

[0092] In some embodiments, ring Q is selected from a phenyl group, a pyridyl group, a pyrazolyl group, a pyrimidinyl group, or a pyrazinyl group, wherein the phenyl group, the pyridyl group, the pyrazolyl group, the pyrimidinyl group, or the pyrazinyl group is optionally selected from R 3 Each R is replaced by 3 are independently selected from halogen, CN, a C3-C6 cycloalkyl group, a C2-C3 alkynyl group, a C1-C6 alkyl group optionally substituted with a halogen (e.g., F), or a C1-C6 alkoxy group optionally substituted with a halogen (e.g., F).

[0093] In some embodiments, ring Q is selected from a phenyl group, a pyridyl group, a pyrazolyl group, a pyrimidinyl group, or a pyrazinyl group, wherein the phenyl group, the pyridyl group, the pyrazolyl group, the pyrimidinyl group, or the pyrazinyl group is optionally selected from R 3 Each R is replaced by 3are independently selected from F, Cl, Br, CN, an isopropyl group, a cyclopropyl group, a methyl group, an ethyl group, a trifluoromethyl group, an ethynyl group, OCHF2, or a methoxy group.

[0094] In some embodiments, ring Q is [ka]

[0095] In some embodiments, ring Q is [ka]

[0096] In some embodiments, ring Q is [ka]

[0097] In some embodiments, ring Q is [ka]

[0098] In some embodiments, ring Q is [ka]

[0099] In some embodiments, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:

[0100] [ka]

[0101] [ka]

[0102]

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[0103]

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[0104]

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[0105]

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[0106]

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[0107]

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[0108]

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[0109]

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[0110]

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[0111]

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[0112]

change

[0113] The present application also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Furthermore, the present application relates to the use of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of an antitumor drug.

[0114] Furthermore, the present application relates to the use of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a drug for preventing or treating a tumor with reduced MTAP activity or a tumor lacking MTAP. Furthermore, the present application relates to the use of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in antitumor therapy.

[0115] Furthermore, the present application relates to the use of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prevention or treatment of tumors with reduced MTAP activity or in which MTAP is deficient. Furthermore, the present application relates to an antitumor compound of general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0116] Furthermore, the present application relates to a compound of general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating a tumor with reduced MTAP activity or deficient MTAP.

[0117] The present application also relates to a method for treating tumors, which method comprises administering to a patient a pharmaceutical formulation comprising a therapeutically effective dose of a compound of general formula (I) as described herein or a pharmaceutically acceptable salt thereof.

[0118] The present application also relates to a method for treating tumors with reduced MTAP activity or MTAP deficiency, which method comprises administering to a patient a pharmaceutical formulation comprising a therapeutically effective dose of a compound of general formula (I) described herein or a pharmaceutically acceptable salt thereof.

[0119] The present application also relates to a method for treating tumors, which method comprises administering to a patient a therapeutically effective dose of a compound of general formula (I) as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0120] The present application also relates to a method for treating a tumor with reduced MTAP activity or a tumor lacking MTAP, the method comprising administering to a patient a therapeutically effective dose of a compound of general formula (I) described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0121] In some embodiments, the tumor is gastric cancer, colon cancer, liver cancer, or pancreatic cancer.

[0122] Definitions and explanations of terms Unless otherwise specified, the definitions of groups and terms described in the specification and claims of this application, including illustrative definitions, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in the examples, etc., can be arbitrarily combined or combined with each other. The group definitions and compound structures after such combinations and combinations shall fall within the scope described in the specification of this application. When a trade name appears in this specification, it is intended to refer to the corresponding trade name or its active ingredient.

[0123] In this specification, bonds depicted with solid and dashed lines [ka]

[0124] Graphical representations of racemic or enantiomerically pure compounds herein are taken from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise indicated, wedge bonds and dashed wedge bonds are [ka] represents the relative configuration of stereocenters (e.g., cis-trans configuration in alicyclic compounds).

[0125] The term "tautomer" refers to a functional isomer resulting from the rapid shift of an atom in a molecule between two positions. The compounds of the present application may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Tautomers generally exist in equilibrium, and isolating a single tautomer usually produces a mixture whose physicochemical properties match those of the mixture of compounds. The position of the equilibrium is determined by the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present application includes all tautomeric forms of the compounds.

[0126] The term "stereoisomer" refers to isomers resulting from different arrangements in space of atoms in molecules, and includes cis-trans isomers, enantiomers and diastereomers.

[0127] The compounds of the present application may contain asymmetric atoms, such as carbon, sulfur, nitrogen, phosphorus, or asymmetric double bonds, and therefore may exist in particular geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may include cis- and trans-isomers, E- and Z-geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, atropisomers, and racemic or other mixtures thereof, e.g., enantiomerically or diastereomerically enriched mixtures. All of these isomers and mixtures thereof are within the scope of the definition of the compound of the present application. Substituents, such as alkyl groups, may contain other asymmetric carbon, sulfur, nitrogen, or phosphorus atoms, and all of these isomers and mixtures thereof are within the scope of the definition of the compound of the present application. Compounds of the present application containing an asymmetric atom can be isolated in optically pure or racemic form; optically pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0128] The compounds of the present application can exist in the form of atropisomers, which are stereoisomers that arise when the rotation of a single bond within a molecule is hindered or significantly slowed. If the rotational barrier around a single bond is sufficiently high and the interconversion between isomers is sufficiently slow, single isomers can be separated by methods known in the art, such as crystallization or chiral chromatography. Atropisomers of the compounds of the present application can be designated as "P" or "M" configurations or labeled by other common methods known in the art. For more information on atropisomers, see Andrew Clark, Introduction to Stereochemistry, 147-148 (2020, first edition).

[0129] The term "substituted" means that any one or more hydrogen atoms at a specified atom are replaced with a substituent, and the substituent may be a mixture of deuterium and hydrogen, provided that the valence of the specified atom is normal and the substituted compound is stable. When a substituent is oxo (i.e., =0), it means that two hydrogen atoms are replaced; oxo does not occur in aromatic groups.

[0130] The terms "optionally" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and the description includes cases where the described event or circumstance occurs and cases where it does not occur. For example, an ethyl group being "optionally" substituted with a halogen means that the ethyl group can be unsubstituted (CHCH), monosubstituted (CHCHF, CHCHCl, etc.), polysubstituted (CHFCHF, CHCHF, CHFCHCl, CHCHCl, etc.), or fully substituted (CFCF, CFCCl, CClCCl, etc.). One skilled in the art will understand that for any group containing one or more substituents, any substitution or substitution pattern that is sterically impossible and / or cannot be synthesized is not introduced.

[0131] Any variable (e.g., R a , R b ) When any group occurs more than once in a composition or structure of a compound, its definition on each occurrence is independent. For example, when a group is represented by two R b When replaced by, each R b has independent options.

[0132] When the number of one linking group is 0, for example, -(CH2)0-, this indicates that the linking group is a bond. When one of the variables is selected from a chemical bond or is absent, it indicates that the two groups being linked are directly linked; for example, when L in ALZ represents a bond, it indicates that the structure is actually AZ.

[0133] In the present specification, when the linking group does not specify the linking direction, the linking direction is arbitrary. For example, [ka] L in 1 is selected from "C1-C3 alkylene group -O", then L 1 is the ring Q and R from left to right. 1 and "Ring Q-C1-C3 alkylene group -OR 1 " and from right to left, we can form rings Q and R 1 and linking them to form a ring QO-C1-C3 alkylene group -R 1 " can also be formed.

[0134] When a bond of a substituent bridges two atoms in a ring, such substituent can be bonded to any atom in that ring. For example, the structural unit [ka] is R 5 can be substituted at any position on the benzene ring.

[0135] In this specification, C m ~C n means that the group has an integer number of carbon atoms within the range of m to n. For example, "C1 to C 10 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.

[0136] The term "alkyl group" refers to a group having the general formula C n H 2n+1 The term "C1-C alkyl group" refers to a hydrocarbon group having a C1-C 10The term "alkyl group" should be understood to mean a linear or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, and specific examples of the alkyl group include, but are not limited to, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an isopentyl group, a 2-methylbutyl group, a 1-methylbutyl group, a 1-ethylpropyl group, a 1,2-dimethylpropyl group, a neopentyl group, a 1,1-dimethylpropyl group, a 4-methylpentyl group, a 3-methylpentyl group, a 2-methylpentyl group, a 1-methylpentyl group, a 2-ethylbutyl group, a 1-ethylbutyl group, a 3,3-dimethylbutyl group, a 2,2-dimethylbutyl group, a 1,1-dimethylbutyl group, a 2,3-dimethylbutyl group, a 1,3-dimethylbutyl group or a 1,2-dimethylbutyl group. The term "C1-C6 alkyl group" may be understood to mean an alkyl group having 1 to 6 carbon atoms, and specific examples include, but are not limited to, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 3-methylbutyl group, a neopentyl group, a hexyl group, a 2-methylpentyl group, and the like. The term "C1-C3 alkyl group" may be understood to mean a linear or branched saturated alkyl group having 1 to 3 carbon atoms. The above "C1-C 10 The "alkyl group" may include ranges such as "C1 to C6 alkyl group" or "C1 to C3 alkyl group", and the "C1 to C6 alkyl group" may further include "C1 to C3 alkyl group".

[0137] The term "alkoxy group" refers to a group obtained by removing a hydrogen atom on a hydroxyl group from a straight or branched chain alcohol, and may also be understood as an "alkyloxy group" or an "alkyl group -O-". 10 "Alkoxy group" means "C1-C 10 Alkyloxy group" or "C1-C 10The term "C1 to C6 alkoxy group" may be understood as "C1 to C6 alkyloxy group" or "C1 to C6 alkyl group -O-". 10 The "alkoxy group" may include ranges such as "C1 to C6 alkoxy group" and "C1 to C3 alkoxy group", and the "C1 to C6 alkoxy group" may further include "C1 to C3 alkoxy group".

[0138] The term "alkenyl group" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms and having at least one double bond. 10 An "alkenyl group" may be understood to mean a straight or branched chain unsaturated hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, and "C2-C 10 The "alkenyl group" is preferably a "C2 to C6 alkenyl group", more preferably a "C2 to C4 alkenyl group", and even more preferably a C2 or C3 alkenyl group.

[0139] It should be understood that when the alkenyl group contains more than one double bond, the double bonds may be separated or conjugated with each other. The alkenyl group includes, but is not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, and (Z)-1-methylprop-1-enyl groups.

[0140] The term "alkynyl group" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms and having at least one triple bond. 10An "alkynyl group" may be understood to mean a straight or branched chain unsaturated hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. 10 Examples of "alkynyl groups" include [ka]

[0141] The term "cycloalkyl" refers to a fully saturated carbocyclic group that can exist as a single ring, a fused ring, a bridged ring, or a spiro ring. Unless otherwise specified, the carbocyclic ring typically has 3 to 10 members. For example, the term "C3-C 10 "Cycloalkyl group" refers to a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9, or 10 ring carbon atoms, and specific examples of the cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornanyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decane, and the like. 10 The term "cycloalkyl group" may include "C3-C6 cycloalkyl group", and the term "C3-C6 cycloalkyl group" refers to a cycloalkyl group having 3, 4, 5 or 6 ring carbon atoms, and specific examples include, but are not limited to, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and the like.

[0142] The term "cycloalkyloxy group" may be understood as "cycloalkyl group -O-". Preferably, "C3 to C 10 The "cycloalkyloxy group" may include a "C3 to C6 cycloalkyloxy group".

[0143] The term "heterocyclyl group" refers to a fully saturated or partially saturated monocyclic, fused, spiro, or bridged ring group containing 1 to 5 heteroatoms or heteroatomic groups (i.e., atomic groups containing heteroatoms) among its ring atoms, where the "heteroatoms or heteroatomic groups" include, but are not limited to, nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), -S(=O)-, -S(=O)-, -P(=O)-, -P(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH-, or -NHC(=O)NH-.

[0144] The term "3- to 10-membered heterocyclyl group" refers to a heterocyclyl group having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, including 1 to 5 heteroatoms or heteroatom groups independently selected from the above. The "heterocyclyl group" is entirely non-aromatic. The term "3- to 10-membered heterocyclyl group" can include 1, 2, or 3 heteroatoms or heteroatom groups. For example, the heteroatom may be selected from a nitrogen atom (N), an oxygen atom (O), a sulfur atom (S), a phosphorus atom (P), or a boron atom (B), and the heteroatom group may be selected from -S(=O)2-, -S(=O)-, -P(=O)2-, -P(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH-, or -NHC(=O)NH-.

[0145] The "4- to 7-membered heterocyclyl group" and the "5- to 7-membered heterocyclyl group" can contain one, two, or three heteroatoms or heteroatom groups, respectively. Preferably, the "3- to 10-membered heterocyclyl group" encompasses the ranges of "4- to 10-membered heterocyclyl group," "4- to 7-membered heterocyclyl group," "5- to 7-membered heterocyclyl group," etc., among which, examples of 4-membered heterocyclyl groups include, but are not limited to, azetidinyl and oxetanyl groups, and examples of 5-membered heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrofuran ... Examples of 6-membered heterocyclyl groups include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridyl, or 4H-[1,3,4]thiadiazinyl groups, and examples of 7-membered heterocyclyl groups include, but are not limited to, diazepanyl groups.

[0146] The heterocyclyl group may be a bicyclic group, of which specific examples of 5,5-membered bicyclic groups include, but are not limited to, hexahydrocyclopenta[c]pyrrolo-2(1H)-yl, and specific examples of 5,6-membered bicyclic groups include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl.

[0147] Preferably, the heterocyclyl group may be a benzo-fused ring group of the above 4- to 7-membered heterocyclyl group, examples of which include, but are not limited to, a dihydroisoquinolinyl group. Preferably, the "3- to 10-membered heterocyclyl group" may include the ranges of "4- to 7-membered heterocyclyl group," "5- to 7-membered heterocyclyl group," "5- to 6-membered heterocyclyl group," "4- to 7-membered heterocycloalkyl group," "5- to 7-membered heterocycloalkyl group," "5- to 6-membered heterocycloalkyl group," etc., and the "4- to 7-membered heterocyclyl group" may further include the ranges of "5- to 7-membered heterocyclyl group," "5- to 6-membered heterocyclyl group," "5- to 7-membered heterocycloalkyl group," "5- to 6-membered heterocycloalkyl group," etc. In this application, some bicyclic heterocyclyl groups partially contain one benzene ring or one heteroaryl ring, but the heterocyclyl group as a whole remains non-aromatic.

[0148] The term "heterocyclyloxy group" may be understood as "heterocyclyl group -O-", and the term "3- to 10-membered heterocyclyloxy group" may be understood as "3- to 10-membered heterocyclyl group -O-".

[0149] The term "heterocycloalkyl group" refers to a fully saturated cyclic group that contains 1 to 5 heteroatoms or heteroatomic groups (i.e., atomic groups containing heteroatoms) among the ring atoms of the ring, and may exist in the form of a monocyclic, fused, bridged, or spirocyclic ring, where the "heteroatom or heteroatom group" includes, but is not limited to, a nitrogen atom (N), an oxygen atom (O), a sulfur atom (S), a phosphorus atom (P), a boron atom (B), -S(=O)-, -S(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH-, or -NHC(=O)NH-.

[0150] The term "3- to 10-membered heterocycloalkyl group" can contain 1, 2, or 3 heteroatoms or heteroatom groups. For example, the heteroatom can be selected from a nitrogen atom (N), an oxygen atom (O), a sulfur atom (S), a phosphorus atom (P), or a boron atom (B), and the heteroatom group can be selected from -S(=O)2-, -S(=O)-, -P(=O)2-, -P(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH-, or -NHC(=O)NH-. A "4- to 7-membered heterocycloalkyl group" and a "5- to 7-membered heterocycloalkyl group" can contain 1, 2, or 3 heteroatoms or heteroatom groups, respectively.

[0151] The term "3- to 10-membered heterocycloalkyl group" means a heterocycloalkyl group having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, and the ring atoms include 1 to 5 heteroatoms or heteroatom groups independently selected from the above. Preferably, the "3- to 10-membered heterocycloalkyl group" includes a "4- to 7-membered heterocycloalkyl group", and examples of 4-membered heterocycloalkyl groups include, but are not limited to, an azetidinyl group, an oxetanyl group, and a thietidinyl group. Examples of 5-membered heterocycloalkyl groups include, but are not limited to, a tetrahydrofuranyl group, a tetrahydrothiophenyl group, a pyrrolidinyl group, an isoxazolidinyl group, an oxazolidinyl group, an isothiazolidinyl group, a thiazolidinyl group, an imidazolidinyl group ... Examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl groups; and examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxepanyl, and thiepanyl groups.

[0152] The term "heterocycloalkyloxy group" may also be understood as "heterocycloalkyl group -O-". The term "heteroaryl group" refers to a monocyclic or fused polycyclic ring system having aromatic character, which is an aromatic ring group containing at least one ring atom selected from N, O, S, the remaining ring atoms being C. The term "5- to 10-membered heteroaryl group" should be understood to mean a monovalent monocyclic or bicyclic aromatic ring system having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and containing 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and S, and which in each case may be benzo-fused. In particular, the "5- to 10-membered heteroaryl group" is selected from a thienyl group, a furanyl group, a pyrrolyl group, an oxazolyl group, a thiazolyl group, an imidazolyl group, a pyrazolyl group, an isoxazolyl group, an isothiazolyl group, an oxadiazolyl group, a triazolyl group, a thiadiazolyl group, and the like, and benzo derivatives thereof, such as a benzofuranyl group, a benzothienyl group, a benzothiazolyl group, a benzoxazolyl group, a benzisoxazolyl group, a benzimidazolyl group, a benzotriazolyl group, an indazolyl group, an indolyl group, an isoindolyl group, and the like, or a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazinyl group, and the like, and benzo derivatives thereof, such as a quinolinyl group, a quinazolinyl group, an isoquinolinyl group, and the like.

[0153] The term "5- to 6-membered heteroaryl group" is to be understood as a monovalent aromatic ring system having 5 or 6 ring atoms, containing 1 to 3 heteroatoms independently selected from N, O and S, in particular selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.

[0154] The term "heteroaryloxy group" may also be understood as "heteroaryl group -O-". The term "aryl group" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated pi-electron system. 10An "aryl group" is to be understood as denoting a monovalent aromatic or partially aromatic hydrocarbon ring, preferably having 6 to 10 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl group"), such as a phenyl group, or a ring having 9 carbon atoms ("C9 aryl group"), such as an indanyl or indenyl group, or a ring having 10 carbon atoms ("C9 aryl group"), such as a tetrahydronaphthyl, dihydronaphthyl or naphthyl group. 10 aryl group).

[0155] The term "aryloxy group" may also be understood as "aryl group -O-". The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine. The term "prevention" means preventing the occurrence of a disease or disease state in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as suffering from the disease state.

[0156] The term "treatment" means administering a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with said disease, and includes: (i) inhibiting the disease or disease state, i.e., arresting its progression; (ii) alleviating the disease or disease state, even if the disease or disease state is cured.

[0157] The term "therapeutically effective amount" refers to a dose of a compound of the present application that (i) treats a particular disease, condition, or disorder, (ii) reduces, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present application that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the method of administration, and the age of the mammal being treated, but can be determined routinely by one of ordinary skill in the art according to their own knowledge and the present disclosure.

[0158] The term "pharmaceutically acceptable additive" refers to an additive that does not have an obvious irritating effect on an organism and does not impair the biological activity and performance of the active compound. Suitable additives are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0159] The words "comprise", "containing" or "comprise" and their English variants, such as comprises or comprising, are to be understood in an open and non-exclusive sense, i.e. "including but not limited to".

[0160] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitution forms well known to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present application.

[0161] The present application further includes isotopically labeled compounds of the present application that are the same as those described herein, except that one or more atoms have been replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Illustrative isotopes that can be attached to the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, e.g., 2 H (i.e., D), 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.

[0162] Some isotopically labeled compounds of the present application (e.g., 3 H and 14 C) can be used in compound and / or substrate tissue distribution analysis. 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred for their ease of preparation and detectability. 15 O. 13 N, 11 C. 18 Positron-emitting isotopes, such as F, can be used to measure substrate occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the present application can generally be prepared by procedures similar to those disclosed in the following schemes and / or examples, substituting isotopically labeled reagents for non-isotopically labeled reagents.

[0163] Note that relatively heavy isotopes (e.g., deuterium (i.e. 2 H, D)) substitution can provide several therapeutic advantages arising from higher metabolic stability (e.g., increased in vivo half-life or reduced required dosage) and may be preferable in some cases, wherein deuterium substitution can be partial or complete, with partial deuterium substitution meaning that at least one hydrogen is replaced with at least one deuterium.

[0164] The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, and can be prepared into solid, semi-solid, liquid, or gaseous preparations such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, and aerosols.

[0165] Representative routes of administration of the compounds of the present application, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0166] The pharmaceutical compositions of the present application can be prepared by methods well known in the art, such as, for example, conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, lyophilizing or the like.

[0167] In some embodiments, the pharmaceutical composition is in oral dosage form. For oral administration, the pharmaceutical composition can be prepared by mixing the active compound with pharmaceutically acceptable additives known in the art. These additives can be used to prepare the compound of the present application in the form of tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.

[0168] Solid oral compositions can be prepared by conventional mixing, filling or tableting methods.For example, the active compound is mixed with a solid additive, optionally pulverized, and optionally other suitable additives are added, and then the mixture is processed into granules to obtain tablets or dragee cores.Suitable additives include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.

[0169] The pharmaceutical compositions are also applicable for parenteral administration, such as sterile solutions, suspensions, or lyophilized products in suitable unit dosage forms. In all administration methods of the compound of general formula (I) described herein, the daily dose is 0.01 to 100 mg / kg body weight, preferably 0.05 to 50 mg / kg body weight, more preferably 0.1 to 30 mg / kg body weight, in the form of individual or divided doses.

[0170] The chemical reactions of the specific embodiments of the present application are completed in a suitable solvent, which must be suitable for the chemical transformations of the present application and the necessary reagents and materials. To obtain the compounds of the present application, those skilled in the art may need to modify or select synthetic steps or reaction processes based on the existing embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0171] The present invention will be described in detail below with reference to examples, but these examples are not intended to limit the present application in any way. Although the present specification has already described the present application in detail and disclosed specific examples, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application. All reagents used in the present application are commercially available and can be used without further purification.

[0172] Unless otherwise specified, the ratio of the mixed solvents is a volume ratio. Unless otherwise specified, % refers to wt%. Compounds are named artificially or with ChemDraw® software; commercially available compounds use names from the manufacturer's catalog.

[0173] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts are in units of 10 -6 The solvents used for NMR measurements were deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard was tetramethylsilane (TMS). 50 " refers to the half maximal inhibitory concentration, the concentration at which half of the maximum inhibitory effect is achieved.

[0174] Explanation of terms or abbreviations: Me: methyl group Et: ethyl group Ph: phenyl group t-Bu: tert-butyl group DMF: N,N-dimethylformamide LCMS / LC-MS: Liquid Chromatography Mass Spectrometry

[0175] DCE: 1,2-dichloroethane t-BuONO: tert-butyl nitrite THF: tetrahydrofuran NBS: N-bromosuccinimide DPPA: Diphenylphosphoryl azide TEA: Triethylamine toluene: toluene DCM: dichloromethane

[0176] SEMCl: 2-(trimethylsilyl)ethoxymethyl chloride SEM: 2-(trimethylsilyl)ethoxymethyl Pd(dppf)Cl2 / PdCl2(dppf):[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dioxane: dioxane

[0177] Pd(dtbpf)Cl2: 1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium DMSO: dimethyl sulfoxide Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene Pin2B2: Bis(pinacolato)diboron

[0178] NMP: N-methylpyrrolidone TFA: Trifluoroacetic acid LiHMDS: lithium bis(trimethylsilyl)amide BrettPhos: Dicyclohexyl(2,4,6-triisopropyl-3,6-dimethoxy-[1,1-biphenyl]-2-yl)phosphine BrettPhos Pd G3: (2-Di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)palladium(II) methanesulfonate

[0179] t-AmylOH: tert-amyl alcohol HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate DIEA: Diisopropylethylamine xylene: xylene DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene ACN: acetonitrile CD3I: Deuterated iodomethane

[0180] Methanol: Methanol -OTBS: (tert-butyldimethylsilyl)oxy MsCl: methanesulfonyl chloride NCS: N-chlorosuccinimide EtI: Iodoethane O(Tf)2: Trifluoromethanesulfonic anhydride Lutidine: 2,6-dimethylpyridine Chloroform: Chloroform Pd(PPh3)4: Tetrakis(triphenylphosphine)palladium

[0181] SOCl2: Thionyl chloride LDA: lithium diisopropylamide Ruphos: 2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl Ruphos Pd G3: (2-Dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) methanesulfonate LiHMDS: lithium bis(trimethylsilyl)amide TMAF: Tetramethylammonium fluoride BTMPO: N,N'-bis(2,4,6-trimethoxyphenyl)ethanediamide acetone: acetone

[0182] Example 1, 5-(2-chlorophenyl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 1)

[0183] [ka]

[0184] Step 1: Synthesis of 2-((2-chlorophenyl)amino)-6-(trifluoromethyl)-3-cyanopyridine (Intermediate 1-2) o-Chloroaniline (7.20 g, 56.46 mmol) was dissolved in DMF (100 mL). Under nitrogen protection, sodium hydride (9.68 g, 242.07 mmol, active content 60%) was added at 0 °C. The mixture was maintained at 0 °C for 1 h. A solution of reactant 1-1 (10 g, 48.41 mmol) in DMF (20 mL) was added dropwise to the reaction mixture at 0 °C and the mixture was stirred at 25 °C for 16 h. LCMS confirmed the completion of the reaction. The reaction mixture was quenched with 200 mL of water at 0 °C, diluted with 200 mL of ethyl acetate, and extracted three times with ethyl acetate (200 mL × 3). The organic phase was washed three times with brine (400 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was separated by column chromatography (ISCO®; 120 g SepaFlash® flash silica gel column, eluent 0-2% ethyl acetate / petroleum ether, gradient @ 100 mL / min) to give the title compound (5.16 g). MS m / z (ESI): 297.9 [M+H] + .

[0185] Step 2: Synthesis of methyl 4-amino-1-(2-chlorophenyl)-2-oxo-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 1-3) Intermediate 1-2 (5.16 g, 17.34 mmol) and tin tetrachloride (18.06 g, 69.34 mmol) were dissolved in 1,2-dichloroethane (100 mL), and dimethyl malonate (6.87 g, 52.01 mmol) was added at 25°C under nitrogen protection. The reaction mixture was heated to 70°C and reacted at 70°C for 16 hours with stirring.

[0186] Next, under nitrogen protection, tin tetrachloride (2.23 g, 8.56 mmol) and dimethyl malonate (1.15 g, 8.70 mmol) were added at 25 °C, and the reaction mixture was heated to 70 °C and stirred at 70 °C for 4 hours. LC-MS showed the reaction was complete. The reaction mixture was quenched with water (150 mL), diluted with ethyl acetate (150 mL), and extracted three times with ethyl acetate (150 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The concentrate was separated by column chromatography (ISCO®; 120 g SepaFlash® flash silica gel column, eluent: 0-100% ethyl acetate / petroleum ether, gradient @ 100 mL / min; eluent: 0-20% methanol / ethyl acetate, gradient @ 100 mL / min) to give the crude title compound (11.64 g). MS m / z (ESI): 389.0 [M+H] + .

[0187] Step 3: Synthesis of 4-amino-1-(2-chlorophenyl)-7-(trifluoromethyl)-1,8-naphthyridin-2(1H)-one (Intermediate 1-4) Intermediate 1-3 (11.64 g, 29.27 mmol) was dissolved in methanol (115 mL) and aqueous sodium hydroxide (10 M, 87.80 mL) was added dropwise at 0 °C. The reaction mixture was warmed to 25 °C and stirred at 25 °C for 16 hours. The reaction mixture was then warmed to 50 °C and stirred at 50 °C for 70 hours. LC-MS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove methanol. The concentrate was diluted with water (150 mL) and extracted four times with ethyl acetate (200 mL × 4). The organic phase was dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Separation by column chromatography (ISCO®; 80 g SepaFlash® flash silica gel column, eluent: 0-4% methanol / dichloromethane, gradient @ 100 mL / min) afforded the title compound (4.5 g). MS m / z (ESI): 340.1 [M+H] + .

[0188] Step 4: Synthesis of 4-amino-1-(2-chloro-4-nitrophenyl)-3-nitro-7-(trifluoromethyl)-1,8-naphthyridin-2(1H)-one (Intermediate 1-5) Intermediate 1-4 (100 mg, 294.38 μmol) was dissolved in sulfuric acid (552.00 mg, 5.63 mmol), and fuming nitric acid (92.75 mg, 1.47 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 0.5 hours. LC-MS confirmed that all the starting materials had reacted completely and the target product had been formed. The reaction mixture was slowly poured into water (20 mL) at 0°C, adjusted to pH 8 with saturated aqueous sodium bicarbonate, extracted three times with ethyl acetate, and the organic layer was concentrated to dryness under reduced pressure to obtain the crude title compound (135 mg). MS m / z (ESI): 430.1 [M+H] + .

[0189] Step 5: Synthesis of 3,4-diamino-1-(4-amino-2-chlorophenyl)-7-(trifluoromethyl)-1,8-naphthyridin-2(1H)-one (Intermediate 1-6) Intermediate 1-5 (110 mg, 256.00 μmol) was dissolved in methanol (4 mL), and iron powder (220.00 mg), ammonium chloride (109.55 mg, 2.05 mmol), and water (1 mL) were added. The reaction mixture was stirred at 90°C for 16 hours. LC-MS confirmed that all the starting materials had reacted completely and the target product had been formed. The reaction mixture was concentrated under reduced pressure, extracted three times with ethyl acetate, and the organic layer was concentrated to dryness under reduced pressure. The crude title compound (94 mg) was obtained. MS m / z (ESI): 370.1 [M+H] + .

[0190] Step 6: Synthesis of 5-(4-amino-2-chlorophenyl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Intermediate 1-7) Intermediate 1-6 (90 mg, 243.42 μmol) was dissolved in triethyl orthoformate (2.45 g, 16.56 mmol). Under nitrogen protection, the reaction mixture was stirred at 120° C. for 4 hours. LC-MS confirmed that all the starting materials had reacted completely and the target product had been formed. The reaction mixture was concentrated under reduced pressure to remove triethyl orthoformate, yielding the crude title compound (92 mg). MS m / z (ESI): 379.9 [M+H] + .

[0191] Step 7: Synthesis of 5-(2-chlorophenyl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 1) Intermediate 1-7 (90 mg, 237.01 μmol) was dissolved in tetrahydrofuran (5 mL) and DMF (0.5 mL), and tert-butyl nitrite (36.66 mg, 355.52 μmol) was added at 25 °C. The reaction mixture was stirred at 70 °C for 1 hour. LC-MS confirmed that all the starting materials had reacted completely and the target product had formed. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran, and the residue was purified by high-performance liquid chromatography (column: YMC Triart C18 150 × 30 mm × 5 μm; mobile phase: [A: 0.05% aqueous ammonia (v / v), B: acetonitrile]; B%: 30% to 50%, 11 min) to give the title compound (7.2 mg).

[0192] 1 H NMR (400MHz, DMSO-d6) δ = 14.17 (s, 1H), 8.79 (d, J = 7.8 Hz, 1H), 8.51 (s, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.75-7.67 (m, 1H), 7.59-7.50 (m, 3H); MS m / z (ESI): 365.0 [M+H] + .

[0193] Example 2, 5-(2-chlorophenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 2)

[0194] [ka]

[0195] Step 1: Synthesis of 4-amino-3-bromo-1-(2-chlorophenyl)-7-(trifluoromethyl)-1,8-naphthyridin-2(1H)-one (Intermediate 2-1) Intermediate 1-4 (400 mg, 1.18 mmol) was dissolved in acetonitrile (8 mL), and N-bromosuccinimide (209.58 mg, 1.18 mmol) was added at 25 °C. The reaction mixture was stirred at 25 °C for 0.1 h. LC-MS confirmed that all the starting materials had reacted completely and the target product had formed. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 48% to 100%) to give the title compound (488.0 mg). MS m / z (ESI): 420.1 [M+H] + .

[0196] Step 2: Synthesis of 1-(2-chlorophenyl)-4-(methylamino)-7-(trifluoromethyl)-1,8-naphthyridin-2(1H)-one (Intermediate 2-2) Intermediate 2-1 (488.0 mg, 1.17 mmol) was dissolved in THF (10 mL) and, under nitrogen protection, sodium hydride (93.59 mg, 2.34 mmol, active content 60%) was added at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Iodomethane (166.07 mg, 1.17 mmol) was added at 0 °C, and the mixture was stirred at 20 °C for 16 h. LC-MS confirmed the complete reaction of all the starting materials and the formation of the target product. The reaction mixture was quenched with water (10 mL) at 0 °C and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (column: ISCO®; 12 g SepaFlash®; mobile phase: ethyl acetate / petroleum ether; ethyl acetate %: 0-74%) to give the title compound (109 mg). MS m / z (ESI): 353.9 [M+H] + .

[0197] Step 3: Synthesis of 1-(2-chloro-4-nitrophenyl)-4-(methylamino)-3-nitro-7-(trifluoromethyl)-1,8-naphthyridin-2(1H)-one (Intermediate 2-3) Intermediate 2-2 (109 mg, 308.15 μmol) was dissolved in sulfuric acid (0.3 mL), and nitric acid (38.83 mg, 616.30 μmol) was added dropwise at 0°C. The mixture was allowed to react at 0°C for 1 hour. LC-MS confirmed that all the starting materials had reacted completely and the target product had been formed. The reaction mixture was diluted with water (50 mL) at 0°C, adjusted to pH 8 with saturated aqueous sodium carbonate, and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the title compound (129 mg). MS m / z (ESI): 444.0 [M+H] + .

[0198] Step 4: Synthesis of 3-amino-1-(4-amino-2-chlorophenyl)-4-(methylamino)-7-(trifluoromethyl)-1,8-naphthyridin-2(1H)-one (Intermediate 2-4) Intermediate 2-3 (129 mg, 290.72 μmol) was dissolved in methanol (2 mL), and iron powder (243.53 mg, 4.36 mmol), ammonium chloride (124.41 mg, 2.33 mmol), and water (0.5 mL) were added at 25 °C. The reaction mixture was then heated at 90 °C for 16 hours. LC-MS confirmed that all the starting materials had reacted completely and the target product had formed. The reaction mixture was filtered and concentrated under reduced pressure to remove methanol. The mixture was extracted three times with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the title compound (97 mg). MS m / z (ESI): 384.0 [M+H] + .

[0199] Step 5: Synthesis of 5-(4-amino-2-chlorophenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Intermediate 2-5) Intermediate 2-4 (97 mg, 252.77 μmol) was dissolved in triethyl orthoformate (864.27 mg, 5.83 mmol, 970.00 μL), and the reaction mixture was heated at 120° C. for 4 hours. LC-MS confirmed that all the starting materials had reacted completely and the target product had formed. The reaction mixture was concentrated to dryness under reduced pressure to give the title compound (110 mg). MS m / z (ESI): 393.9 [M+H] + .

[0200] Step 6: Synthesis of 5-(2-chlorophenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 2) Intermediate 2-5 (110 mg, 279.37 μmol) was dissolved in tetrahydrofuran (2 mL) and tert-butyl nitrite (129.64 mg, 1.26 mmol) and N,N-dimethylformamide (DMF) (2.04 mg, 27.94 μmol) were added at 25 °C. The reaction mixture was then heated at 70 °C for 1 h. LC-MS confirmed the complete reaction of all the starting materials and the formation of the target product. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by high-performance liquid chromatography (YMC-Actus Triart C18 150 × 30 mm × 5 μm column; mobile phase: A: water (containing 0.05% ammonia v / v), B: acetonitrile); B%: 38% to 58%, 11 min) to give the title compound (3.1 mg).

[0201] 1 H NMR (400MHz, METHANOL-d4) δ 8.90 (d, J = 8.1 Hz, 1H), 8.35-8.19 (m, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.71-7.63 (m, 1H), 7.60-7.50 (m, 2H), 7.48-7.41 (m, 1H), 4.35 (s, 3H); MS m / z (ESI): 379.0 [M+H] + .

[0202] Example 3, 5-(2-chlorophenyl)-3-methyl-7-(trifluoromethyl)-3,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 3)

[0203] [ka]

[0204] Compound 1 (117 mg, 320.80 μmol) was dissolved in N,N-dimethylformamide (1.5 mL). Sodium hydride (25.66 mg, 641.61 μmol, active content 60%) was added at 0 °C, and the reaction mixture was incubated at 0 °C for 0.1 h. Iodomethane (45.53 mg, 320.80 μmol) was added dropwise to the reaction mixture at 0 °C, and the reaction mixture was incubated at 0 °C for 0.9 h. LC-MS monitored the formation of the target product. The reaction mixture was quenched with water, diluted with methanol (1.5 mL), and purified by high-performance liquid chromatography (column: YMC-Actus Triart C18 150 × 30 mm × 5 μm; mobile phase: [A: water (0.05% aqueous ammonia v / v), B: acetonitrile]; B%: 40% to 60%, 11 min) to obtain the title compound (5.2 mg).

[0205] 1 H NMR (400MHz, Methanol-d4) δ 8.81 (d, J = 8.0 Hz, 1H), 8.36 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.71-7.65 (m, 1H), 7.60-7.51 (m, 2H), 7.50-7.44 (m, 1H), 4.20 (s, 3H); MS m / z (ESI): 379.0 [M+H] + .

[0206] Example 4, 5-(2-chlorophenyl)-7-(trifluoromethyl)-3,5-dihydro-1H-imidazo[4,5-c][1,8]naphthyridine-2,4-dione (Compound 4)

[0207] [ka]

[0208] Step 1: Synthesis of intermediate 4-1 Intermediate 1-3 (1 g, 2.51 mmol) was dissolved in methanol, and aqueous sodium hydroxide (10 M) was added. The reaction mixture was stirred at 25°C for 16 hours. LC-MS confirmed that all the starting materials had reacted completely and the target product had formed. The reaction mixture was adjusted to pH 7 with 6 M hydrochloric acid, extracted three times with ethyl acetate, and the organic layer was concentrated to dryness under reduced pressure to give the crude title compound (590 mg). MS m / z (ESI): 384.0[M+H] + .

[0209] Step 2: Synthesis of 5-(2-chlorophenyl)-7-(trifluoromethyl)-3,5-dihydro-1H-imidazo[4,5-c][1,8]naphthyridine-2,4-dione (compound 4) Intermediate 4-1 (50 mg, 130.31 μmol) was dissolved in toluene, and triethylamine (19.78 mg, 195.46 μmol) and diphenylphosphoryl azide (39.45 mg, 143.34 μmol) were added. The reaction mixture was stirred at 100 °C for 16 h. LC-MS confirmed the complete reaction of all the starting materials and the formation of the target product. The organic layer was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether: (ethyl acetate / ethanol = 3 / 1) = 1:1) and further purified by high-performance liquid chromatography (column: YMC-Actus Triart C18 150 × 30 mm × 5 μm; mobile phase: [A: water (0.05% aqueous ammonia v / v), B: acetonitrile]; B%: 20% to 40%, 11 min) to give the title compound (3.4 mg). MS m / z (ESI): 381.1[M+H] + .

[0210] 1 H NMR (400MHz, Methanol-d4) δ 8.48 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 9.3 Hz, 1H), 7.58-7.51 (m, 2H), 7.47-7.41 (m, 1H).

[0211] Example 5, 5-(2-chlorophenyl)-2-methoxy-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 5)

[0212] [ka]

[0213] Compound 4 (60 mg, 157.60 μmol) was dissolved in dichloromethane, and trimethyloxonium tetrafluoroborate (46.62 mg, 315.20 μmol) was added. The reaction mixture was stirred at 40 °C for 16 h. LC-MS confirmed the complete reaction of all raw materials and the formation of the target product. The organic layer was concentrated to dryness under reduced pressure and purified by high-performance liquid chromatography (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [A: water (0.225% formic acid v / v), B: acetonitrile]; B%: 25% to 55%, 12 min) to give the title compound (3.7 mg). MS m / z (ESI): 395.0 [M+H] + .

[0214] 1 H NMR (400MHz, DMSO-d6) δ13.48 (s, 1H), 8.67 (d, J = 8.6 Hz, 1H), 7.81 (d, J = 9.1 Hz, 1H), 7.70 (d, J = 5.1 Hz, 1H), 7.56-7.52 (m, 3H), 4.18 (s, 3H).

[0215] Example 6, 5-(2-chlorophenyl)-7-(trifluoromethyl)-3,5-dihydro-4H-pyrazolo[3,4-c][1,8]naphthyridin-4-one (Compound 6)

[0216] [ka]

[0217] Step 1: Synthesis of ethyl 4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (Intermediate 6-2) Intermediate 6-1 (1 g, 3.75 mmol) was dissolved in THF (15 mL). The reaction mixture was cooled to 0 °C, sodium hydride (300 mg, 7.51 mmol, active content 60%) was added, and the mixture was stirred at 25 °C for 0.5 h. 2-(Trimethylsilyl)ethoxymethyl chloride (936 mg, 5.63 mmol) was added to the mixture under an ice-water bath. The mixture was stirred at 25 °C for 15 h under nitrogen protection. LC-MS confirmed the completion of the reaction. After cooling to room temperature, the mixture was slowly quenched with ice-water (10 mL) and then extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with brine (50 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The title compound (700 mg) was obtained by preparative thin-layer chromatography (silica, petroleum ether:ethyl acetate = 10:3). MS m / z (ESI): 397 [M+H] + .

[0218] Step 2: Synthesis of ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (Intermediate 6-3) Intermediate 6-2 (700 mg, 1.76 mmol) and bis(pinacolato)diboron (897 mg, 3.53 mmol) were dissolved in anhydrous dimethyl sulfoxide (10 mL). Potassium acetate (345 mg, 3.53 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (Pd(dppf)Cl2) (128 mg, 0.17 mmol) were added. The reaction mixture was stirred at 100 °C for 15 h under nitrogen protection. LC-MS confirmed the reaction was complete. After cooling to room temperature, water (20 mL) and ethyl acetate (40 mL) were added sequentially. The organic phase was washed with water (30 mL × 2) and dried over anhydrous sodium sulfate. Preparative thin-layer chromatography (silica, dichloromethane:methanol = 10:1) afforded the title compound (500 mg). MS m / z (ESI): 397 [M+H] + .

[0219] Step 3: Synthesis of ethyl 4-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate (Intermediate 6-5) Intermediate 6-3 (500 mg, 1.25 mmol) and Intermediate 6-4 (489 mg, 1.88 mmol) were dissolved in dioxane (6 mL) and water (2 mL). Potassium phosphate (534 mg, 2.51 mmol) and Pd(dtbpf)Cl2 (81.98 mg, 0.12 mmol) were added, and the reaction mixture was stirred at 100 °C for 16 h under nitrogen protection. LC-MS confirmed the completion of the reaction. After cooling to room temperature, water (30 mL) and ethyl acetate (40 mL) were added sequentially. The organic phase was washed with water (30 mL × 2) and dried over anhydrous sodium sulfate. Preparative thin-layer chromatography (silica, dichloromethane:methanol = 5:1) afforded the title compound (300 mg). MS m / z (ESI): 450 [M+H] + .

[0220] Step 4: Synthesis of 5-(2-chlorophenyl)-7-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2,5-dihydro-4H-pyrazolo[3,4-c][1,8]naphthyridin-4-one (Intermediate 6-7) Intermediate 6-5 (150 mg, 0.33 mmol) and intermediate 6-6 (85 mg, 0.66 mmol) were dissolved in N-methylpyrrolidone (4 mL). Sodium tert-butoxide (63.56 mg, 0.64 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos) (20 mg, 0.03 mmol), and tris(dibenzylideneacetone)dipalladium (Pd2(dba)3) (30.51 mg, 33.33 μmol) were added. The reaction mixture was stirred at 100 °C for 15 h under nitrogen protection. LC-MS confirmed the completion of the reaction. After cooling to room temperature, water (15 mL) and ethyl acetate (20 mL) were added sequentially. The organic phase was washed with water (30 mL × 2) and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave the crude title compound (160 mg). MS m / z (ESI): 495 [M+H] + .

[0221] Step 5: Synthesis of 5-(2-chlorophenyl)-7-(trifluoromethyl)-3,5-dihydro-4H-pyrazolo[3,4-c][1,8]naphthyridin-4-one (compound 6) Intermediate 6-7 (160 mg) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (1.5 mL) was added, and the reaction mixture was stirred at 25 °C for 0.5 h. After monitoring the completion of the reaction by TLC, saturated aqueous sodium bicarbonate (20 mL) was added to adjust the pH to 8, followed by extraction with dichloromethane (20 mL × 3). The organic phase was washed with water (30 mL × 2). The washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by preparative high-performance liquid chromatography (chromatography column: Gemini NX C18 5 μm × 10 × 150 mm; mobile phase: A: 0.05% TFA). v / v, B: acetonitrile; B%: 40% to 45%, 12 min), the title compound (2.3 mg) was obtained. MS m / z (ESI): 365 [M+H] + .

[0222] 1 H NMR (400 MHz, DMSO-d6) δ 14.70 (s, 1H), 8.86 (s, 1H), 8.80 (d, J = 7.9 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.79 - 7.67 (m, 1H), 7.59 - 7.51 (m, 3H).

[0223] Example 7, 5-(2-chlorophenyl)-7-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[4,3-c][1,8]naphthyridin-4-one (Compound 7)

[0224] [ka]

[0225] Step 1: Synthesis of ethyl 5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate (Intermediate 7-2) Intermediate 7-1 (4.0 g, 15.04 mmol) was dissolved in tetrahydrofuran (40 mL). Sodium hydride (active content 60%) (820 mg, 20.5 mmol) was added at 0-5°C. The reaction mixture was stirred at 5°C for 0.5 h. 2-(Trimethylsilyl)ethoxymethyl chloride (SEMCl) (4.56 g, 26.34 mmol) was added to the reaction mixture and stirred at room temperature for 12 h. After completion of the reaction was confirmed by LC-MS, the reaction mixture was slowly poured into saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (60 mL x 2). The combined organic phase was washed with saturated brine (100 mL). The washed organic phase was dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated to dryness under reduced pressure. The residue was purified by preparative thin-layer chromatography (silica, petroleum ether:ethyl acetate = 10:1) to obtain the title compound (2.7 g). MS m / z (ESI): 397.0 [M+H] + .

[0226] Step 2: Synthesis of ethyl 5-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate (Intermediate 7-4) Intermediate 7-2 (1.4 g, 4.55 mmol) and Intermediate 7-3 (2.17 g, 5.46 mmol) were dissolved in anhydrous dioxane (15 mL). Water (4 mL), potassium phosphate (1.93 g, 9.11 mmol), and Pd(dtbpf)Cl (297 mg, 0.46 mmol) were added. The reaction mixture was stirred at 80 °C for 2 h under nitrogen protection. LC-MS confirmed the completion of the reaction. After cooling to room temperature, water (15 mL) and ethyl acetate (15 mL) were added sequentially. The organic phase was washed with water (15 mL × 2). The washed organic phase was dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to dryness. The residue was purified by preparative thin-layer chromatography (silica, petroleum ether:ethyl acetate = 10:1) to give the title compound (800 mg). MS m / z (ESI): 450.0 [M+H] + .

[0227] Step 3: Synthesis of 5-(2-chlorophenyl)-7-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[4,3-c][1,8]naphthyridin-4-one (compound 7) Intermediate 7-4 (250.0 mg, 0.56 mmol) was dissolved in N-methylpyrrolidone (3 mL), and Intermediate 7-5 (141.8 mg, 1.11 mmol), sodium tert-butoxide (106.8 mg, 1.11 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos) (64.3 mg, 0.11 mmol), and Pd(dba) (50.9 mg, 0.06 mmol) were added. The reaction mixture was stirred at 100 °C for 12 h under nitrogen protection. LC-MS showed the reaction was complete. The reaction mixture was filtered, concentrated to dryness under reduced pressure, and purified by preparative high-performance liquid chromatography (YMC-Actus Triart C18 column, 5 μm silica, 30 mm diameter, 150 mm length; eluent: a decreasingly polar mixture of water (containing 0.05% NH4HCO3) and acetonitrile, with a gradient of 55% to 80% acetonitrile, and an elution time of 13 min) to give the title compound (2 mg).

[0228] MS m / z (ESI): 365.0 [M+H] + . 1 H NMR (400 MHz, Methanol-d4) δ 8.79 (d, J = 7.7 Hz, 1H), 8.59 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.65 - 7.63 (m, 1H), 7.54 - 7. 49 (m, 2H), 7.44 - 7.41 (m, 1H).

[0229] Example 8, 5-(2-chlorophenyl)-7-(trifluoromethyl)oxazolo[4,5-c][1,8]naphthyridin-4(5H)-one (Compound 8)

[0230] [ka]

[0231] Step 1: Synthesis of 2-((2-chlorophenyl)amino)-6-(trifluoromethyl)pyridine-3-formic acid (Intermediate 8-3) Intermediate 8-1 (1.0 g, 4.5 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and a THF solution of lithium bis(trimethylsilyl)amide (LiHMDS) (1 M, 9.76 mL, 9.76 mmol) was added dropwise at -78 °C. After the addition was complete, the mixture was reacted at -78 °C for 1 h. Intermediate 8-2 (840.66 mg, 5.3 mmol) was then added to the reaction mixture. The mixture was warmed to room temperature and reacted for 3 h. Saturated ammonium chloride (10 mL) and ethyl acetate (10 mL × 3) were added sequentially to the reaction mixture, and the organic phase was washed with water (10 mL × 2). The washed organic phase was dried over anhydrous sodium sulfate and concentrated. Purification by preparative high-performance liquid chromatography (chromatography column: Gemini NX C18 5 μm × 10 × 150 mm; mobile phase: A: water (0.225% formic acid v / v), B: acetonitrile; B%: 30% to 50%, 11 min) gave the title compound (400 mg). MS m / z (ESI): 317.1 [M+H] + .

[0232] Step 2: Synthesis of ethyl 5-(2-((2-chlorophenyl)amino)-6-(trifluoromethyl)pyridin-3-yl)oxazole-4-carboxylate (Intermediate 8-5) Intermediate 8-3 (200 mg, 631.59 μmol) and cesium carbonate (412 mg, 1.26 mmol) were dissolved in N,N-dimethylformamide (4 mL). Diphenylphosphoryl azide (DPPA) (347.63 mg, 1.26 mmol) was added at 0 °C. The mixture was allowed to react at room temperature for 1 h. Intermediate 8-4 (71.4 mg, 631.59 μmol) was added at 0 °C. The mixture was stirred at 25 °C for 2 h. Water (5 mL) and ethyl acetate (5 mL × 3) were added sequentially to the reaction mixture, and the mixture was separated. The organic phase was washed with saturated brine (5 mL × 2). The washed organic phase was dried over anhydrous sodium sulfate and purified by preparative thin-layer chromatography (silica, petroleum ether:ethyl acetate = 100:0 to 50:50) to obtain the title compound (90 mg). MS m / z (ESI): 411.9 [M+H] + .

[0233] Step 3: Synthesis of 5-(2-chlorophenyl)-7-(trifluoromethyl)oxazolo[4,5-c][1,8]naphthyridin-4(5H)-one (compound 8) Intermediate 8-5 (80 mg, 194.29 μmol) and cesium carbonate (190 mg, 582.86 μmol) were dissolved in N,N-dimethylformamide (1 mL) and reacted at 60 °C for 3 h. The reaction mixture was filtered and purified by preparative high-performance liquid chromatography (chromatography column: Gemini NX C18 5 μm × 10 × 150 mm; mobile phase: A: water (0.225% formic acid v / v), B: acetonitrile; B%: 30% to 50%, 11 min) to give the title compound (30 mg).

[0234] MS m / z (ESI): 366.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.84 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.78 - 7.70 (m, 1H), 7.62 - 7.55 (m, 3H).

[0235] Example 9, 5-(2-chlorophenyl)-2,7-bis(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 9)

[0236] [ka]

[0237] Step 1: Synthesis of 5-(4-amino-2-chlorophenyl)-2,7-bis(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Intermediate 9-1) Intermediate 1-6 (58 mg, 156.87 μmol) was added to trifluoroacetic acid, and the reaction mixture was stirred at 70° C. for 16 hours. LCMS showed the formation of the target product. The reaction mixture was concentrated to dryness under reduced pressure to give the title compound (60 mg). MS m / z (ESI): 448.0 [M+H] + .

[0238] Step 2: Synthesis of 5-(2-chlorophenyl)-2,7-bis(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 9) Intermediate 9-1 (60 mg, 134.01 μmol) was dissolved in N,N-dimethylamide and tetrahydrofuran, and tert-butyl nitrite (62.19 mg, 603.05 μmol) was added. The reaction mixture was stirred at 70°C for 1 hour. LCMS analysis showed the formation of the target product. The reaction mixture was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (chromatography column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 39% to 59%, 12 min) to give the title compound (13.9 mg).

[0239] MS m / z (ESI): 433.0 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ = 8.85 (d, J = 7.9 Hz, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.71-7.66 (m, 1H), 7.59-7.55 (m, 2H), 7.51-7.46 (m, 1H)

[0240] Example 10, 5-(4-(difluoromethoxy)phenyl)-7-ethoxy-3,5-dihydro-1H-imidazo[4,5-c][1,8]naphthyridine-2,4-dione (Compound 10)

[0241] [ka]

[0242] Step 1: Synthesis of 2-chloro-6-ethoxy-3-cyanopyridine (Intermediate 10-2) At 25°C, intermediate 10-1 (10 g, 57.80 mmol) was dissolved in N,N-dimethylformamide (200 mL), and then sodium ethoxide (3.93 g, 57.80 mmol) was added. Under nitrogen protection, the reaction mixture was stirred at 25°C for 16 hours. LCMS showed that the target product had already been formed. After the reaction was completed, ethyl acetate (200 mL) and water (400 mL) were added to the reaction mixture, and the mixture was extracted twice with aqueous lithium chloride solution (500 mL). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The title compound (9.7 g) was obtained. MS m / z (ESI): 183.1 [M+H] + .

[0243] Step 2: Synthesis of 2-((4-(difluoromethoxy)phenyl)amino)-6-ethoxy-3-cyanopyridine (Intermediate 10-3) At 20°C, intermediate 10-2 (7.7 g, 42.17 mmol) was dissolved in tert-amyl alcohol (120 mL), and the reaction mixture was added with potassium carbonate (17.48 g, 126.50 mmol), dicyclohexyl(2,4,6-triisopropyl-3,6-dimethoxy-[1,1-biphenyl]-2-yl)phosphine (BrettPhos) (1.13 g, 2.11 mmol), (2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)palladium(II) methanesulfonate methanesulfonate (BrettPhos Pd To the reaction mixture were added (1.91 g, 2.11 mmol) of G3) and p-difluoromethoxyaniline (8.05 g, 50.60 mmol). Under nitrogen protection, the reaction mixture was stirred at 100°C for 16 hours. LCMS analysis revealed the formation of the target product. After the reaction was complete, the organic phase was concentrated under reduced pressure to remove the solvent. Ethyl acetate (50 mL) and water (100 mL) were added, and the mixture was extracted twice with water (100 mL). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 9 / 1) to obtain the title compound (6 g). MS m / z (ESI): 305.9 [M+H] + .

[0244] Step 3: Synthesis of ethyl 4-amino-1-(4-(difluoromethoxy)phenyl)-7-ethoxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-formate (Intermediate 10-4) Intermediate 10-3 (5.2 g, 17.03 mmol) was dissolved in ethanol (60 mL) at 20 °C, and sodium ethoxide (4.64 g, 68.13 mmol) and diethyl malonate (8.18 g, 51.10 mmol) were added to the reaction mixture. Under nitrogen protection, the reaction mixture was stirred at 90 °C for 16 hours. LCMS analysis showed the formation of the target product. After the reaction was completed, the organic phase was concentrated under reduced pressure to remove the solvent. Ethyl acetate (100 mL) and water (200 mL) were added to the mixture, and the mixture was extracted twice with water (200 mL). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give the title compound (4.5 g). MS m / z (ESI): 420.1 [M+H] + .

[0245] Step 4: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-7-ethoxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid (Intermediate 10-5) Intermediate 10-4 (2 g, 4.77 mmol) was dissolved in methanol (32 mL) at 20°C, and lithium hydroxide monohydrate (4.00 g, 95.38 mmol) was added to the reaction mixture. Under nitrogen protection, the reaction mixture was stirred at 50°C for 16 hours. LCMS analysis showed the formation of the target product. After the reaction was completed, the organic phase was concentrated under reduced pressure to remove the solvent. Ethyl acetate (30 mL) and water (60 mL) were added, and the mixture was extracted twice with water (60 mL). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The title compound (1.8 g) was obtained. MS m / z (ESI): 392.0 [M+H] + .

[0246] Step 5: Synthesis of 5-(4-(difluoromethoxy)phenyl)-7-ethoxy-3,5-dihydro-1H-imidazo[4,5-c][1,8]naphthyridine-2,4-dione (compound 10) Intermediate 10-5 (900 mg, 2.30 mmol) was dissolved in toluene (8 mL) at 20 °C, and diphenylphosphoryl azide (1.27 g, 4.60 mmol) and triethylamine (349.08 mg, 3.45 mmol) were added to the reaction mixture. The reaction mixture was stirred at 100 °C for 16 hours. LCMS analysis showed the formation of the target product. After completion of the reaction, ethyl acetate (20 mL) and water (40 mL) were added to the reaction mixture, followed by extraction twice with water (40 mL). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure (0.01 MPa) to remove the solvent. The residue was purified by silica gel column chromatography (petroleum ether / tetrahydrofuran = 1 / 0 to 0 / 1) to give the title compound (700 mg). The title compound (50 mg) was collected and purified by high performance liquid chromatography (column: YMC-Actus Triart C18 150 × 30 mm × 5 μm; mobile phase: A: water (0.05% aqueous ammonia), B: acetonitrile; B%: 25% to 45%, 11 min) to give the title compound (6.5 mg).

[0247] MS m / z (ESI): 389.1 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ = 8.80 (d, J = 8.5 Hz, 1H), 8.43 (s, 1H), 7.38-7.29 (m, 4H), 6.93 (t, J = 74.4 Hz, 1H), 6.75 (d, J = 3.1 Hz, 1H), 4.02 (d, J = 7.0 Hz, 2H), 1.18-1.13 (m, 3H).

[0248] Example 11, 5-(4-(difluoromethoxy)phenyl)-7-ethoxy-2-methoxy-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 11)

[0249] [ka]

[0250] Compound 10 (100 mg, 257.52 μmol) was dissolved in dichloromethane (1 mL) at 20°C, and trimethyloxonium tetrafluoroborate (76.18 mg, 515.03 μmol) was added to the reaction mixture. The reaction mixture was stirred at 40°C for 16 hours. LCMS analysis showed the formation of the target product. After completion of the reaction, dichloromethane (5 mL) and water (10 mL) were added to the reaction mixture, followed by extraction twice with water (10 mL). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by high-performance liquid chromatography (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: A: water (0.225% formic acid), B: acetonitrile; B%: 25% to 55%, 12 min) to obtain the title compound (7.9 mg).

[0251] 1 H NMR (400MHz, Methanol-d4) δ = 8.43 (s, 1H), 7.35 (s, 4H), 6.95 (t, J = 73.8 Hz, 1H), 6.73 (d, J = 8.5 Hz, 1H), 4.23 (s, 3H), 3.97 (q, J = 7.1 Hz, 2H), 1.13 (t, J = 7.0 Hz, 3H). MS m / z (ESI): 403.1 [M+H] + .

[0252] Example 12, 5-(4-(difluoromethoxy)phenyl)-2-methyl-7-(trifluoromethyl)-2,5-dihydro-4H-pyrazolo[3,4-c][1,8]naphthyridin-4-one (Compound 12)

[0253] [ka]

[0254] Step 1: Synthesis of ethyl 4-iodo-1-methyl-1H-pyrazole-3-carboxylate (Intermediate 12-2) Intermediate 12-1 (5 g, 18.79 mmol) was dissolved in DMF (50 mL), and cesium carbonate (12 g, 37.59 mmol) and iodomethane (5.3 g, 37.59 mmol) were added to the reaction mixture. Under nitrogen protection, the reaction mixture was stirred at 25 °C for 18 h. Water (50 mL) and ethyl acetate (100 mL) were added sequentially, and the organic phase was washed with water (30 mL × 2). The washed organic phase was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The title compound (2 g) was obtained by preparative thin-layer chromatography (silica, petroleum ether:ethyl acetate = 10:3). MS m / z (ESI): 281.0 [M+H] + .

[0255] Step 2: Synthesis of ethyl 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-3-carboxylate (Intermediate 12-3) Intermediate 12-2 (1.5 g, 5.33 mmol) and bis(pinacolato)diboron (2.7 g, 10.67 mmol) were dissolved in anhydrous dimethyl sulfoxide (10 mL). Potassium acetate (1.04 g, 10.67 mmol) and Pd(dppf)Cl (387 mg, 0.53 mmol) were added, and the reaction mixture was stirred at 100 °C for 15 h under nitrogen protection. After cooling to room temperature, water (60 mL) and ethyl acetate (80 mL) were added sequentially. The organic phase was washed with water (30 mL × 2) and dried over anhydrous sodium sulfate. Preparative thin-layer chromatography (silica, dichloromethane:methanol = 10:1) afforded the title compound (750 mg). MS m / z (ESI): 281.0 [M+H] + .

[0256] Step 3: Synthesis of ethyl 4-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-1-methyl-1H-pyrazole-3-carboxylate (Intermediate 12-4) Intermediate 12-3 (350 mg, 1.24 mmol) and 3-bromo-2-chloro-6-(trifluoromethyl)pyridine (483 mg, 1.86 mmol) were dissolved in dioxane (6 mL) and water (2 mL). Potassium phosphate (534 mg, 2.51 mmol) and Pd(dtbpf)Cl (81.98 mg, 0.12 mmol) were added, and the reaction mixture was stirred at 100 °C for 16 h under nitrogen protection. After cooling to room temperature, water (30 mL) and ethyl acetate (40 mL) were added sequentially. The organic phase was washed with water (30 mL × 2) and dried over anhydrous sodium sulfate. Preparative thin-layer chromatography (silica, dichloromethane:methanol = 5:1) afforded the title compound (300 mg). MS m / z (ESI): 334.1[M+H] + .

[0257] Step 4: Synthesis of 5-(4-(difluoromethoxy)phenyl)-2-methyl-7-(trifluoromethyl)-2,5-dihydro-4H-pyrazolo[3,4-c][1,8]naphthyridin-4-one (compound 12) Intermediate 12-4 (70 mg, 0.21 mmol) and intermediate 12-5 (50 mg, 0.31 mmol) were dissolved in N-methylpyrrolidone (2 mL), and sodium tert-butoxide (40 mg, 0.42 mmol) and Pd(dba) (1.9 mg, 0.02 mmol) were added. The reaction mixture was stirred at 100 °C for 15 h under nitrogen protection. After cooling to room temperature, water (15 mL) and ethyl acetate (30 mL) were added sequentially. The organic phase was washed with water (30 mL × 2). The washed organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by TLC (dichloromethane:methanol = 10:1) and then by preparative high-performance liquid chromatography (chromatography column: Gemini NX C18 5 μm × 10 × 150 mm; mobile phase: A: 0.05% trifluoroacetic acid v / v, B: acetonitrile; B%: 40% to 45%, 12 min) to give the title compound (2.5 mg).

[0258] MS m / z (ESI): 411.0 [M+H] +. 1 H NMR (400 MHz, Methanol-d4) δ 8.69 (s, 1H), 8.54 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.38-7.27 (m, 4H), 7.16-6.73 (m, 1H), 4.24 (s, 3H).

[0259] Example 13, 5-(4-(difluoromethoxy)phenyl)-7-ethoxy-2-methyl-2,5-dihydro-4H-pyrazolo[3,4-c][1,8]naphthyridin-4-one (Compound 13)

[0260] [ka]

[0261] Step 1: Synthesis of ethyl 4-(6-ethoxy-2-fluoropyridin-3-yl)-1-methyl-1H-pyrazole-3-carboxylate (Intermediate 13-2) Intermediate 12-3 (350 mg, 1.24 mmol) and intermediate 13-1 (409 mg, 1.86 mmol) were dissolved in dioxane (6 mL) and water (2 mL). Potassium phosphate (534 mg, 2.51 mmol) and Pd(dtbpf)Cl (81.98 mg, 0.12 mmol) were added, and the reaction mixture was stirred at 100 °C for 16 h under nitrogen protection. After cooling to room temperature, water (30 mL) and ethyl acetate (40 mL) were added sequentially. The organic phase was washed with water (30 mL × 2) and dried over anhydrous sodium sulfate. Preparative thin-layer chromatography (silica, dichloromethane:methanol = 5:1) afforded the title compound (250 mg). MS m / z (ESI): 294.0 [M+H] + .

[0262] Step 2: Synthesis of 5-(4-(difluoromethoxy)phenyl)-7-ethoxy-2-methyl-2,5-dihydro-4H-pyrazolo[3,4-c][1,8]naphthyridin-4-one (compound 13) Intermediate 13-2 (70 mg, 0.23 mmol) and intermediate 12-5 (50 mg, 0.31 mmol) were dissolved in N-methylpyrrolidone (2 mL), and sodium tert-butoxide (40 mg, 0.46 mmol) and Pd(dba) (1.9 mg, 0.02 mmol) were added. The reaction mixture was stirred at 100 °C for 15 h under nitrogen protection. After cooling to room temperature, water (15 mL) and ethyl acetate (30 mL) were added sequentially. The organic phase was washed with water (30 mL × 2). The washed organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by TLC (dichloromethane:methanol = 10:1) and then by preparative high-performance liquid chromatography (chromatography column: Gemini NX C18 5 μm × 10 × 150 mm; mobile phase: A: 0.05% trifluoroacetic acid v / v, B: acetonitrile; B%: 40% to 48%, 12 min) to give the title compound (5.2 mg).

[0263] MS m / z (ESI): 387.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.64 - 7.00 (m, 5H), 6.70 (d, J = 8.4 Hz, 1H), 4.16 (s, 3H), 3.87 (q, J = 7.0 Hz, 2H), 1.04 (t, J = 7.0 Hz, 3H).

[0264] Example 14, 5-(4-(difluoromethoxy)phenyl)-7-ethoxy-1-methyl-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 14)

[0265] [ka]

[0266] Step 1: Synthesis of 3-bromo-6-ethoxy-2-fluoropyridine (Intermediate 14-2) Intermediate 14-1 (0.9 g, 4.69 mmol) was dissolved in toluene (5 mL), and silver carbonate (1.55 g, 5.63 mmol) and iodoethane (1.46 g, 9.38 mmol) were added sequentially. The mixture was heated to 100 °C and stirred for 16 h. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted three times with ethyl acetate (10 mL). The combined organic phases were concentrated to dryness under reduced pressure, and the residue was purified by flash silica gel column chromatography (ISCO®; 12 g SepaFlash® silica gel column, eluent gradient 0-12% ethyl acetate / petroleum ether, 30 mL / min) to give the title compound (600 mg). MS m / z (ESI): 219.0 [M+H] + .

[0267] Step 2: Synthesis of 6-ethoxy-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Intermediate 14-3) Intermediate 14-2 (300 mg, 1.36 mmol) and bis(pinacolato)diboron (380.84 mg, 1.50 mmol) were dissolved in dioxane (8 mL), potassium acetate (401.41 mg, 4.09 mmol) was added, and under nitrogen protection, PdCl(dppf) (49.88 mg, 68.17 μmol) was added, and the reaction mixture was stirred at 90 °C for 2 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated to give the title compound (364 mg).

[0268] Step 3: Synthesis of methyl 5-(6-ethoxy-2-fluoropyridin-3-yl)-1-methyl-1H-imidazole-4-formate (Intermediate 14-4) Intermediate 14-3 (360 mg, 1.35 mmol) and methyl 5-bromo-1-methyl-1H-imidazole-4-carboxylate (206.65 mg, 943.45 μmol, synthesized according to the method reported in patent document WO2017218960) were dissolved in dioxane (3 mL) and water (0.5 mL). Under nitrogen protection, Pd(dtbpf)Cl2 (87.84 mg, 134.78 μmol) and potassium phosphate (286.10 mg, 1.35 mmol) were added and the mixture was stirred at 50 °C for 16 hours. After the reaction was completed, the mixture was cooled to 20 °C and extracted twice with ethyl acetate (10 mL). The organic phase was concentrated to dryness under reduced pressure, and the residue was purified by preparative thin-layer chromatography (silica, petroleum ether: ethyl acetate = 3:1). The title compound (0.5 g) was obtained. MS m / z (ESI): 280.0 [M+H] + .

[0269] Step 4: Synthesis of 5-(6-ethoxy-2-fluoropyridin-3-yl)-1-methyl-1H-imidazole-4-formic acid (Intermediate 14-5) Intermediate 14-4 (170 mg, 608.74 μmol) was dissolved in water (2 mL) and methanol (2 mL), lithium hydroxide monohydrate (80 mg, 1.91 mmol) was added, and the reaction mixture was stirred at 60° C. for 2 hours. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure to obtain the title compound (161 mg). MS m / z (ESI): 265.9 [M+H] + .

[0270] Step 5: Synthesis of 5-(4-(difluoromethoxy)phenyl)-7-ethoxy-1-methyl-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 14) Intermediate 14-5 (161 mg, 607.00 μmol) and 4-(difluoromethoxy)aniline (193.19 mg, 1.21 mmol) were dissolved in N,N-dimethylformamide (2 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (346.20 mg, 910.50 μmol) and diisopropylethylamine (156.90 mg, 1.21 mmol) were added sequentially. The reaction was carried out at 20°C for 16 hours with stirring. After the reaction solution was converted to the intermediate, lithium hydroxide monohydrate (76.42 mg, 1.82 mmol) was added, and the reaction was carried out at 100°C for 5 hours with stirring.

[0271] After completion of the reaction, the mixture was filtered and the filtrate was purified by preparative high-performance liquid chromatography (column: Boston Prime C18 150 × 30 mm × 5 μm; mobile phase: [A: water (0.05% ammonia water + 10 mM ammonium bicarbonate), B: acetonitrile]; B%: 36% to 66%, 10 min), and the residue was purified by high-performance liquid chromatography (formic acid conditions, column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 20% to 50%, 12 min) to obtain the title compound (14.8 mg).

[0272] MS m / z (ESI): 387.0 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ = 8.53 (d, J = 8.8 Hz, 1H), 8.05 (s, 1H), 7.39-7.28 (m, 4H), 6.94 (t, J = 74.4 Hz, 1H), 6.76 (d, J = 8.5 Hz, 1H), 4.23 (s, 3H), 3.95 (q, J = 7.0 Hz, 2H), 1.10 (t, J = 7.2 Hz, 3H).

[0273] Example 15, 5-(4-(difluoromethoxy)phenyl)-1-methyl-7-(trifluoromethyl)-1H-imidazo[4,5-c][1,8]naphthyridin-4(5H)-one (Compound 15)

[0274] [ka]

[0275] Step 1: Synthesis of 3-bromo-N-(4-(difluoromethoxy)phenyl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 15-2) p-Difluoromethoxyaniline (611.02 mg, 3.84 mmol) was dissolved in N,N-dimethylformamide (15 mL), and sodium hydride (active content 60%, 230.38 mg, 5.76 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours. Intermediate 15-1 (1 g, 3.84 mmol) was dissolved in N,N-dimethylformamide (3 mL) and added dropwise to the reaction mixture. The reaction mixture was stirred at 0 °C for 12 hours. The reaction mixture was quenched with water (5 mL), extracted three times with ethyl acetate (10 mL × 3), washed with saturated brine, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the title compound (300 mg). MS m / z (ESI): 384.9 [M+H] + .

[0276] Step 2: Synthesis of N-(4-(difluoromethoxy)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 15-3) Intermediate 15-2 (100 mg, 261.02 μmol) was dissolved in dioxane (4 mL), and bis(pinacolato)diboron (79.54 mg, 313.23 μmol), potassium acetate (76.85 mg, 783.06 μmol), and Pd(dppf)Cl (9.55 mg, 13.05 μmol) were added. The reaction mixture was heated to 80 °C and stirred under nitrogen protection for 2 hours. The title compound obtained was used directly in the next step. MS m / z (ESI): 431.1[M+H] + .

[0277] Step 3: Synthesis of 5-(4-(difluoromethoxy)phenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 15) Water (1 mL) was added to a dioxane solution containing intermediate 15-3 (100 mg, 232.46 μmol), and intermediate 15-4 (152.75 mg, synthesized according to the method reported in patent document WO2017218960), potassium carbonate (48.21 mg, 697.39 μmol), and Pd(dtbpf)Cl (15.15 mg, 23.25 μmol) were added. Under nitrogen protection, the reaction mixture was stirred at 100 °C for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure and purified by preparative high-performance liquid chromatography (column: Boston Prime C18 150 × 30 mm × 5 μm); mobile phase: (A: water (0.05% ammonia water + 10 mM ammonium bicarbonate), B: acetonitrile); B%: 37% to 67%, 10 min) to obtain the title compound (13.1 mg).

[0278] MS m / z (ESI): 411.0[M+H] + . 1 H NMR (400MHz, Methanol-d4) δ = 8.88 (d, J = 8.0 Hz, 1H), 8.24 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.35 (s, 4H), 6.98 (t, J = 74 Hz, 1H), 4.34 (s, 3H)

[0279] Example 16, 5-(4-(difluoromethoxy)phenyl)-7-(trifluoromethyl)oxazolo[4,5-c][1,8]naphthyridin-4(5H)-one (Compound 16)

[0280] [ka]

[0281] Step 1: Synthesis of 2-((4-(difluoromethoxy)phenyl)amino)-6-(trifluoromethyl)pyridine-3-formic acid (Intermediate 16-1) Intermediate 8-1 (1.0 g, 4.5 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and a THF solution of lithium bis(trimethylsilyl)amide (1 M, 9.76 mL, 9.76 mmol) was added dropwise at −78°C. After the addition was complete, the mixture was reacted at −78°C for 1 h. Intermediate 12-5 (842.7 mg, 5.3 mmol) was then added to the reaction mixture. The mixture was warmed to room temperature and reacted for 3 h. Saturated aqueous ammonium chloride solution (10 mL) and ethyl acetate (10 mL × 3) were added sequentially to the reaction mixture, and the organic phase was washed with water (10 mL × 2). The washed organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative high performance liquid chromatography (chromatography column: Gemini NX C18 5 μm × 10 × 150 mm; mobile phase: A: water (0.225% formic acid v / v), B: acetonitrile; B%: 30% to 50%) to give the title compound (900.0 mg). MS m / z (ESI): 349.1 [M+H] + .

[0282] Step 2: Synthesis of ethyl 5-(2-((4-(difluoromethoxy)phenyl)amino)-6-(trifluoromethyl)pyridin-3-yl)oxazole-4-carboxylate (Intermediate 16-2) Intermediate 16-1 (150 mg, 430.76 μmol) and cesium carbonate (281 mg, 861.51 μmol) were dissolved in N,N-dimethylformamide (4 mL). Diphenylphosphoryl azide (DPPA) (209.52 mg, 861.51 mmol) was added at 0 °C. The mixture was allowed to react at room temperature for 1 h. Intermediate 8-4 (48.72 mg, 430.76 μmol) was added at 0 °C. The mixture was stirred at 25 °C for 2 h. Water (5 mL) and ethyl acetate (5 mL × 3) were added sequentially to the reaction mixture, and the mixture was separated. The organic phase was washed with saturated brine (5 mL × 2). The washed organic phase was dried over anhydrous sodium sulfate and purified by preparative thin-layer chromatography (silica, petroleum ether:ethyl acetate = 100:0 to 50:50) to obtain the title compound (90 mg). MS m / z (ESI): 433.1 [M+H] + .

[0283] Step 3: Synthesis of 5-(4-(difluoromethoxy)phenyl)-7-(trifluoromethyl)oxazolo[4,5-c][1,8]naphthyridin-4(5H)-one (compound 16) Intermediate 16-2 (100 mg, 225.57 μmol) and cesium carbonate (220.47 mg, 676.71 μmol) were dissolved in N,N-dimethylformamide (4 mL) and reacted at 60 °C for 3 h. The reaction mixture was filtered and purified by preparative high-performance liquid chromatography (chromatography column: Gemini NX C18 5 μm × 10 × 150 mm; mobile phase: A: water (0.225% formic acid v / v), B: acetonitrile; B%: 30% to 50%, 11 min) to give the title compound (24.0 mg).

[0284] MS m / z (ESI): 398.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.79 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.62 - 7.20 (m, 5H).

[0285] Example 17, 5-(2-chlorophenyl)-7-ethoxy-1-methyl-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 17

[0286] [ka]

[0287] Intermediate 14-4 (130 mg, 465.51 μmol) and 2-chloroaniline (59.39 mg, 465.51 μmol) were dissolved in N,N-dimethylformamide (3 mL), sodium tert-butoxide (134.21 mg, 1.40 mmol) was added, and the reaction mixture was stirred at 80 °C for 1 hour. After the reaction was completed, the mixture was filtered to obtain a filtrate, which was purified by preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 19% to 49%, 12 min) to obtain the title compound (6.4 mg).

[0288] MS m / z (ESI): 355.2[M+H] + . 1 H NMR (400MHz, Methanol-d4) δ = 8.57 (d, J = 8.8 Hz, 1H), 8.09 (s, 1H), 7.73-7.63 (m, 1H), 7.59-7.50 (m, 2H), 7.48-7.37 (m, 1H), 6.80 (d, J = 8.8 Hz, 1H), 4.26 (s, 3H), 3.99-3.85 (m, 2H), 1.09 (t, J = 7.0 Hz, 3H)

[0289] Example 18, 5-(4-(difluoromethoxy)phenyl)-7-(trifluoromethyl)oxazolo[5,4-c][1,8]naphthyridin-4(5H)one (Compound 18)

[0290] [ka]

[0291] Step 1: Synthesis of 3-bromo-N-(4-(difluoromethoxy)phenyl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 18-1) Intermediate 15-1 (2.0 g, 7.72 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and lithium bis(trimethylsilyl)amide (LiHMDS) (1 M, 9.26 mL, 9.26 mmol) was added dropwise at −78 °C. After the addition was complete, the mixture was allowed to react at −78 °C for 1 h. Intermediate 12-5 (1.23 g, 7.72 mmol) was then added to the reaction mixture. The mixture was warmed to room temperature and allowed to react for 3 h. Saturated aqueous ammonium chloride (20 mL) and ethyl acetate (20 mL × 3) were added sequentially to the reaction mixture. The organic phase was washed with water (20 mL). The washed organic phase was dried over anhydrous sodium sulfate and concentrated. Preparative thin-layer chromatography (silica, petroleum ether:ethyl acetate = 100:0 to 50:50) afforded the title compound (900 mg). MS m / z (ESI): 383.1 [M+H] + .

[0292] Step 2: Synthesis of 5-(4-(difluoromethoxy)phenyl)-7-(trifluoromethyl)oxazolo[5,4-c][1,8]naphthyridin-4(5H)one (Compound 18) Intermediate 18-1 (350 mg, 916.23 μmol) and bis(pinacolato)diboron (348 mg, 1.37 mmol) were dissolved in dioxane (5 mL). Potassium acetate (179 mg, 1.83 mmol) and Pd(dppf)Cl (66.85 mg, 91.36 μmol) were added, and the reaction mixture was stirred at 90 °C for 1 h under nitrogen protection. The reaction mixture was cooled to room temperature, and intermediate 18-2 (239.37 mg, 1.09 mmol), cesium carbonate (591 mg, 1.81 mmol), water (1 mL), and Pd(dtbpf)Cl (59.0 mg, 90.66 μmol) were added, and the reaction mixture was stirred at 90 °C for 5 h under nitrogen protection. The reaction mixture was filtered, concentrated to dryness under reduced pressure, and purified by preparative high-performance liquid chromatography (chromatography column: Gemini NX C18 5 μm × 10 × 150 mm; mobile phase: A: water (0.225% formic acid v / v), B: acetonitrile; B%: 30% to 50%, 11 min) to obtain the title compound (50.0 mg).

[0293] MS m / z (ESI): 398.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.82 (d, J = 7.9 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.61 - 7.21 (m, 5H).

[0294] Example 19, 5-(4-chlorophenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 19)

[0295] [ka]

[0296] Step 1: Synthesis of 3-bromo-N-(4-chlorophenyl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 19-1) 4-Chloroaniline (244.92 mg, 1.92 mmol) was dissolved in N,N-dimethylformamide (5 mL), and sodium hydride (active content 60%, 115.18 mg, 2.88 mmol) was added at 0°C. The mixture was stirred at 0°C for 30 minutes, and an N,N-dimethylformamide solution of intermediate 15-1 (500 mg, 1.92 mmol) was added. The reaction mixture was stirred at 20°C for 16 hours, and sodium hydride (active content 60%, 76.79 mg, 1.92 mmol) was added again, and the mixture was stirred at 40°C for 30 minutes. After cooling to 0°C, the mixture was quenched by the addition of water (5 mL), extracted with ethyl acetate (30 mL), washed with brine, and the organic phase was concentrated to dryness under reduced pressure. The residue was purified by flash silica gel column (ISCO®; 4 g SepaFlash® silica gel column, 0-15% ethyl acetate / petroleum ether gradient elution @ 20 mL / min) to give the title compound (250 mg). MS m / z (ESI): 352.7 [M+H] + .

[0297] Step 2: Synthesis of N-(4-chlorophenyl)-6-(trifluoromethyl)-3-(trimethylstannyl)pyridin-2-amine (Intermediate 19-2) Intermediate 19-1 (250 mg, 711.14 μmol), hexamethyldistannane (465.97 mg, 1.42 mmol), and tetrakis(triphenylphosphine)palladium (82.18 mg, 71.11 μmol) were dissolved in xylene (5 mL) and reacted under nitrogen protection at 140 °C for 5 h with stirring. After completion of the reaction, the mixture was cooled to 20 °C and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified using a silica gel column (ISCO®; 12 g SepaFlash® silica gel column, 0-10% ethyl acetate / petroleum ether gradient elution @ 30 mL / min) to give the title compound (240 mg). MS m / z (ESI): 436.9 [M+H] + .

[0298] Step 3: Synthesis of 5-(4-chlorophenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 19) Intermediate 19-2 (240 mg, 551.14 μmol), intermediate 15-4 (120.72 mg), and tetrakis(triphenylphosphine)palladium (63.69 mg, 55.11 μmol) were dissolved in xylene (4 mL) and reacted under nitrogen protection at 140 °C for 16 hours with stirring. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 26% to 46%, 12 min) to give the title compound (47.1 mg).

[0299] MS m / z (ESI): 379.0 [M+H] + ; 1 H NMR (400MHz, Methanol-d4) δ = 8.86 (d, J = 8.3 Hz, 1H), 8.22 (s, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 4.32 (s, 3H).

[0300] Example 20, 1-methyl-5-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 20)

[0301] [ka]

[0302] Step 1: Synthesis of methyl 1-methyl-5-(trimethylstannyl)-1H-imidazole-4-formate (Intermediate 20-1) Intermediate 15-4 (1 g) was dissolved in xylene (6 mL), and tetrakis(triphenylphosphine)palladium (11.44 mg, 9.90 μmol) and hexamethyldistannane (2.99 g, 9.13 mmol) were added. The reaction mixture was heated to 140 °C and stirred under nitrogen protection for 4 h. After completion of the reaction, the reaction mixture was added dropwise to saturated aqueous potassium fluoride solution (10 mL). After stirring for 2 h, water (200 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic layer was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 0:1) to obtain the title compound (470 mg). MS m / z (ESI): 304.9[M+H] + .

[0303] Step 2: Synthesis of 3-bromo-N-(2-methylpyridin-3-yl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 20-3) Under nitrogen protection, intermediate 20-2 (207.61 mg, 1.92 mmol) was dissolved in anhydrous N,N-dimethylformamide (8 mL). The mixture was cooled to 0 °C, and sodium hydride (60% active content, 153.57 mg, 3.84 mmol) was added to the reaction mixture. The mixture was stirred at 0 °C for 30 min. Intermediate 15-1 (500 mg, 1.92 mmol) was then added, and the mixture was stirred at 20 °C for 16 h under nitrogen protection. After completion of the reaction, water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL x 3 times). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 50:1) to obtain the title compound (320 mg).

[0304] MS m / z (ESI): 331.7 [M+H] + . 1H NMR (400MHz, Methanol-d4) δ 8.27 (d, J = 4.9 Hz, 1H), 8.14-8.03 (m, 2H), 7.35-7.33 (m, 1H), 7.09 (d, J = 7.8 Hz, 1H), 2.49 (s, 3H).

[0305] Step 3: Synthesis of 1-methyl-5-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 20) Under nitrogen protection, intermediate 20-3 (38.37 mg, 115.53 μmol) was added to anhydrous xylene (1 mL), and Pd(PPh3)4 (13.35 mg, 11.55 μmol) and intermediate 20-1 (35 mg, 115.53 μmol) were added to the reaction mixture. The reaction mixture was then stirred at 140 °C for 16 h under nitrogen protection. After completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure to remove the solvent. The residue was purified by preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 0% to 30%, 12 min) to obtain the title compound (10 mg, racemic).

[0306] 1 H NMR (400MHz, Methanol-d4) δ 8.93 (d, J = 8.3 Hz, 1H), 8.60 (dd, J = 1.4, 4.9 Hz, 1H), 8.28 (s, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.75 (dd, J = 1.4, 7.9 Hz, 1H), 7.55-7.52 (m, 1H), 4.36 (s, 3H), 2.21 (s, 3H). MS m / z (ESI): 360.1 [M+H] + .

[0307] Compound 20 (80 mg) was separated by supercritical fluid chromatography (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: A: carbon dioxide; B: 35% ethanol (0.1% aqueous ammonia); flow rate: 80 mL / min) to give compound 20-P1 (10.9 mg, RT: 1.349 min) and compound 20-P2 (10.7 mg, RT: 1.586 min).

[0308] Compound 20-P1: 1 H NMR (400MHz, Methanol-d4) δ 8.93 (d, J = 8.0 Hz, 1H), 8.60 (dd, J = 1.4, 4.9 Hz, 1H), 8.27 (s, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.75 (dd, J = 1.4, 7.9 Hz, 1H), 7.52 (dd, J = 4.9, 7.9 Hz, 1H), 4.36 (s, 3H), 2.21 (s, 3H). MS m / z (ESI): 360.1 [M+H] + .

[0309] Compound 20-P2: 1 H NMR (400MHz, Methanol-d4) δ 8.93 (d, J = 8.0 Hz, 1H), 8.60 (dd, J = 1.4, 4.9 Hz, 1H), 8.27 (s, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.76 (dd, J = 1.4, 7.9 Hz, 1H), 7.53 (dd, J = 5.0, 8.0 Hz, 1H), 4.36 (s, 3H), 2.21 (s, 3H). MS m / z (ESI): 360.1 [M+H] + .

[0310] Example 21, 1-methyl-5-phenyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 21)

[0311] [ka]

[0312] Compound 19 (50 mg, 132.02 μmol) was dissolved in methanol (10 mL), wet palladium-carbon (7.02 mg, 6.60 μmol, 10% purity) was added, hydrogen gas was passed through, and the reaction mixture was stirred at 50 °C for 24 hours. After completion of the reaction, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by high-performance liquid chromatography (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 22% to 42%, 12 min) to give the title compound (10.2 mg).

[0313] MS m / z (ESI): 345.0 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ = 8.86 (d, J = 8.1 Hz, 1H), 8.22 (s, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.61-7.53 (m, 2H), 7.53-7.48 (m, 1H), 7.28 (d, J = 7.3 Hz, 2H), 4.33 (s, 3H).

[0314] Example 22, 5-(3-chlorophenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 22)

[0315] [ka]

[0316] Step 1: Synthesis of 3-bromo-N-(3-chlorophenyl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 22-2) Intermediate 22-1 (244.92 mg, 1.92 mmol) was dissolved in N,N-dimethylformamide (5 mL), sodium hydride (active content 60%, 153.57 mg, 3.84 mmol) was added at 0 °C, and the mixture was stirred at 0 °C for 30 minutes. Intermediate 15-1 (500 mg, 1.92 mmol) in N,N-dimethylformamide was added, and the reaction mixture was stirred at 20 °C for 16 hours. After completion of the reaction, the mixture was cooled to 0 °C, quenched by adding water (5 mL), extracted with ethyl acetate (30 mL), and the organic phase was concentrated to dryness under reduced pressure. The residue was purified by flash silica gel column (ISCO®; 4 g SepaFlash® silica gel column, 0-5% ethyl acetate / petroleum ether gradient elution @ 20 mL / min) to give the title compound (420 mg). MS m / z (ESI): 352.8 [M+H] + .

[0317] Step 2: Synthesis of N-(3-chlorophenyl)-6-(trifluoromethyl)-3-(trimethylstannyl)pyridin-2-amine (Intermediate 22-3) Intermediate 22-2 (290 mg, 824.92 μmol), hexamethyldistannane (540.54 mg, 1.65 mmol), and tetrakis(triphenylphosphine)palladium (82.18 mg, 71.11 μmol) were dissolved in xylene (5 mL) and the mixture was purged with nitrogen gas three times and stirred at 140 °C for 5 hours. After completion of the reaction, the mixture was cooled to 20 °C, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified using a silica gel column (ISCO®; 12 g SepaFlash® silica gel column, 0-10% ethyl acetate / petroleum ether gradient elution @ 30 mL / min) to give the title compound (270 mg). MS m / z (ESI): 436.7 [M+H] + .

[0318] Step 3: Synthesis of 5-(3-chlorophenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 22) Intermediate 22-3 (270 mg, 620.04 μmol), intermediate 15-4 (135.81 mg), and tetrakis(triphenylphosphine)palladium (71.65 mg, 62.00 μmol) were dissolved in xylene (4 mL) and reacted under nitrogen protection at 140 °C for 16 hours with stirring. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 26% to 46%, 12 min) to give the title compound (78.2 mg).

[0319] MS m / z (ESI): 379.0 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ = 8.86 (d, J = 8.0 Hz, 1H), 8.22 (s, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.60-7.49 (m, 2H), 7.41-7.34 (m, 1H), 7.28-7.22 (m, 1H), 4.32 (s, 3H).

[0320] Example 23, 5-(2-fluorophenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 23)

[0321] [ka]

[0322] Step 1: Synthesis of 3-bromo-N-(2-fluorophenyl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 23-2) Reactant 23-1 (213.33 mg, 1.92 mmol, 185.50 μL) was dissolved in N,N-dimethylformamide (5 mL). Under nitrogen protection, sodium hydride (60% active content, 153.57 mg, 3.84 mmol) was added to the reaction mixture at 0 °C and stirred for 30 min. A solution of intermediate 15-1 (500 mg, 1.92 mmol) in N,N-dimethylformamide (2 mL) was added to the reaction mixture at 0 °C and the reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was quenched with water (20 mL) and extracted three times with ethyl acetate (20 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash chromatography column, gradient 0-100% ethyl acetate / petroleum ether @ 40 mL / min) to give the title compound (440 mg). MS m / z (ESI): 334.9 [M+H] + .

[0323] Step 2: Synthesis of N-(2-fluorophenyl)-6-(trifluoromethyl)-3-(trimethylstannyl)pyridin-2-amine (Intermediate 23-3) Intermediate 23-2 (150 mg, 447.63 μmol) was dissolved in xylene (2 mL), and Pd(PPh3)4 (51.73 mg, 44.76 μmol) and hexamethyldistannane (586.63 mg, 1.79 mmol, 371.28 μL) were added at 20 °C. The reaction mixture was stirred at 140 °C for 1 hour under nitrogen protection. The reaction mixture was quenched with aqueous cesium fluoride (20 mL) and extracted three times with ethyl acetate (20 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (silica, petroleum ether:ethyl acetate = 15:1) to give the title compound (170 mg). MS m / z (ESI): 419.0 [M+H] + .

[0324] Step 3: Synthesis of 5-(2-fluorophenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 23) Intermediate 23-3 (170 mg, 405.72 μmol) and intermediate 15-4 (133.30 mg) were dissolved in xylene (2 mL). Pd(PPh3)4 (70.33 mg, 60.86 μmol) was added at 20 °C. The reaction mixture was stirred at 140 °C for 16 h under nitrogen protection. The reaction mixture was diluted with water and extracted three times with ethyl acetate (20 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (silica, petroleum ether:ethyl acetate = 15:1). The residue was then further purified by high-performance liquid chromatography (column: YMC-Actus Triart C18 150 × 30 mm × 5 μm; mobile phase: [A: water (0.05% ammonia water v / v), B: acetonitrile]; B%: 42% to 62%, 11 min) to give the title compound (25.5 mg).

[0325] MS m / z (ESI): 363.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 8.86 (d, J = 8.3 Hz, 1H), 8.35 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.61-7.53 (m, 1H), 7.51-7.43 (m, 2H), 7.43-7.36 (m, 1H), 4.27 (s, 3H)

[0326] Example 24, 5-(2-chloro-5-fluorophenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 24)

[0327] [ka]

[0328] Step 1: Synthesis of 3-bromo-N-(2-chloro-5-fluorophenyl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 24-2) Intermediate 24-1 (558.96 mg, 3.84 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL) at 25 °C. After cooling to 0 °C, sodium hydride (active content 60%, 230.38 mg, 5.76 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0 °C for 30 minutes under nitrogen protection, and then intermediate 15-1 (1 g, 3.84 mmol) was added to the reaction mixture. The reaction mixture was stirred at 20 °C for 16 hours under nitrogen protection. Completion of the reaction was confirmed by LCMS. After cooling to 0 °C, water (10 mL) was added, and the mixture was extracted twice with ethyl acetate (10 mL). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 0-5%, flow rate: 40 mL / min) to obtain the title compound (1 g). MS m / z (ESI): 368.8 [M+H] + .

[0329] Step 2: Synthesis of N-(2-chloro-5-fluorophenyl)-6-(trifluoromethyl)-3-(trimethylstannyl)pyridin-2-amine (Intermediate 24-3) Intermediate 24-2 (50 mg, 135.30 μmol) was dissolved in anhydrous xylene (1 mL) at 25 °C, and Pd(PPh3)4 (15.64 mg, 13.53 μmol) and hexamethyldistannane (44.33 mg, 135.30 μmol) were added to the reaction mixture. Under nitrogen protection, the reaction mixture was stirred at 140 °C for 16 hours. LCMS analysis showed the formation of the target product. After completion of the reaction, cesium fluoride (10 mL) was added to the reaction mixture, which was then extracted twice with ethyl acetate (10 mL). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent, and the residue was purified by preparative thin-layer chromatography (mobile phase: petroleum ether: ethyl acetate = 1:1, flow rate: 40 mL / min) to give the title compound (35 mg). MS m / z (ESI): 455.0 [M+H] + .

[0330] Step 3: Synthesis of 5-(2-chloro-5-fluorophenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 24) Intermediate 24-3 (35.00 mg, 77.19 μmol) was added to anhydrous xylene (1 mL) at 25°C. Pd(PPh3)4 (8.92 mg, 7.72 μmol) and intermediate 15-4 (25.36 mg) were added to the reaction mixture, and the mixture was reacted at 140°C for 16 hours under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure to remove the solvent. The residue was purified by preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 30% to 40%, 12 min) to obtain the title compound (2.2 mg).

[0331] MS m / z (ESI): 397.0 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ = 8.91 (d, J = 8.0 Hz, 1H), 8.26 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.69 (dd, J = 5.4, 8.7 Hz, 1H), 7.39-7.30 (m, 2H), 4.35 (s, 3H).

[0332] Example 25, 5-(2-chloro-3-fluorophenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 25)

[0333] [ka]

[0334] Step 1: Synthesis of 3-bromo-N-(2-chloro-3-fluorophenyl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 25-2) Reactant 25-1 (279.45 mg, 1.92 mmol) was dissolved in N,N-dimethylformamide (5 mL). Under nitrogen protection, sodium hydride (60% active content, 153.57 mg, 3.84 mmol) was added to the reaction mixture at 0°C and stirred for 30 minutes. Next, Reactant 15-1 (500 mg, 1.92 mmol) was dissolved in N,N-dimethylformamide (2 mL) and added dropwise to the reaction mixture. The mixture was stirred at 20°C for 16 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried and concentrated under reduced pressure. The residue was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash chromatography column, gradient 0-100% ethyl acetate / petroleum ether @ 40 mL / min) to give the title compound (580 mg).

[0335] MS m / z (ESI): 368.9 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ 8.38 (d, J = 8.5 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.38-7.34 (m, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.03-7.00 (m, 1H).

[0336] Step 2: Synthesis of N-(2-chloro-3-fluorophenyl)-6-(trifluoromethyl)-3-(trimethylstannyl)pyridin-2-amine (Intermediate 25-3) Intermediate 25-2 (150 mg, 405.91 μmol) was dissolved in xylene (2 mL), and Pd(PPh3)4 (46.91 mg, 40.59 μmol) and hexamethyldistannane (531.95 mg, 1.62 mmol) were added at 20 °C. The mixture was stirred at 140 °C for 1 hour under nitrogen protection. The reaction mixture was quenched with saturated aqueous cesium fluoride solution and extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 15:1) to obtain the title compound (165 mg). MS m / z (ESI): 454.9[M+H] + .

[0337] Step 3: Synthesis of 5-(2-chloro-3-fluorophenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 25) Intermediate 25-3 (160 mg, 352.85 μmol) and intermediate 15-4 (115.93 mg) were dissolved in xylene (2 mL), and Pd(PPh3)4 (61.16 mg, 52.93 μmol) was added at 20 °C. The reaction mixture was stirred at 140 °C for 16 hours under nitrogen protection. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3 times). The combined organic phase was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate=15:1) and then further purified by high-performance liquid chromatography (column: YMC-Actus Triart C18 150 × 30 mm × 5 μm; mobile phase: [A: water (0.05% aqueous ammonia v / v), B: acetonitrile]; B%: 40% to 60%, 11 min) to obtain the title compound (24.7 mg, racemic).

[0338] MS m / z (ESI): 397.0 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ 8.89 (d, J = 8.0 Hz, 1H), 8.36 (s, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.65-7.57 (m, 2H), 7.43-7.40 (m, 1H), 4.28 (s, 3H).

[0339] Compound 25 (26mg) supercritical fluid クロマトグラフィー(カラム:DAICEL CHIRALCEL OJ (250mm×30mm, 10μm); mobile phase: A: carbon dioxide; B: イソプロパノール (0.1% アンモニアwater); B%: 50%; flow rate: 80mL / After separation), compound 25-P1 (7.7 mg, RT: 1.688 min) and compound 25-P2 (3.9 mg, RT: 2.349 min) were obtained.

[0340] Compound 25-P1: 1 H NMR (400MHz, DMSO-d6) δ 8.88 (d, J = 8.0 Hz, 1H), 8.36 (s, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.65-7.58 (m, 2H), 7.43-7.39 (m, 1H), 4.28 (s, 3H). MS m / z (ESI): 397.1 [M+H] + .

[0341] Compound 25-P2: 1 H NMR (400MHz, DMSO-d6) δ 8.88 (d, J = 8.3 Hz, 1H), 8.36 (s, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.66-7.57 (m, 2H), 7.45-7.38 (m, 1H), 4.28 (s, 3H). MS m / z (ESI): 397.1 [M+H] + .

[0342] Example 26, 5-(2-chloro-6-fluorophenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 26)

[0343] [ka]

[0344] Step 1: Synthesis of 3-bromo-N-(2-chloro-6-fluorophenyl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 26-2) Reactant 26-1 (279.48 mg, 1.92 mmol) was dissolved in N,N-dimethylformamide (10 mL), and sodium hydride (active content 60%, 115.20 mg, 2.88 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours. Intermediate 15-1 (500 mg, 1.92 mmol) was dissolved in N,N-dimethylformamide (5 mL) and added dropwise to the reaction mixture. The reaction mixture was stirred at 0 °C for 12 hours. The reaction mixture was quenched with water (5 mL), extracted three times with ethyl acetate (10 mL × 3), washed with saturated brine, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the title compound (473 mg). MS m / z (ESI): 368.7 [M+H] + .

[0345] Step 2: Synthesis of 5-(2-chloro-6-fluorophenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 26) Intermediate 26-2 (36.59 mg, 99.03 μmol) was dissolved in xylene (2 mL), and intermediate 20-1 (30 mg, 99.03 μmol) and tetrakis(triphenylphosphine)palladium (11.44 mg, 9.90 μmol) were added. The reaction mixture was heated to 140 °C and stirred under nitrogen protection for 12 hours. The reaction mixture was concentrated to dryness under reduced pressure and purified by preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 25% to 45%, 12 min) to give the title compound (2.5 mg).

[0346] MS m / z (ESI): 397.0[M+H] + . 1 H NMR (400MHz, Methanol-d4) δ = 8.93 (d, J = 8.3Hz, 1H), 8.27 (s, 1H), 7.83 (d, J = 8.2Hz, 1H), 7.63-7.56 (m, 1H), 7.54-7.50 (m, 1H), 7.41-7.33 (m, 1H), 4.36 (s, 3H)

[0347] Example 27, 1-methyl-5-(3-methylpyridin-4-yl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 27)

[0348] [ka]

[0349] Step 1: Synthesis of 3-bromo-N-(3-methylpyridin-4-yl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 27-2) Intermediate 27-1 (207.61 mg, 1.92 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL) at 25 °C. The temperature was lowered to 0 °C, and sodium hydride (active content 60%, 153.57 mg, 3.84 mmol) was slowly added. After stirring for 30 min, intermediate 15-1 (500 mg, 1.92 mmol) was dissolved in anhydrous N,N-dimethylformamide (2 mL) and added to the reaction mixture. The reaction mixture was stirred at 25 °C for 16 h under nitrogen protection. LCMS analysis showed that the target product had already been formed. After completion of the reaction, the temperature was lowered to 0 °C, and the mixture was quenched with aqueous solution (5 mL). Ethyl acetate (50 mL) and water (100 mL) were added to the reaction mixture, which was then washed twice with saturated aqueous sodium chloride solution (100 mL). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether: 0 to 70%, 40 mL / min) to give the title compound (300 mg). MS m / z (ESI): 331.8 [M+H] + .

[0350] Step 2: Synthesis of 1-methyl-5-(3-methylpyridin-4-yl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 27) Intermediate 27-2 (43.85 mg, 132.04 μmol) was dissolved in anhydrous xylene (1 mL) at 20 °C, and Pd(PPh3)4 (15.26 mg, 13.20 μmol) and intermediate 20-1 (40 mg, 132.04 μmol) were added to the reaction mixture. Under nitrogen protection, the reaction mixture was stirred at 140 °C for 16 hours. LCMS analysis showed the formation of the target product. After completion of the reaction, ethyl acetate (10 mL) and water (20 mL) were added to the reaction mixture, which was then extracted twice with water (20 mL). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by high-performance liquid chromatography (column: Boston Prime C18 150 × 30 mm × 5 μm; mobile phase: A: water (0.05% aqueous ammonia + 10 mM ammonium bicarbonate), B: acetonitrile; B%: 25% to 55%, 10 min) to obtain the title compound (9.2 mg).

[0351] MS m / z (ESI): 360.1 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ = 8.93 (d, J = 8.0 Hz, 1H), 8.69 (s, 1H), 8.60 (d, J = 5.3 Hz, 1H), 8.28 (s, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.38 (d, J = 5.3 Hz, 1H), 4.36 (s, 3H), 2.05 (s, 3H).

[0352] Example 28, 1-methyl-5-(4-methylpyridin-3-yl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 28)

[0353] [ka]

[0354] Step 1: Synthesis of 3-bromo-N-(4-methylpyridin-3-yl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 28-2) Intermediate 28-1 (207.61 mg, 1.92 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL) at 25 °C. The temperature was lowered to 0 °C, and sodium hydride (active content 60%, 153.57 mg, 3.84 mmol) was slowly added. After stirring for 30 min, intermediate 15-1 (500 mg, 1.92 mmol) was dissolved in anhydrous N,N-dimethylformamide (2 mL) and added to the reaction mixture. The reaction mixture was stirred at 25 °C for 16 h under nitrogen protection. LCMS analysis showed that the target product had already been formed. After completion of the reaction, the temperature was lowered to 0 °C, and the sodium hydride was quenched with aqueous sodium hydride (5 mL). Ethyl acetate (50 mL) and water (100 mL) were added to the reaction mixture, which was then washed twice with saturated aqueous sodium chloride (100 mL). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether: 0 to 50%, 40 mL / min) to obtain the title compound (350 mg). MS m / z (ESI): 331.8 [M+H] + .

[0355] Step 2: Synthesis of 1-methyl-5-(4-methylpyridin-3-yl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 28) At 20 °C, intermediate 28-2 (43.85 mg, 132.04 μmol) was dissolved in anhydrous xylene (1 mL), and Pd(PPh3)4 (15.26 mg, 13.20 μmol) and intermediate 20-1 (40 mg, 132.04 μmol) were added to the reaction mixture. Under nitrogen protection, the reaction mixture was stirred at 140 °C for 16 hours. LCMS analysis showed the formation of the target product. After completion of the reaction, ethyl acetate (10 mL) and water (20 mL) were added to the reaction mixture, which was then washed twice with saturated sodium chloride solution (20 mL). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by high-performance liquid chromatography (column: Boston Prime C18 150 × 30 mm × 5 μm; mobile phase: A: water (0.05% aqueous ammonia + 10 mM ammonium bicarbonate), B: acetonitrile; B%: 25% to 55%, 10 min) to obtain the title compound (7.5 mg).

[0356] 1 H NMR (400MHz, Methanol-d4) δ = 8.93 (d, J = 8.3 Hz, 1H), 8.56 (d, J = 5.3 Hz, 1H), 8.37 (s, 1H), 8.28 (s, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.58 (d, J = 5.0 Hz, 1H), 4.36 (s, 3H), 2.08 (s, 3H). MS m / z (ESI): 360.1 [M+H] + .

[0357] Example 29, 1-methyl-5-(3-methylpyridin-2-yl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 29)

[0358] [ka]

[0359] Step 1: Synthesis of 3-bromo-N-(3-methylpyridin-2-yl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 29-2) Intermediate 29-1 (207.61 mg, 1.92 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL) at 25 °C. The temperature was lowered to 0 °C, and sodium hydride (active content 60%, 153.57 mg, 3.84 mmol) was slowly added. After stirring for 30 min, intermediate 15-1 (500 mg, 1.92 mmol) was dissolved in anhydrous N,N-dimethylformamide (2 mL) and added to the reaction mixture. The reaction mixture was stirred at 25 °C for 16 h under nitrogen protection. LCMS analysis showed that the target product had already been formed. After completion of the reaction, the temperature was lowered to 0 °C, and the sodium hydride was quenched with aqueous sodium hydride (5 mL). Ethyl acetate (50 mL) and water (100 mL) were added to the reaction mixture, which was then washed twice with saturated aqueous sodium chloride (100 mL). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether: 0 to 5%, 40 mL / min) to give the title compound (200 mg). MS m / z (ESI): 331.9 [M+H] + .

[0360] Step 2: Synthesis of 1-methyl-5-(3-methylpyridin-2-yl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 29) Intermediate 29-2 (43.85 mg, 132.04 μmol) was dissolved in anhydrous xylene (1 mL) at 20 °C, and Pd(PPh3)4 (15.26 mg, 13.20 μmol) and intermediate 20-2 (40 mg, 132.04 μmol) were added to the reaction mixture. Under nitrogen protection, the reaction mixture was stirred at 140 °C for 16 hours. LCMS analysis showed the formation of the target product. After completion of the reaction, ethyl acetate (10 mL) and water (20 mL) were added to the reaction mixture, which was then extracted twice with aqueous solution (20 mL). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by high-performance liquid chromatography (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: A: water (0.225% formic acid), B: acetonitrile; B%: 37% to 47%, 12 min) to give the title compound (1.7 mg).

[0361] 1 H NMR (400MHz, Methanol-d4) δ = 8.93 (d, J = 8.0 Hz, 1H), 8.50 (d, J = 3.5 Hz, 1H), 8.28 (s, 1H), 8.00 (d, J = 6.8 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.57 (m, J = 5.0, 7.8 Hz, 1H), 4.36 (s, 3H), 2.10 (s, 3H). MS m / z (ESI): 360.1 [M+H] + .

[0362] Example 30, 5-(2-chlorophenyl)-7-(trifluoromethyl)-3,5-dihydro-4H-pyrrolo[2,3-c][1,8]naphthyridin-4-one (Compound 30)

[0363] [ka]

[0364] Step 1: Synthesis of 3-bromo-N-(2-chlorophenyl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 30-2) Reactant 30-1 (489.83 mg, 3.84 mmol) was dissolved in N,N-dimethylformamide (10 mL), and sodium hydride (active content 60%, 230.38 mg, 5.76 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours. Intermediate 15-1 (1 g, 3.84 mmol) was dissolved in N,N-dimethylformamide (5 mL) and added dropwise to the reaction mixture. The reaction mixture was stirred at 0 °C for 12 hours. The reaction mixture was quenched with water (5 mL), extracted three times with ethyl acetate (10 mL × 3), and the organic layer was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the title compound (500 mg). MS m / z (ESI): 350.8 [M+H] + .

[0365] Step 2: Synthesis of N-(2-chlorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 30-3) Intermediate 30-2 (450 mg, 1.28 mmol) was dissolved in dioxane (6 mL), and bis(pinacolato)diboron (390.06 mg, 1.54 mmol), potassium acetate (376.87 mg, 3.84 mmol), and Pd(dppf)Cl (46.83 mg, 64.00 μmol) were added. The reaction mixture was heated to 90 °C and stirred under nitrogen protection for 1 hour. Water (5 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (5 mL × 3). The organic layer was concentrated to dryness under reduced pressure, and the title compound (100 mg) was obtained by preparative thin-layer chromatography (silica, petroleum ether:ethyl acetate = 10:1). MS m / z (ESI): 399.0[M+H] + .

[0366] Step 3: Synthesis of 5-(2-chlorophenyl)-7-(trifluoromethyl)-3,5-dihydro-4H-pyrrolo[2,3-c][1,8]naphthyridin-4-one (compound 30) Intermediate 30-3 (95 mg, 238.33 μmol) was dissolved in dioxane (4 mL) and water (1 mL), and intermediate 30-4 (145.87 mg, 714.98 μmol), potassium carbonate (98.82 mg, 714.98 μmol), and Pd(dtbpf)Cl (15.53 mg, 23.83 μmol) were added. The reaction mixture was stirred at 100 °C for 2 h under nitrogen protection. The mixture was concentrated to dryness under reduced pressure and purified by preparative high-performance liquid chromatography (Column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; Mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 35% to 55%, 12 min) to give the title compound (13.9 mg).

[0367] MS m / z (ESI): 364.0[M+H] + . 1 H NMR (400MHz, Methanol-d4) δ = 8.64 (d, J = 8.0 Hz, 1H), 7.76-7.62 (m, 2H), 7.58-7.49 (m, 3H), 7.47-7.41 (m, 1H), 7.11 (t, J = 2.7 Hz, 1H).

[0368] Example 31, 1-methyl-5-(2-methylphenyl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 31)

[0369] [ka]

[0370] Step 1: Synthesis of 3-bromo-N-(2-methylphenyl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 31-2) Intermediate 31-1 (205.72 mg, 1.92 mmol) was dissolved in N,N-dimethylformamide (5 mL), and sodium hydride (active content 60%, 191.97 mg, 4.80 mmol) was added at 0°C. The mixture was stirred at 0°C for 30 minutes, and an N,N-dimethylformamide solution of intermediate 15-1 (500 mg, 1.92 mmol) was added. The reaction mixture was stirred at 20°C for 16 hours, and sodium hydride (76.79 mg, 1.92 mmol, active content 60%) was added again, and the mixture was stirred at 40°C for 30 minutes. The reaction mixture was cooled to 0°C, quenched by the addition of water (5 mL), and extracted with ethyl acetate (30 mL). The organic phase was concentrated to dryness under reduced pressure, and the residue was purified using a flash silica gel column (ISCO®; 4 g SepaFlash® silica gel column, 0-10% ethyl acetate / petroleum ether gradient elution @ 20 mL / min) to obtain the title compound (140 mg). MS m / z (ESI): 330.9 [M+H] + .

[0371] Step 2: Synthesis of N-(2-methylphenyl)-6-(trifluoromethyl)-3-(trimethylstannyl)pyridin-2-amine (Intermediate 31-3) Intermediate 31-2 (110 mg, 332.20 μmol), hexamethyldistannane (217.67 mg, 664.39 μmol), and tetrakis(triphenylphosphine)palladium (38.39 mg, 33.22 μmol) were dissolved in xylene (5 mL) and reacted under nitrogen protection at 140 °C for 5 h with stirring. After the reaction was completed, the mixture was cooled to 20 °C and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column (ISCO®; 12 g SepaFlash® silica gel column, 0-10% ethyl acetate / petroleum ether gradient elution @ 30 mL / min) to give the title compound (137 mg). MS m / z (ESI): 414.9 [M+H] + .

[0372] Step 3: Synthesis of 1-methyl-5-(2-methylphenyl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 31) Intermediate 31-3 (137 mg, 330.09 μmol), intermediate 15-4 (72.30 mg), and tetrakis(triphenylphosphine)palladium (38.14 mg, 33.01 μmol) were dissolved in xylene (4 mL) and reacted under nitrogen protection at 140 °C for 16 hours with stirring. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 30% to 60%, 12 min) to obtain the title compound (5.1 mg).

[0373] MS m / z (ESI): 359.1 [M+H] + 1 H NMR (400MHz, Methanol-d4) δ = 8.88 (d, J = 8.0 Hz, 1H), 8.24 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.46-7.40 (m, 2H), 7.40-7.34 (m, 1H), 7.15 (d, J = 7.5 Hz, 1H), 4.34 (s, 3H), 1.94 (s, 3H).

[0374] Example 32, 5-(2-chloro-4-fluorophenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 32)

[0375] [ka]

[0376] Step 1: Synthesis of 3-bromo-N-(2-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 32-2) Reactant 32-1 (279.45 mg, 1.92 mmol) was dissolved in N,N-dimethylformamide (10 mL), and sodium hydride (active content 60%, 115.19 mg, 2.88 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours. Intermediate 15-1 (500 mg, 1.92 mmol) was dissolved in N,N-dimethylformamide (5 mL) and added dropwise to the reaction mixture. The reaction mixture was stirred at 0 °C for 12 hours. The reaction mixture was quenched with water (5 mL), extracted three times with ethyl acetate (10 mL × 3), and the organic layer was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the title compound (470 mg). MS m / z (ESI): 368.8 [M+H] + .

[0377] Step 2: Synthesis of N-(2-chloro-4-fluorophenyl)-6-(trifluoromethyl)-3-(trimethylstannyl)pyridin-2-amine (Intermediate 32-3) Intermediate 32-2 (200 mg, 541.21 μmol) was dissolved in xylene (3 mL), and hexamethyldistannane (709.27 mg, 2.16 mmol) and tetrakis(triphenylphosphine)palladium (62.54 mg, 54.12 μmol) were added. The reaction mixture was heated to 140 °C and stirred for 2 h under nitrogen protection. Saturated potassium fluoride solution (5 mL) was added to the reaction mixture, which was then extracted three times with ethyl acetate (5 mL × 3). The organic layer was concentrated to dryness under reduced pressure, and the title compound (190 mg) was obtained by preparative thin-layer chromatography (silica, dichloromethane:methanol = 10:1). MS m / z (ESI): 453.0[M+H]+.

[0378] Step 3: Synthesis of 5-(2-chloro-4-fluorophenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 32) Intermediate 32-3 (190 mg, 419.01 μmol) was dissolved in xylene (2 mL), and intermediate 15-4 (91.78 mg) and tetrakis(triphenylphosphine)palladium (48.42 mg, 41.90 μmol) were added. Under nitrogen protection, the reaction mixture was stirred at 140 °C for 12 h. The reaction mixture was concentrated to dryness under reduced pressure and purified by preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 30% to 50%, 12 min) to give the title compound (4.1 mg).

[0379] MS m / z (ESI): 397.0 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ = 8.91 (d, J = 8.5 Hz, 1H), 8.26 (s, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.55-7.51 (m, 2H), 7.36-7.31 (m, 1H), 4.35 (s, 3H)

[0380] Example 33, 5-(2-methoxyphenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 33)

[0381] [ka]

[0382] Step 1: Synthesis of 3-bromo-N-(2-methoxyphenyl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 33-2) Under a nitrogen atmosphere, intermediate 33-1 (236.43 mg, 1.92 mmol) was dissolved in anhydrous N,N-dimethylformamide (8 mL) at 25 °C. The mixture was cooled to 0 °C, and then sodium hydride (active content 60%, 153.57 mg, 3.84 mmol) was added to the reaction mixture. The mixture was stirred at 0 °C for 30 minutes. Intermediate 15-1 (500 mg, 1.92 mmol) was then added. The reaction mixture was stirred at 20 °C for 16 hours under nitrogen protection. LCMS analysis showed the formation of the target product. After completion of the reaction, water (200 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (100 mL). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 50:1) to obtain the title compound (185 mg). MS m / z (ESI): 346.8 [M+H] + .

[0383] Step 2: Synthesis of 5-(2-methoxyphenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 33) Intermediate 33-2 (40.10 mg, 115.53 μmol) was added to anhydrous xylene (1 mL) at 25°C under a nitrogen atmosphere. Pd(PPh3)4 (13.35 mg, 11.55 μmol) and intermediate 20-1 (35 mg, 115.53 μmol) were added to the reaction mixture, and the mixture was reacted at 140°C for 16 hours under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure to remove the solvent. The residue was purified by preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 24% to 44%, 12 min) to obtain the title compound (1.7 mg).

[0384] 1H NMR (400MHz, Methanol-d4) δ = 8.92 (d, J = 8.3 Hz, 1H), 8.33 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.62-7.55 (m, 1H), 7.37-7.28 (m, 2H), 7.25-7.19 (m, 1H), 4.38 (s, 3H), 3.73 (s, 3H). MS m / z (ESI): 375.0 [M+H] + .

[0385] Example 34, 5-(2-isopropylphenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 34)

[0386] [ka]

[0387] Step 1: Synthesis of 3-bromo-N-(2-isopropylphenyl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 34-2) Intermediate 34-1 (259.57 mg, 1.92 mmol) was dissolved in N,N-dimethylformamide (7 mL), and sodium hydride (active content 60%, 230.36 mg, 5.76 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 30 min. A solution of Intermediate 15-1 (500 mg, 1.92 mmol) in N,N-dimethylformamide (7 mL) was added, and the reaction mixture was stirred at 20 °C for 16 h. The mixture was cooled to 0 °C, quenched with water (5 mL), extracted with ethyl acetate (30 mL), and the organic phase was concentrated to dryness under reduced pressure. The residue was purified by flash silica gel column (ISCO®; 4 g SepaFlash® silica gel column, 0-10% ethyl acetate / petroleum ether gradient elution @ 40 mL / min) to give the title compound (160 mg). MS m / z (ESI): 358.8 [M+H] +

[0388] Step 2: Synthesis of 5-(2-isopropylphenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 34) Intermediate 34-2 (160 mg, 356.36 μmol), Intermediate 20-1 (107.96 mg, 356.36 μmol), and tetrakis(triphenylphosphine)palladium (41.18 mg, 35.64 μmol) were dissolved in xylene (5 mL) successively, and the mixture was reacted under nitrogen protection at 140° C. for 5 hours with stirring. After completion of the reaction, the temperature was lowered to 20°C, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; B: acetonitrile, B%: 35% to 45%, 12 minutes), and the residue was purified by preparative high-performance liquid chromatography (column: Boston Prime C18 150 × 30 mm × 5 μm; mobile phase: [A: water (0.05% aqueous ammonia + 10 mM ammonium bicarbonate), B: acetonitrile]; B%: 40% to 70%, 10 minutes) to obtain the title compound (5.3 mg).

[0389] MS m / z (ESI): 387.1 [M+H] + ; 1 H NMR (400 MHz, Methanol-d4) δ = 8.88 (d, J = 8.3 Hz, 1H), 8.23 ​​(s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.58-7.46 (m, 2H), 7.36-7.34 (m, 1H), 7.13-7.05 (m, 1H), 4.34 (s, 3H), 2.48-2.36 (m, 1H), 1.13 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H).

[0390] Example 35, 5-(2-chloro-3-fluorophenyl)-7-(trifluoromethyl)oxazolo[4,5-c][1,8]naphthyridin-4(5H)-one (Compound 35)

[0391] [ka]

[0392] Step 1: Synthesis of 2-((2-chloro-3-fluorophenyl)amino)-6-(trifluoromethyl)pyridine-3-formic acid (Intermediate 35-2) Intermediate 35-1 (1.0 g, 4.5 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and LiHMDS (1 M, 9.76 mL, 9.76 mmol) was added dropwise thereto at −78° C. After the addition was completed, the mixture was stirred at −78° C. for 1 hour, and then Intermediate 25-1 (768 mg, 5.3 mmol) was added to the reaction mixture. The mixture was slowly warmed to room temperature and stirred for 3 hours. A saturated aqueous ammonium chloride solution (10 mL) and ethyl acetate (10 mL × 3) were added to the reaction mixture, and the organic phase was washed with water (10 mL × 2). The washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate and filtered. The organic phase was then concentrated under reduced pressure to remove the solvent. The residue was purified by preparative high-performance liquid chromatography (column: Gemini NX C18 5 μm × 10 × 150 mm; mobile phase: A: water (0.225% formic acid v / v), B: acetonitrile; B%: 30% to 50%) to obtain the title compound (460 mg). MS m / z (ESI): 335.1 [M+H] + .

[0393] Step 2: Synthesis of ethyl 5-(2-((2-chloro-3-fluorophenyl)amino)-6-(trifluoromethyl)pyridin-3-yl)oxazole-4-carboxylate (Intermediate 35-4) Intermediate 35-2 (250 mg, 0.75 mmol) and cesium carbonate (489 mg, 1.50 mmol) were dissolved in N,N-dimethylformamide (4 mL). Diphenylphosphoryl azide (DPPA) (412 mg, 1.50 mmol) was added at 0 °C and stirred at room temperature for 1 hour. Intermediate 35-3 (85 mg, 0.75 mmol) was added at 0 °C and the reaction mixture was stirred at 25 °C for 2 hours. Water (10 mL) and ethyl acetate (10 mL × 3) were added sequentially to the reaction mixture. The organic phase was washed with saturated brine (10 mL × 2). The washed organic phase was dried over anhydrous sodium sulfate and filtered. The organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 100:0 to 50:50) to give the title compound (169 mg). MS m / z (ESI): 429.9 [M+H] + .

[0394] Step 3: Synthesis of 5-(2-chloro-3-fluorophenyl)-7-(trifluoromethyl)oxazolo[4,5-c][1,8]naphthyridin-4(5H)-one (compound 35) Intermediate 35-4 (80 mg, 0.19 mmol) and cesium carbonate (182 mg, 0.56 mmol) were dissolved in N,N-dimethylformamide (1 mL) and stirred at 60 °C for 3 hours. The reaction mixture was filtered, and the residue was purified by preparative high-performance liquid chromatography (column: Gemini NX C18 5 μm × 10 × 150 mm; mobile phase: A: water (0.225% formic acid v / v), B: acetonitrile; B%: 30% to 50%, 11 min) to give the title compound (29 mg).

[0395] MS m / z (ESI): 383.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.85 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.74 - 7.59 (m, 2H), 7.49 - 7.47 (m, 1H).

[0396] Example 36, 5-(2-chloro-3-methylphenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 36)

[0397] [ka]

[0398] Step 1: Synthesis of 3-bromo-N-(2-chloro-3-methylphenyl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 36-2) Intermediate 36-1 (271.87 mg, 1.92 mmol) was dissolved in N,N-dimethylformamide (5 mL), and NaH (115.19 mg, 2.88 mmol, active content 60%) was added at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours. Intermediate 15-1 (500 mg, 1.92 mmol) was dissolved in N,N-dimethylformamide (5 mL) and added dropwise to the reaction mixture. The mixture was stirred at 0 °C for 12 hours. After completion of the reaction, water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic layer was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. After filtration, the organic layer was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the title compound (400 mg). MS m / z (ESI): 364.9 [M+H] + .

[0399] Step 2: Synthesis of N-(2-chloro-3-methylphenyl)-6-(trifluoromethyl)-3-(trimethylstannyl)pyridin-2-amine (Intermediate 36-3) Intermediate 36-2 (400 mg, 1.09 mmol) was dissolved in xylene (4 mL), and hexamethyldistannane (716.96 mg, 2.19 mmol) and tetrakis(triphenylphosphine)palladium (126.44 mg, 109.42 μmol) were added. The reaction mixture was heated to 140 °C and stirred under nitrogen protection for 2 hours. After completion of the reaction, saturated potassium fluoride solution (5 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (5 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent, and the residue was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain the title compound (320 mg). MS m / z (ESI): 451.0[M+H] + .

[0400] Step 3: Synthesis of 5-(2-chloro-3-methylphenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 36) Intermediate 36-3 (320 mg, 711.93 μmol) was dissolved in xylene (3 mL), and intermediate 15-4 (155.94 mg, 711.93 μmol) and tetrakis(triphenylphosphine)palladium (82.27 mg, 71.19 μmol) were added. Under nitrogen protection, the reaction mixture was stirred at 140 °C for 12 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; B: acetonitrile; B%: 35% to 55%, 12 min) to obtain the title compound (29.9 mg).

[0401] MS m / z (ESI): 393.0[M+H] + . 1H NMR (400MHz, Methanol-d4) δ = 8.90 (d, J = 8.3 Hz, 1H), 8.25 (s, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.52-7.48 (m, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.26 (d, J = 6.9 Hz, 1H), 4.36 (s, 3H), 2.50 (s, 3H)

[0402] Example 37, 5-(2,3-dichlorophenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 37)

[0403] [ka]

[0404] Step 1: Synthesis of 3-bromo-N-(2,3-dichlorophenyl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 37-2) Intermediate 37-1 (273.72 mg, 1.69 mmol) was dissolved in N,N-dimethylformamide (6 mL). Under nitrogen protection, NaH (122.86 mg, 3.07 mmol, active content 60%) was added to the reaction mixture at 0 °C and stirred for 30 minutes. Intermediate 15-1 (400 mg, 1.54 mmol) was added to the reaction mixture at 0 °C and dissolved in N,N-dimethylformamide (2 mL). The mixture was stirred at 20 °C for 16 hours. After completion of the reaction, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (column: ISCO®; 12 g SepaFlash®; mobile phase: 100% petroleum ether @ 40 mL / min) to obtain the title compound (500 mg). MS m / z (ESI): = 384.8 [M+H] + .

[0405] Step 2: Synthesis of N-(2,3-dichlorophenyl)-6-(trifluoromethyl)-3-(trimethylstannyl)pyridin-2-amine (Intermediate 37-3) Intermediate 37-2 (300 mg, 777.21 μmol) was dissolved in xylene (3 mL) and Pd(PPh3)4 (89.81 mg, 77.72 μmol) and hexamethyldistannane (1.02 g, 3.11 mmol, 644.65 μL) were added at 20 °C. The reaction mixture was stirred at 140 °C under nitrogen protection for 1 hour. After completion of the reaction, the mixture was quenched with aqueous cesium fluoride solution (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (column: ISCO®; 20 g SepaFlash® 100% petroleum ether @ 40 mL / min) to give the title compound (283 mg). MS m / z (ESI): 470.9 [M+H] + .

[0406] Step 3: Synthesis of 5-(2,3-dichlorophenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 37) Intermediate 37-3 (150 mg, 319.21 μmol) and intermediate 15-4 (104.88 mg, 478.82 μmol) were dissolved in xylene (2 mL), and Pd(PPh3)4 (55.33 mg, 47.88 μmol) was added at 20 °C. The reaction mixture was stirred at 140 °C for 16 hours under nitrogen protection. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3 times). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (petroleum ether / tetrahydrofuran = 10:1) and then further purified by high-performance liquid chromatography (column: YMC-Actus Triart C18 250 × 50 mm × 7 μm; mobile phase: [A: water (0.05% aqueous ammonia v / v), B: acetonitrile]; B%: 42% to 62%, 11 min) to obtain the title compound (33.2 mg).

[0407] 1 H NMR (400MHz, DMSO-d6) δ = 8.88 (d, J = 8.0 Hz, 1H), 8.36 (s, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.83 (dd, J = 1.6, 7.9 Hz, 1H), 7.62-7.52 (m, 2H), 4.28 (s, 3H). MS m / z (ESI): 412.9 [M+H] + .

[0408] Example 38, 5-(2-chloro-3-fluorophenyl)-1,7-dimethyl-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 38)

[0409] [ka]

[0410] Step 1: Synthesis of 3-bromo-N-(2-chloro-3-fluorophenyl)-6-methylpyridin-2-amine (Intermediate 38-2) Intermediate 25-1 (2 g, 13.79 mmol) was dissolved in tetrahydrofuran (20 mL). The reaction mixture was cooled to 0 °C. NaH (1.1 g, 27.5 mmol, active content 60%) was added, and the mixture was stirred at 25 °C for 0.5 h. The reaction mixture was cooled to 0 °C, and Intermediate 38-1 (2.8 g, 13.79 mmol) was added to the mixture. The mixture was stirred at room temperature for 4 h. The reaction mixture was then cooled to 0 °C and slowly quenched with ice water (10 mL). The mixture was then extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with brine (20 mL × 3). The organic phase was dried over anhydrous Na2SO4 and filtered. The organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 10:3) to give the title compound (900 mg). MS m / z (ESI): 315.1 [M+H] + .

[0411] Step 2: Synthesis of N-(2-chloro-3-fluorophenyl)-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (Intermediate 38-3) Intermediate 38-2 (900 mg, 2.87 mmol) and bis(pinacolato)diboron (1.4 g, 5.7 mmol) were dissolved in 1,4-dioxane (10 mL). Potassium acetate (560 mg, 5.7 mmol) and Pd(dppf)Cl (209 mg, 0.28 mmol) were added, and the reaction mixture was stirred at 100 °C for 15 h under nitrogen protection. After cooling to room temperature, water (60 mL) and ethyl acetate (80 mL) were added sequentially. The organic phase was washed with water (30 mL × 2) and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give the title compound (200 mg). MS m / z (ESI): 363.2 [M+H] + .

[0412] Step 3: Synthesis of methyl 5-(2-((2-chloro-3-fluorophenyl)amino)-6-methylpyridin-3-yl)-1-methyl-1H-imidazole-4-carboxylate (Intermediate 38-4) Intermediate 38-3 (200 mg, 0.55 mmol) and intermediate 15-4 (180 mg, 0.82 mmol) were dissolved in dioxane (6 mL) and water (2 mL). Cesium fluoride (249 mg, 1.65 mmol) and Pd(dtbpf)Cl (35 mg, 0.05 mmol) were added, and the reaction mixture was stirred at 100 °C for 16 h under nitrogen protection. After cooling to room temperature, water (30 mL) and ethyl acetate (40 mL) were added sequentially. The organic phase was washed with water (30 mL × 2). The washed organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol = 5:1) to give the title compound (55 mg). MS m / z (ESI): 375.3 [M+H] + .

[0413] Step 4: Synthesis of 5-(2-chloro-3-fluorophenyl)-1,7-dimethyl-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 38) Intermediate 38-4 (55 mg, 0.15 mmol) was dissolved in acetonitrile (2 mL), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (112 mg, 0.73 mmol) was added thereto. The reaction mixture was stirred at 25°C for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (column: Gemini NX C18 5 μm × 10 × 150 mm; mobile phase: A: 0.05% TFA). v / v, B: acetonitrile; B%: 40% to 45%, 12 min), the title compound (15 mg) was obtained.

[0414] MS m / z (ESI): 343.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 8.1 Hz, 1H), 8.20 (s, 1H), 7.62 - 7.52 (m, 2H), 7.40 - 7.30 (m, 1H), 7.28 (d, J = 8.1 Hz, 1H), 4.21 (s, 3H), 2.34 (s, 3H).

[0415] Example 39, 7-chloro-5-(2-chloro-3-fluorophenyl)-1-methyl-1,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one (Compound 39)

[0416] [ka]

[0417] Step 1: Synthesis of 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (Intermediate 39-2) Intermediate 39-1 (5 g, 24.2 mmol) was dissolved in anhydrous 1,4-dioxane (50 mL). Bis(pinacolato)diboron (7.4 g, 29.0 mmol), Pd(dppf)Cl (1.8 g, 2.4 mmol), and potassium acetate (4.8 g, 48.4 mmol) were added. The reaction mixture was stirred at 100 °C for 12 h under nitrogen protection. After cooling to room temperature, water (100 mL) and ethyl acetate (100 mL) were added sequentially. The organic phase was washed with water (50 mL × 2). The washed organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 100:1) to obtain the title compound (5 g). MS m / z (ESI): 254.0 [M+H] + .

[0418] Step 2: Synthesis of methyl 5-(2-amino-4-chlorophenyl)-1-methyl-1H-imidazole-4-carboxylate (Intermediate 39-3) Intermediate 39-2 (25 mg, 98.6 μmol) and intermediate 15-4 (21.6 mg, 98.6 μmol) were dissolved in 1,4-dioxane (2.5 mL) and water (0.5 mL). Pd(dtpf)Cl (6.4 mg, 9.8 μmol) and KPO (62.7 mg, 295.8 μmol) were added, and the reaction mixture was stirred at 100 °C for 12 h under nitrogen protection. After cooling to room temperature, water (5 mL) and ethyl acetate (5 mL) were added sequentially. The organic phase was washed with water (5 mL × 2) and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to give the title compound (15 mg). MS m / z (ESI): 266.0 [M+H] + .

[0419] Step 3: Synthesis of 7-chloro-5-(2-chloro-3-fluorophenyl)-1-methyl-1,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one (compound 39) Intermediate 39-3 (10 mg, 37.6 μmol) and intermediate 39-4 (11 mg, 56.4 μmol) were dissolved in anhydrous 1,4-dioxane (5 mL). Pd(dba) (3.45 mg, 3.7 μmol), CsCO (24 mg, 75 μmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (2.18 mg, 3.76 μmol) were added to the solution, and the reaction mixture was stirred at 100° C. for 12 hours under nitrogen protection. After cooling to room temperature, the reaction mixture was filtered, concentrated to dryness under reduced pressure, and purified by preparative high-performance liquid chromatography (YMC-Actus Triart C18 column, 5 μm silica, 30 mm diameter, 150 mm length; eluent: a decreasingly polar mixture of water (containing 0.05% NH4HCO3) and acetonitrile, with a gradient of 40% to 70% acetonitrile, and a 15-minute elution time) to give the title compound (5.0 mg).

[0420] MS m / z (ESI): 362.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.6 Hz, 1H), 7.82 (s, 1H), 7.56 - 7.44 (m, 1H), 7.42 - 7.36 (m, 1H), 7.32 - 7.28 (m, 1H), 7.22 - 7.17 (m, 1H), 6.63 (d, J = 2.0 Hz, 1H), 4.22 (s, 3H).

[0421] Example 40, 5-(2-methylpyridin-3-yl)-7-(trifluoromethyl)oxazolo[4,5-c][1,8]naphthyridin-4(5H)-one (Compound 40)

[0422] [ka]

[0423] Step 1: Synthesis of 2-((2-methylpyridine)amino)-6-(trifluoromethyl)pyridine-3-formic acid (Intermediate 40-1) Intermediate 35-1 (200 mg, 0.89 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL), and a THF solution of LiHMDS (1 M, 1.8 mL, 1.8 mmol) was added dropwise thereto at −78° C. After the addition was completed, the mixture was stirred at −78° C. for 1 hour, and then 3-amino-2-methylpyridine (115 mg, 1.1 mmol) was added to the reaction mixture. The mixture was allowed to warm to room temperature and react for 3 hours. A saturated aqueous ammonium chloride solution (8 mL) and ethyl acetate (8 mL × 3) were added to the reaction mixture, and the organic phase was washed with water (8 mL × 2). The washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate and filtered. The organic phase was then concentrated under reduced pressure to remove the solvent. The residue was purified by preparative high-performance liquid chromatography (column: Gemini NX C18 5 μm × 10 × 150 mm; mobile phase: A: water (0.225% formic acid v / v), B: acetonitrile; B%: 30% to 50%) to obtain the title compound (105 mg). MS m / z (ESI): 298.0 [M+H] + .

[0424] Step 2: Synthesis of ethyl 5-(2-((2-methylpyridin-3-yl)amino)-6-(trifluoromethyl)pyridin-3-yl)oxazole-4-carboxylate (Intermediate 40-2) Intermediate 40-1 (105 mg, 0.35 mmol) and cesium carbonate (228 mg, 0.70 mmol) were dissolved in N,N-dimethylformamide (1 mL). Diphenylphosphoryl azide (DPPA) (192 mg, 0.70 mmol) was added at 0 °C. The mixture was allowed to react at room temperature for 1 hour. Intermediate 35-3 (40 mg, 0.35 μmol) was added at 0 °C. The mixture was stirred at 25 °C for 2 hours. Water (5 mL) and ethyl acetate (5 mL × 3) were added sequentially to the reaction mixture. The organic phase was washed with saturated brine (5 mL × 2). The washed organic phase was dried over anhydrous sodium sulfate and filtered. The organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 100:0 to 50:50) to give the title compound (75 mg). MS m / z (ESI): 393.1 [M+H] + .

[0425] Step 3: Synthesis of 5-(2-methylpyridin-3-yl)-7-(trifluoromethyl)oxazolo[4,5-c][1,8]naphthyridin-4(5H)-one (compound 40) Intermediate 40-2 (58 mg, 0.15 mmol) and cesium carbonate (147 mg, 0.45 mmol) were dissolved in N,N-dimethylformamide (1 mL) and stirred at 60 °C for 3 hours. The reaction mixture was filtered and purified by preparative high-performance liquid chromatography (column: Gemini NX C18 5 μm × 10 × 150 mm; mobile phase: A: water (0.225% formic acid v / v), B: acetonitrile; B%: 30% to 50%, 11 min) to give the title compound (14 mg).

[0426] MS m / z (ESI): 347.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.75 (d, J = 8.0 Hz, 1H), 8.53 (dd, J = 4.8, 1.5 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.67 (dd, J = 7.9, 1.5 Hz, 1H), 7.39 (dd, J = 7.9, 4.8 Hz, 1H), 2.06 (s, 3H).

[0427] Example 41, 1-methyl-7-(trifluoromethyl)-5-(2-(trifluoromethyl)pyridin-3-yl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 41)

[0428] [ka]

[0429] Step 1: Synthesis of 3-bromo-6-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-3-yl)pyridin-2-amine (Intermediate 41-2) Under nitrogen protection, intermediate 15-1 (300 mg, 1.15 mmol) and intermediate 41-1 (186.74 mg, 1.15 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL). Potassium tert-butoxide (323.14 mg, 2.88 mmol) was added to the reaction mixture, and the mixture was stirred at 20 °C for 16 hours. After completion of the reaction, water (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent, and the residue was purified by thin-layer chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the title compound (247.9 mg). MS m / z (ESI): 387.8 [M+H] + .

[0430] Step 2: Synthesis of 1-methyl-7-(trifluoromethyl)-5-(2-(trifluoromethyl)pyridin-3-yl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 41) Under nitrogen protection, intermediate 41-2 (127.45 mg, 330.09 μmol) was added to anhydrous xylene (6 mL), and tetrakis(triphenylphosphine)palladium (38.14 mg, 33.01 μmol) and intermediate 20-1 (100 mg, 330.09 μmol) were added to the reaction mixture. The reaction mixture was then stirred at 140 °C for 16 hours under nitrogen protection. After completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure to remove the solvent. The residue was purified by preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 27% to 47%, 14 min) to obtain the title compound (15.3 mg).

[0431] MS m / z (ESI): 414.1 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ 8.93 (d, J = 8.1 Hz, 1H), 8.89 (d, J = 4.3 Hz, 1H), 8.28 (s, 1H), 8.05-8.00 (m, 1H), 7.93 (dd, J = 4.7, 8.1 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 4.36 (s, 3H).

[0432] Compound 41 (13.6 mg) was separated by supercritical fluid chromatography (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: A: carbon dioxide; B: ethanol (0.1% aqueous ammonia); B%: 25%; flow rate: 75 mL / min) to give compound 41-P1 (2.3 mg, RT: 3.547 min) and compound 41-P2 (2.3 mg, RT: 3.954 min).

[0433] Compound 41-P1: 1 H NMR (400MHz, Methanol-d4) δ = 8.93 (d, J = 8.3 Hz, 1H), 8.89 (d, J = 4.5 Hz, 1H), 8.27 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.92 (dd, J = 4.6, 8.2 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 4.36 (s, 3H). MS m / z (ESI): 414.0 [M+H] + .

[0434] Compound 41-P2: 1 H NMR (400MHz, Methanol-d4) δ = 8.93 (d, J = 8.3 Hz, 1H), 8.89 (d, J = 3.8 Hz, 1H), 8.27 (s, 1H), 8.03 (d, J = 7.5 Hz, 1H), 7.92 (dd, J = 4.8, 8.0 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 4.36 (s, 3H). MS m / z (ESI): 414.0 [M+H] + .

[0435] Example 42, 5-(2-cyclopropylpyridin-3-yl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 42)

[0436] [ka]

[0437] Step 1: Synthesis of 2-cyclopropyl-3-nitropyridine (Intermediate 42-3) Under nitrogen protection, intermediate 42-1 (2.5 g, 15.77 mmol) and intermediate 42-2 (4.67 g, 31.54 mmol) were dissolved in dioxane (50 mL) and water (17 mL). Cesium carbonate (10.28 g, 31.54 mmol) and Pd(dppf)Cl (576.90 mg, 788.43 μmol) were added to the reaction mixture. Under nitrogen protection, the reaction mixture was stirred at 90 °C for 16 hours. After completion of the reaction, water (40 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (40 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent, and the residue was purified by flash (ISCO®; 20 g SepaFlash® Silica Flash chromatography column, gradient 0-12% ethyl acetate / petroleum ether @ 80 mL / min) to give the title compound (2.0 g). MS m / z (ESI): 164.8 [M+H] + .

[0438] Step 2: Synthesis of 2-cyclopropylpyridin-3-amine (Intermediate 42-4) Under nitrogen protection, intermediate 42-3 (2.00 g, 12.15 mmol) was dissolved in methanol (30 mL) and water (15 mL). Iron powder (3.39 g, 60.76 mmol) and ammonium chloride (6.50 g, 121.53 mmol) were added to the reaction mixture. The reaction mixture was stirred at 25 °C for 16 h under nitrogen protection. After completion of the reaction, water (40 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (40 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash chromatography column, gradient 0-15% ethyl acetate / petroleum ether @ 40 mL / min) to give the title compound (254.7 mg). MS m / z (ESI): 134.9 [M+H] + .

[0439] Step 3: Synthesis of 3-bromo-N-(2-cyclopropylpyridin-3-yl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 42-5) Under nitrogen protection, intermediate 42-4 (154.56 mg, 1.15 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL). The mixture was cooled to 0 °C, and then NaH (69.11 mg, 1.73 mmol, active content 60%) was added to the reaction mixture. The mixture was stirred at 0 °C for 30 min. Intermediate 15-1 (300 mg, 1.15 mmol) was added, and the mixture was stirred at 20 °C for 16 h under nitrogen protection. After completion of the reaction, water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash chromatography column, gradient 0-13% ethyl acetate / petroleum ether @ 40 mL / min) to give the title compound (60.9 mg). MS m / z (ESI): 357.9 [M+H] + .

[0440] Step 4: Synthesis of 5-(2-cyclopropylpyridin-3-yl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 42) Under nitrogen protection, intermediate 42-5 (58.14 mg, 162.33 μmol) was added to anhydrous xylene (2 mL), and tetrakis(triphenylphosphine)palladium (41.96 mg, 36.31 μmol) and intermediate 20-1 (110.00 mg, 363.10 μmol) were added to the reaction mixture. Under nitrogen protection, the reaction mixture was stirred at 140 °C for 16 hours. After completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure to remove the solvent. The residue was purified by preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 16% to 36%, 12 min) to obtain the title compound (19.1 mg).

[0441] MS m / z (ESI): 386.1 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ 8.92 (d, J = 8.1 Hz, 1H), 8.53 (dd, J = 1.3, 4.8 Hz, 1H), 8.26 (s, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.66 (dd, J = 1.4, 7.9 Hz, 1H), 7.38 (dd, J = 4.9, 7.9 Hz, 1H), 4.35 (s, 3H), 1.60-1.51 (m, 1H), 1.15-1.07 (m, 1H), 0.90-0.82 (m, 1H), 0.79-0.70 (m, 1H), 0.65-0.55 (m, 1H)

[0442] Compound 42 (17.0mg) supercritical fluid クロマトグラフィー(カラム:DAICEL CHIRALPAK AD (250mm × 30mm, 10μm); mobile phase: A: carbon dioxide; B: エタノール (0.1% アンモニアwater); B%: 30%; flow rate: 70mL / min) Compound 42-P1 (3.3 mg, RT: 4.350 min) and compound 42-P2 (3.4 mg, RT: 4.073 min) were prepared and separated by により.

[0443] Compound 42-P1: 1 H NMR (400MHz, Methanol-d4) δ = 8.92 (d, J = 8.3 Hz, 1H), 8.54 (dd, J = 1.6, 4.9 Hz, 1H), 8.27 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.67 (dd, J = 1.5, 8.0 Hz, 1H), 7.39 (dd, J = 4.8, 7.8 Hz, 1H), 4.36 (s, 3H), 1.60-1.52 (m, 1H), 1.16-1.09 (m, 1H), 0.91-0.83 (m, 1H), 0.80-0.72 (m, 1H), 0.64-0.56 (m, 1H). MS m / z (ESI): 386.1 [M+H] + .

[0444] Compound 42-P2: 1 H NMR (400MHz, Methanol-d4) δ = 8.92 (d, J = 8.0 Hz, 1H), 8.54 (dd, J = 1.5, 4.8 Hz, 1H), 8.27 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.67 (dd, J = 1.6, 7.9 Hz, 1H), 7.39 (dd, J = 4.8, 8.0 Hz, 1H), 4.36 (s, 3H), 1.60-1.52 (m, 1H), 1.16-1.09 (m, 1H), 0.91-0.84 (m, 1H), 0.80-0.71 (m, 1H), 0.64-0.56 (m, 1H). MS m / z (ESI): 386.1 [M+H] + .

[0445] Example 43, 5-(3-fluoro-2-methylphenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 43)

[0446] [ka]

[0447] Step 1: Synthesis of 3-bromo-N-(3-fluoro-2-methylphenyl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 43-2) Under nitrogen protection, intermediate 15-1 (300 mg, 1.15 mmol) and intermediate 43-1 (143.91 mg, 1.15 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL), and potassium tert-butoxide (322.60 mg, 2.88 mmol) was added to the reaction solution. The reaction solution was stirred at 20 °C for 16 hours. After completion of the reaction, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent, and the residue was purified by thin-layer chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the title compound (126.3 mg). MS m / z (ESI): 348.8 [M+H] + .

[0448] Step 2: Synthesis of 5-(3-fluoro-2-methylphenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 43) Under nitrogen protection, intermediate 43-2 (115.24 mg, 330.09 μmol) was added to anhydrous xylene (6 mL), and tetrakis(triphenylphosphine)palladium (38.14 mg, 33.01 μmol) and intermediate 20-1 (100 mg, 330.09 μmol) were added to the reaction solution. Then, under nitrogen protection, the reaction solution was stirred at 140° C. for 16 hours. After the reaction was completed, the reaction mixture was filtered and concentrated under reduced pressure to remove the solvent. The residue was purified by preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 25% to 45%, 14 min), and then purified by preparative supercritical fluid chromatography (column: DAICEL CHIRALCEL OJ (250 mm × 30 mm, 10 μm); mobile phase: [A: carbon dioxide, B: ethanol; B%: 20%)) to give compound 43-P1 (1.0 mg, RT: 3.432 min) and compound 43-P2 (1.5 mg, RT: 3.643 min).

[0449] Compound 43-P1: MS m / z (ESI): 377.1 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ 8.91 d, J = 7.9 Hz, 1H), 8.26 (s, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.41-7.38 (m, 1H), 7.25 (t, J = 8.6 Hz, 1H), 7.04 (d, J = 7.4 Hz, 1H), 4.35 (s, 3H), 1.88 (s, 3H).

[0450] Compound 43-P2: MS m / z (ESI): 377.1 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ 8.79 (d, J = 8.1 Hz, 1H), 8.14 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.32-7.23 (m, 1H), 7.13 (t, J = 8.8 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 4.23 (s, 3H), 1.76 (s, 3H).

[0451] Example 44, 5-(2-chloro-3-fluorophenyl)-1-(methyl-d3)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 44)

[0452] [ka]

[0453] Step 1: Synthesis of methyl 5-bromo-1-(methyl-d3)-1H-imidazole-4-formate (Intermediate 44-2) To a solution of intermediate 44-1 (300 mg, 1.46 mmol) in tetrahydrofuran (5 mL) was added NaH (117.06 mg, 2.93 mmol, active content 60%) at 0 °C. The mixture was stirred for 30 min, and then deuterated iodomethane (415.41 mg, 2.93 mmol) was added. The mixture was stirred at 20 °C for 16 h. After completion of the reaction, the mixture was quenched with methanol (10 mL). The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel column (ISCO®; 12 g SepaFlash® silica gel column, eluent: 15-70% ethyl acetate / petroleum ether gradient elution @ 40 mL / min) to give the title compound (270 mg).

[0454] MS m / z (ESI): 222.0 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ = 7.46 (s, 1H), 4.03-3.82 (s, 3H).

[0455] Step 2: Synthesis of 5-(2-chloro-3-fluorophenyl)-1-(methyl-d3)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 44) Intermediate 44-2 (80 mg, 360.27 μmol) and intermediate 25-3 (163.37 mg, 360.27 μmol) were dissolved in xylene (8 mL), tetrakis(triphenylphosphine)palladium (41.63 mg, 36.03 μmol) was added, and the mixture was stirred at 140 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was cooled to 20 °C and concentrated to dryness under reduced pressure. The residue was purified by thin-layer chromatography (tetrahydrofuran:dichloromethane = 1:1) and then by preparative high-performance liquid chromatography (formic acid conditions; column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 30% to 50%, 14 min) to obtain the title compound (41.6 mg).

[0456] MS m / z (ESI): 400.0 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ = 8.89 (d, J = 8.2 Hz, 1H), 8.26 (s, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.58-7.51 (m, 1H), 7.48-7.42 (m, 1H), 7.36-7.27 (m, 1H).

[0457] Example 45. Synthesis of 1-methyl-5-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one (Compound 45)

[0458] [ka]

[0459] Step 1: Synthesis of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)aniline (Intermediate 45-2) Intermediate 45-1 (5 g, 20.83 mmol) and bis(pinacolato)diboron (6.35 g, 25.00 mmol) were dissolved in anhydrous dioxane (50 mL). Potassium acetate (4.09 g, 41.66 mmol) and Pd(dppf)Cl (1.52 g, 2.08 mmol) were added. The reaction mixture was stirred at 80 °C for 4 h under nitrogen protection. After cooling to room temperature, water (50 mL) and ethyl acetate (50 mL) were added sequentially. The organic phase was washed with water (50 mL × 2) and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 10:1) to give the title compound (5.22 g). MS m / z (ESI): 288.0 [M+H] + .

[0460] Step 2: Synthesis of methyl 5-(2-amino-4-(trifluoromethyl)phenyl)-1-methyl-1H-imidazole-4-carboxylate (Intermediate 45-3) Intermediate 45-2 (500 mg, 1.74 mmol) and intermediate 15-4 (318 mg, 1.45 mmol) were dissolved in anhydrous dioxane (5 mL). Potassium phosphate (616 mg, 2.9 mmol), water (0.5 mL), and Pd(dtbpf)Cl (95 mg, 0.1 mmol) were added, and the reaction mixture was stirred at 100 °C for 4 h under nitrogen protection. After cooling to room temperature, water (5 mL) and ethyl acetate (5 mL) were added sequentially. The organic phase was washed with water (5 mL × 2). The washed organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol = 40:1) to give the title compound (200 mg). MS m / z (ESI): 300.0 [M+H] + .

[0461] Step 3: Synthesis of 1-methyl-5-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one (compound 45) Intermediate 45-3 (60 mg, 0.2 mmol) and intermediate 45-4 (69 mg, 0.4 mmol) were dissolved in anhydrous dioxane (1 mL). Cesium carbonate (196 mg, 0.6 mmol), XantPhos (23 mg, 0.04 mmol), and Pd(dba) (11 mg, 0.02 mmol) were added, and the reaction mixture was stirred at 100 °C for 12 h under nitrogen protection. After cooling to room temperature, the reaction mixture was filtered and concentrated to dryness under reduced pressure. The mixture was purified by preparative high-performance liquid chromatography (HPLC) using a YMC-Actus Triart C column (5 μm silica, 30 mm diameter, 150 mm length) with a decreasing polarity mixture of water (containing 0.05% NHHCO) and acetonitrile as the eluent, with a gradient of 55% to 75% acetonitrile, and a 12 min elution time. The title compound (8 mg) was obtained.

[0462] MS m / z (ESI): 359.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.71 - 8.69 (m, 1H), 8.52 (d, J = 8.4 Hz, 1H), 8.31 (s, 1H), 7.84 - 7.82 (m, 1H), 7.72 - 7.70 (m, 1H),7.57 - 7.54 (m, 1H), 6.67 (s, 1H), 4.29 (s, 3H), 2.11 (s, 3H).

[0463] Example 46, 7-chloro-1-methyl-5-(2-methylpyridin-3-yl)-1,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one (Compound 46)

[0464] [ka]

[0465] Step 1: Synthesis of 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (Intermediate 46-2) Reactant 46-1 (5 g, 24.22 mmol) was dissolved in anhydrous 1,4-dioxane (50 mL). Bis(pinacolato)diboron ((BPin)2) (7.38 g, 29.06 mmol), Pd(dppf)Cl2 (1.77 g, 2.42 mmol), and potassium acetate (4.75 g, 48.43 mmol) were added. The reaction mixture was stirred at 100 °C for 12 h under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, and water (50 mL) and ethyl acetate (100 mL) were added sequentially. The organic phase was washed with water (50 mL × 2) and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (petroleum ether:ethyl acetate = 100:1) to obtain the title compound (5 g). MS m / z (ESI): 254.0 [M+H] + .

[0466] Step 2: Synthesis of methyl 5-(2-amino-4-chlorophenyl)-1-methyl-1H-imidazole-4-carboxylate (Intermediate 46-3) Intermediate 46-2 (1.75 g, 6.89 mmol) and intermediate 15-4 (1 g, 4.57 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL). Pd(dppf)Cl (0.1 g, 0.138 mmol) and KPO (1.9 g, 8.95 mmol) were added, and the reaction mixture was stirred at 100 °C for 12 h under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, and water (50 mL) and ethyl acetate (100 mL) were added sequentially. After allowing to stand, the organic phase was separated and washed with water (50 mL × 2) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give the title compound (0.8 g). MS m / z (ESI): 266.0 [M+H] +

[0467] Step 3: Synthesis of 7-chloro-1-methyl-5-(2-methylpyridin-3-yl)-1,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one (compound 46) Intermediate 46-3 (150 mg, 0.56 mmol) and 2-methyl-3-bromopyridine (144.5 mg, 0.84 mmol) were dissolved in anhydrous toluene (5 mL), and Pd(dba) (51 mg, 56 μmol), CsCO (360 mg, 1.10 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (32.7 mg, 56 μmol) were added. The reaction mixture was stirred at 100 °C for 12 h under nitrogen protection. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol=20:1) to obtain the crude product, which was further purified by preparative high-performance liquid chromatography (YMC-Actus Triart C18 column, 5 μm, silica, diameter 30 mm, length 150 mm; using a mixture of water (containing 0.05% NH4HCO3) and acetonitrile with decreasing polarity as the eluent, with an acetonitrile gradient of 40% to 70%, and an elution time of 15 min) to obtain the title compound (21.4 mg).

[0468] MS m / z (ESI): 325.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.69 - 8.67 (m, 1H), 8.31 (d, J = 8.7 Hz, 1H), 8.23 ​​(s, 1H), 7.79 - 7.77 (m, 1H), 7.55 - 7.52 (m, 1H), 7.45 - 7.42 (m, 1H), 6.45 (d, J = 2.1 Hz, 1H), 4.23 (s, 3H), 2.11 (s, 3H).

[0469] Compound 46 (21 mg) was purified by supercritical fluid chromatography (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: A: carbon dioxide, B: ethanol (0.1% aqueous ammonia) B%: 40%) to give compound 46-P1 (5.2 mg, RT: 1.519 min) and compound 46-P2 (5.8 mg, RT: 2.025 min).

[0470] Compound 46-P1: 1 H NMR (400MHz, Chloroform-d) δ = 8.74 (d, J = 3.8 Hz, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.87 (s, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.44 (dd, J = 4.9, 7.7 Hz, 1H), 7.32 (dd, J = 1.9, 8.7 Hz, 1H), 6.63 (d, J = 1.8 Hz, 1H), 4.25 (s, 3H), 2.30 (s, 3H). MS m / z (ESI): 325.1 [M+H] + .

[0471] Compound 46-P2: 1 H NMR (400MHz, Chloroform-d) δ = 8.74 (d, J = 4.0 Hz, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.86 (s, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.44 (dd, J = 5.0, 7.8 Hz, 1H), 7.32 (dd, J = 1.8, 8.5 Hz, 1H), 6.63 (d, J = 1.8 Hz, 1H), 4.25 (s, 3H), 2.30 (s, 3H). MS m / z (ESI): 325.1 [M+H] + .

[0472] Example 47, 7-クロロ-1-メチル-5-(2-(トリフルオロメチル)ピリジン-3-イル)-1,5-ジヒドロ-4H-イミダゾ[4,5-c]キノリン-4-オン (Compound 47)

[0473]

change

[0474] Step 1: Synthesis of 7-chloro-1-methyl-5-(2-(trifluoromethyl)pyridin-3-yl)-1,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one (compound 47) Intermediate 46-3 (150 mg, 0.56 mmol) and 2-trifluoromethyl-3-bromopyridine (189 mg, 0.84 mmol) were dissolved in anhydrous toluene (5 mL), and Pd(dba) (51 mg, 56 μmol), CsCO (360 mg, 1.10 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (32.7 mg, 56 μmol) were added. Under nitrogen protection, the reaction mixture was stirred at 100 °C for 12 h. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, concentrated to dryness under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 20:1) to obtain the crude product. This crude product was then purified by preparative high-performance liquid chromatography (YMC-Actus Triart C18 column, 5 μm, silica, diameter 30 mm, length 150 mm; using a mixture of water (containing 0.05% NH4HCO3) and acetonitrile with decreasing polarity as the eluent, the gradient ratio of acetonitrile was 40% to 70%, and the elution time was 15 min) to obtain the title compound (37.7 mg).

[0475] MS m / z (ESI): 379.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.00 - 8.98 (m, 1H), 8.30 (d, J = 8.7 Hz, 1H), 8.23 ​​(s, 1H), 8.21 - 8.19 (m, 1H), 8.08 - 8.05 (m, 1H), 7.46 - 7.43 (m, 1H), 6.55 (d, J = 2.0 Hz, 1H), 4.23 (s, 3H).

[0476] Compound 47 (35 mg) was purified by supercritical fluid chromatography (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: A: carbon dioxide, B: isopropanol (0.1% aqueous ammonia); B%: 35%; flow rate: 70 mL / min) to give compound 47-P1 (7.6 mg, RT: 1.385 min) and compound 47-P2 (10.6 mg, RT: 1.786 min).

[0477] Compound 47-P1: 1 H NMR (400MHz, Methanol-d4) δ = 8.99 (d, J = 4.0 Hz, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.15 (s, 1H), 8.10-8.06 (m, 1H), 8.04-7.99 (m, 1H), 7.47 (dd, J = 2.0, 8.8 Hz, 1H), 6.59 (d, J = 2.0 Hz, 1H), 4.31 (s, 3H). MS m / z (ESI): 379.0 [M+H] + .

[0478] Compound 47-P2: 1 H NMR (400MHz, Methanol-d4) δ = 8.99 (d, J = 4.3 Hz, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.15 (s, 1H), 8.10-8.05 (m, 1H), 8.04-7.98 (m, 1H), 7.47 (dd, J = 1.9, 8.7 Hz, 1H), 6.59 (d, J = 2.0 Hz, 1H), 4.31 (s, 3H). MS m / z (ESI): 379.0 [M+H] + .

[0479] Example 48, 5-(2-cyclopropylpyridin-3-yl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one (Compound 48)

[0480] [ka]

[0481] Intermediate 45-3 (250 mg, 0.83 mmol) and 3-bromo-2-cyclopropylpyridine (181 mg, 0.91 mmol) were dissolved in anhydrous toluene (3 mL), and cesium carbonate (541 mg, 1.66 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (96 mg, 0.17 mmol), and Pd(dba) (76 mg, 0.08 mmol) were added thereto. The reaction mixture was stirred at 100 °C for 4 h under nitrogen protection. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (YMC-Actus Triart C18 column, 5 μm, silica, diameter 30 mm, length 150 mm; a mixture of water (containing 0.05% NH4HCO3) and acetonitrile with decreasing polarity was used as the eluent, with an acetonitrile gradient of 55% to 75%, and an elution time of 12 min) to obtain the title compound (90 mg).

[0482] MS m / z (ESI): 385.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.67 - 8.64 (m, 1H), 8.51 (d, J = 8.4 Hz, 1H), 8.31 (s, 1H), 7.80 - 7.78 (m, 1H), 7.71 - 7.69 (m, 1H), 7.46 - 7.43 (m, 1H), 6.71 (s, 1H), 4.28 (s, 3H), 1.50 - 1.46 (m, 1H), 1.12 - 1.09 (m, 1H), 0.78 - 0.74 (m, 2H), 0.62 - 0.53 (m, 1H).

[0483] Compound 48 (90mg) supercritical fluid クロマトグラフィー(カラム:DAICEL CHIRALCEL OJ (250mm × 30mm, 10μm); mobile phase: A: carbon dioxide, B: エタノール (0.1% アンモニアwater); B%: 20%; flow rate: 70mL / min) Compound 48-P1 (31.3mg, RT: 3.257min) and compound 48-P2 (33.2mg, RT: 3.564min) prepared by により were obtained.

[0484] Compound 48-P1: 1 H NMR (400MHz, Methanol-d4) δ = 8.66 (d, J = 4.3 Hz, 1H), 8.57 (d, J = 8.5 Hz, 1H), 8.22 (s, 1H), 7.76-7.70 (m, 2H), 7.50-7.40 (m, 1H), 6.91 (s, 1H), 4.36 (s, 3H), 1.60-1.50 (m, 1H), 1.25-1.20 (m, 1H), 0.95-0.90 (m, 1H), 0.84-0.80 (m, 1H), 0.75-0.60 (m, 1H). MS m / z (ESI): 385.1 [M+H] + .

[0485] Compound 48-P2: 1 H NMR (400MHz, Methanol-d4) δ = 8.66 (d, J = 4.8 Hz, 1H), 8.57 (d, J = 8.5 Hz, 1H), 8.23 ​​(s, 1H), 7.77-7.71 (m, 2H), 7.47 (dd, J = 4.8, 7.8 Hz, 1H), 6.91 (s, 1H), 4.37 (s, 3H), 1.60-1.52 (m, 1H), 1.26-1.18 (m, 1H), 0.95-0.87 (m, 1H), 0.87-0.79 (m, 1H), 0.72-0.63 (m, 1H). MS m / z (ESI): 385.1 [M+H] + .

[0486] Example 49, 7-chloro-5-(2-cyclopropylpyridin-3-yl)-1-methyl-1,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one (Compound 49)

[0487] [ka]

[0488] Intermediate 46-3 (150 mg, 0.56 mmol) and 3-bromo-2-cyclopropylpyridine (144.5 mg, 0.73 mmol) were dissolved in anhydrous toluene (5 mL), and Pd(dba) (51 mg, 56 μmol), CsCO (360 mg, 1.10 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (32.7 mg, 56 μmol) were added thereto.

[0489] The reaction mixture was stirred at 100°C for 12 hours under nitrogen protection. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 20:1) to obtain the crude product, which was then purified by preparative high-performance liquid chromatography (YMC-Actus Triart C18 column, 5 μm, silica, 30 mm diameter, 150 mm length; eluting with a decreasingly polar mixture of water (containing 0.05% NH4HCO3) and acetonitrile, with a gradient of 40% to 70% acetonitrile, over a 15-minute period) to obtain the title compound (73.3 mg).

[0490] MS m / z (ESI): 351.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.64-8.62 (m, 1H), 8.30 (d, J = 8.7 Hz, 1H), 8.23 ​​(s, 1H), 7.75 - 7.73 (m, 1H), 7.51 - 7.38 (m, 2H), 6.48 (d, J = 2.1 Hz,1H), 4.23 (s, 3H), 1.53-1.43 (m, 1H), 1.09 - 0.98 (m, 1H), 0.90-0.72 (m, 2H), 0.69-0.62 (m, 1H).

[0491] Compound 49 (73mg) supercritical fluid クロマトグラフィー(カラム: (S, S)WHELK-O1 (250mm×30mm, 5μm); mobile phase: A: carbon dioxide, B: メタノール (0. 1% ammonium hydroxide), B%: 55%) compound 49-P1 (17mg, RT: 2.385min) and compound 49-P2 (21.2mg, RT: 3.855min) were prepared.

[0492] Compound 49-P1: 1 H NMR (400MHz, Methanol-d4) δ = 8.65-8.60 (m, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.15 (s, 1H), 7.70 (d, J = 7.0 Hz, 1H), 7.50-7.40 (m, 2H), 6.67 (s, 1H), 4.31 (s, 3H), 1.60-1.50 (m, 1H), 1.25-1.10 (m, 1H), 1.05-0.90 (m, 1H), 0.88-0.80 (m, 1H), 0.75-0.70 (m, 1H). MS m / z (ESI): 351.1 [M+H] + .

[0493] Compound 49-P2: 1H NMR (400MHz, Methanol-d4) δ = 8.65-8.60 (m, 1H), 8.36 (d, J = 8.5 Hz, 1H), 8.15 (s, 1H), 7.70 (d, J = 7.3 Hz, 1H), 7.50-7.40 (m, 2H), 6.67 (s, 1H), 4.31 (s, 3H), 1.60-1.50 (m, 1H), 1.20-1.10 (m, 1H), 0.99-0.84 (m, 1H), 0.83-0.75 (m, 1H), 0.74-0.68 (m, 1H). MS m / z (ESI): 351.1 [M+H] + .

[0494] Example 50, 5-(2-chlorophenyl)-1-(2-hydroxyethyl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 50)

[0495] [ka]

[0496] Step 1: Synthesis of methyl 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-imidazole-4-formate (Intermediate 50-3) Intermediate 50-1 (5 g) was dissolved in anhydrous N,N-dimethylformamide (70 mL) at 25 °C, and potassium carbonate (16.44 g) and Intermediate 50-2 (11.38 g) were added. The reaction mixture was stirred at 25 °C for 16 hours under nitrogen protection. After completion of the reaction, water (200 mL) and ethyl acetate (100 mL) were added sequentially to the reaction mixture. The organic phase was washed with saturated aqueous sodium chloride (200 mL × 2) and dried over an appropriate amount of anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (0-50% tetrahydrofuran / petroleum ether, 40 mL / min) to give the title compound (6.5 g). MS m / z (ESI): = 284.9 [M+H]+ .

[0497] Step 2: Synthesis of methyl 5-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-imidazole-4-formate (Intermediate 50-4) Intermediate 50-3 (6.5 g) was dissolved in acetic acid (130 mL) at 25 °C, and N-bromosuccinimide (NBS) (4.07 g) was added. The reaction mixture was stirred at 60 °C for 16 hours under nitrogen protection. After completion of the reaction, the reaction mixture was adjusted to pH 7 with saturated aqueous sodium bicarbonate, and water (100 mL) and ethyl acetate (200 mL) were added sequentially. The organic phase was washed with water (100 mL × 2) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to dryness under reduced pressure. The mixture was purified by column chromatography (0-30% tetrahydrofuran / petroleum ether, 60 mL / min) to give the title compound (1 g). MS m / z (ESI): = 362.9 [M+H] + .

[0498] Step 3: Synthesis of 3-bromo-N-(2-chlorophenyl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 50-5) o-Chloroaniline (2.94 g) was dissolved in N,N-dimethylformamide (50 mL), and sodium hydride (60%) (1.15 g) was added at 0-5°C. The reaction mixture was stirred at 0°C for 0.5 h. Intermediate 15-1 (5 g) was added to the reaction mixture and stirred at room temperature for 12 h. The reaction mixture was slowly poured into saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (60 mL x 2). The combined organic phase was washed with saturated brine (100 mL). The washed organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative thin-layer chromatography (silica, petroleum ether:ethyl acetate = 10:1) to give the title compound (3.5 g). MS m / z (ESI): 351.0 [M+H] + .

[0499] Step 4: Synthesis of N-(2-chlorophenyl)-6-(trifluoromethyl)-3-(trimethylstannyl)pyridin-2-amine (Intermediate 50-6) Intermediate 50-5 (500 mg) and hexamethylditin (700 mg) were dissolved in anhydrous xylene (5 mL), Pd(PPh3)4 (164 mg) was added, and the reaction mixture was stirred at 120 °C for 1 hour under nitrogen protection. After cooling to room temperature, water (50 mL) and ethyl acetate (50 mL) were added sequentially, and the organic phase was washed with water (50 mL × 2). The washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate. Preparative thin-layer chromatography (silica, petroleum ether: ethyl acetate = 100:1) afforded the title compound (300 mg). MS m / z (ESI): 437.0 [M+H] +

[0500] Step 5: Synthesis of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(2-chlorophenyl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Intermediate 50-7) Intermediate 50-6 (60 mg) was dissolved in xylene (1 mL) at 25 °C, and catalyst Pd(PPh3)4 (19.08 mg) and intermediate 50-4 (71.91 mg) were added. The reaction mixture was stirred at 140 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, and water (10 mL) and ethyl acetate (5 mL) were added sequentially. The organic phase was washed with water (10 mL × 2). The washed organic phase was dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated to dryness under reduced pressure and purified by preparative thin-layer chromatography (silica, petroleum ether / tetrahydrofuran = 5 / 1) to obtain the title compound (60 mg). MS m / z (ESI): = 523.0 [M+H] + .

[0501] Step 6: Synthesis of 5-(2-chlorophenyl)-1-(2-hydroxyethyl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 50) Intermediate 50-7 (50 mg) was dissolved in anhydrous methanol (1 mL) at 20 °C. Cesium fluoride (145.22 mg) was added to the reaction mixture, and the mixture was stirred at 20 °C for 15 h under nitrogen protection. After the reaction was completed, the mixture was concentrated to dryness under reduced pressure. Water (10 mL) and ethyl acetate (5 mL) were added sequentially, and the organic phase was washed with water (10 mL × 2). The washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate. After filtration, the mixture was concentrated to dryness under reduced pressure and purified by high-performance liquid chromatography (acidic conditions, column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: A: water (0.225% formic acid), B: acetonitrile; B%: 24% to 44%, 12 min) to obtain the title compound (8.1 mg).

[0502] 1 H NMR (400MHz, DMSO-d6) δ = 8.88 (d, J = 8.3 Hz, 1H), 8.33 (s, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.70 (dd, J = 3.4, 6.1 Hz, 1H), 7.57-7.53 (m, 2H), 7.52-7.48 (m, 1H), 5.17 (t, J = 5.3 Hz, 1H), 4.74 (t, J = 5.0 Hz, 2H), 3.93-3.85 (m, 2H). MS m / z (ESI): = 409.0 [M+H] + .

[0503] Example 51, 5-(2-chlorophenyl)-7-(trifluoromethyl)oxazole[5,4-c][1,8]naphthyridin-4(5H)-one (Compound 51)

[0504] [ka]

[0505] Step 1: Synthesis of ethyl 4-(2-((2-chlorophenyl)amino)-6-(trifluoromethyl)pyridin-3-yl)oxazole-5-carboxylate (Intermediate 51-2) Intermediate 50-6 (500 mg) and Intermediate 51-1 (700 mg) were dissolved in anhydrous xylene (5 mL), Pd(PPh3)4 (53.05 mg) was added, and the reaction mixture was stirred at 140 °C for 4 hours under nitrogen protection. After cooling to room temperature, water (50 mL) and ethyl acetate (50 mL) were added sequentially, and the organic phase was washed with water (50 mL × 2). The washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate. Preparative thin-layer chromatography (silica, petroleum ether: ethyl acetate = 3:1) afforded the title compound (100 mg). MS m / z (ESI): 412.0 [M+H] + .

[0506] Step 2: Synthesis of 5-(2-chlorophenyl)-7-(trifluoromethyl)oxazole[5,4-c][1,8]naphthyridin-4(5H)-one (compound 51) Intermediate 51-2 (100 mg) was dissolved in anhydrous acetonitrile (2 mL), KPO (257 mg) was added, and the reaction mixture was stirred at 25 °C for 2 h under nitrogen protection. After cooling to room temperature, the reaction mixture was filtered and concentrated to dryness under reduced pressure. The mixture was purified by high-pressure preparative chromatography (YMC-Actus Triart C18 column, 5 μm silica, 30 mm diameter, 150 mm length; eluting with a decreasing polarity mixture of water (containing 0.05% NH4HCO3) and acetonitrile, with a gradient of 50% to 80% acetonitrile, and elution time of 15 min) to give the title compound (20.0 mg).

[0507] MS m / z (ESI): 366.0 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ 9.27 (s, 1H), 8.88 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.79 - 7.70 (m, 1H), 7.63 - 7.58 (m, 3H).

[0508] Example 52, 3-(1-methyl-4-oxo-7-(trifluoromethyl)-1,4-dihydro-5H-imidazo[4,5-c][1,8]naphthyridin-5-yl)benzonitrile (Compound 52)

[0509] [ka]

[0510] Step 1: Synthesis of 3-((3-bromo-6-(trifluoromethyl)pyridin-2-yl)amino)benzonitrile (Intermediate 52-2) Reactant 52-1 (113.40 mg) was dissolved in N,N-dimethylformamide (10 mL), and reactant 15-1 (250 mg) was added. The reaction mixture was stirred at 60°C for 12 hours. After the reaction was completed, water (5 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (10 mL x 3 times). The organic layer was washed with saturated brine (10 mL x 3 times). The organic phase was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the title compound (190 mg). MS m / z (ESI): = 341.9 [M+H] + .

[0511] Step 2: Synthesis of 3-(1-methyl-4-oxo-7-(trifluoromethyl)-1,4-dihydro-5H-imidazo[4,5-c][1,8]naphthyridin-5-yl)benzonitrile (compound 52) Intermediate 52-2 (190 mg) was dissolved in xylene (3 mL), and intermediate 20-1 (168.25 mg) and tetrakis(triphenylphosphine)palladium (64.18 mg) were added. The reaction mixture was heated to 140 °C and reacted under nitrogen protection with stirring for 12 h. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 26% to 46%, 12 min) to obtain the title compound (6.1 mg).

[0512] MS m / z (ESI): = 370.0 [M+H] + . 1 H NMR (400MHz, METHANOL-d4) δ = 8.90 (d, J = 8.1 Hz, 1H), 8.26 (s, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.82-7.75 (m, 3H), 7.69 (d, J = 8.0 Hz, 1H), 4.35 (s, 3H)

[0513] Example 53, 5-(2-chlorophenyl)-1-(2-(dimethylamino)ethyl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 53)

[0514] [ka]

[0515] Step 1: Synthesis of 2-(5-(2-chlorophenyl)-4-oxo-7-(trifluoromethyl)-4,5-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)ethyl methanesulfonate (Intermediate 53-1) Compound 50 (100 mg) was dissolved in anhydrous dichloromethane (4 mL) at 25°C, and triethylamine (49.51 mg) was added thereto. The temperature of the reaction system was lowered to 0°C, and methanesulfonyl chloride (56.05 mg) was dissolved in anhydrous dichloromethane (1 mL) and slowly added to the reaction solution. The reaction solution was stirred at 25°C for 3 hours under nitrogen protection. After completion of the reaction, the organic phase was concentrated to dryness under reduced pressure to give the title compound (108 mg). MS m / z (ESI): = 487.0 [M+H] + .

[0516] Step 2: Synthesis of 5-(2-chlorophenyl)-1-(2-(dimethylamino)ethyl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 53) Intermediate 53-1 (36 mg) was dissolved in anhydrous dioxane (1 mL) at 20°C, and aqueous dimethylamine solution (416.71 mg) was added to the reaction solution. Under nitrogen protection, the reaction solution was stirred at 100°C for 4 hours. After completion of the reaction, the organic phase was concentrated to dryness under reduced pressure, and the residue was purified by high-performance liquid chromatography (acidic conditions, column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: A: water (0.225% formic acid), B: acetonitrile; B%: 12% to 32%, 12 min) to obtain the title compound (8.8 mg).

[0517] 1 H NMR (400MHz, METHANOL-d4) δ = 8.80 (d, J = 8.3 Hz, 1H), 8.38 (s, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.65 (dd, J =1.6, 7.7 Hz, 1H), 7.59-7.47 (m, 2H), 7.35 (dd, J =1.8, 7.5 Hz, 1H), 4.96-4.92 (m, 2H), 3.19 (t, J = 6.4 Hz, 2H), 2.58 (s, 6H). MS m / z (ESI): = 436.0 [M+H] + .

[0518] Example 54, 5-(2-chlorophenyl)-1-(2-(methylamino)ethyl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 54)

[0519] [ka]

[0520] Intermediate 53-1 (36 mg) was dissolved in anhydrous dioxane (1 mL) at 20°C, and aqueous methylamine solution (114.82 mg) was added to the reaction solution. The mixture was stirred at 100°C for 4 hours under nitrogen protection. After the reaction was completed, the organic phase was concentrated to dryness under reduced pressure, and the residue was purified by high-performance liquid chromatography (acidic conditions, column: Waters Xbridge BEH C18 100 x 25 mm x 5 μm; mobile phase: A: water (0.225% formic acid), B: acetonitrile; B%: 7% to 27%, 12 min) to obtain the title compound (5.3 mg).

[0521] 1 H NMR (400MHz, METHANOL-d4) δ = 8.79 (d, J = 8.0 Hz, 1H), 8.55 (s, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.63-7.58 (m, 1H), 7.50 (dt, J = 1.4, 7.8 Hz, 1H), 7.35 (dt, J =1.3, 7.7 Hz, 1H), 6.79-6.72 (m, 1H), 5.11 (s, 2H), 3.82-3.62 (m, 2H), 2.83 (s, 3H). MS m / z (ESI): = 422.0 [M+H] + .

[0522] Example 55, 1-(2-aminoethyl)-5-(2-chlorophenyl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 55)

[0523] [ka]

[0524] Intermediate 53-1 (36 mg) was dissolved in anhydrous dioxane (1 mL) at 20°C, and aqueous ammonia (392.64 mg) was added to the reaction solution. Under nitrogen protection, the reaction solution was stirred at 100°C for 4 hours. After completion of the reaction, the organic phase was concentrated to dryness under reduced pressure, and the residue was purified by high-performance liquid chromatography (acidic conditions, column: Waters Xbridge BEH C18 100 x 25 mm x 5 μm; mobile phase: A: water (0.225% formic acid), B: acetonitrile; B%: 17% to 37%, 12 min) to obtain the title compound (5.3 mg).

[0525] 1 H NMR (400MHz, METHANOL-d4) δ = 8.78 (d, J = 8.3 Hz, 1H), 8.37 (s, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.65-7.60 (m, 1H), 7.52 (dt, J = 1.3, 7.8 Hz, 1H), 7.42 (dt, J = 1.0, 7.7 Hz, 1H), 6.99 (d, J = 6.8 Hz, 1H), 5.09-4.96 (m, 2H), 3.65 (s, 2H). MS m / z (ESI): = 408.0 [M+H] + .

[0526] Example 56, 5-(2-chlorophenyl)-1,7-dimethyl-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 56)

[0527] [ka]

[0528] Step 1: Synthesis of 3-bromo-N-(2-chlorophenyl)-6-methylpyridin-2-amine (Intermediate 56-3) Reactant 56-2 (3.7 g) was dissolved in tetrahydrofuran (30 mL). Sodium hydride (1.9 g) was added to the reaction mixture at 0°C and stirred at room temperature for 30 min. The reaction mixture was cooled to 0°C, and reactant 56-1 (5 g) was added. The reaction mixture was stirred at 25°C for 6 h under nitrogen protection. After the reaction was completed, the reaction mixture was cooled to 0°C, and water (100 mL) and ethyl acetate (300 mL) were added sequentially. The organic phase was washed with water (60 mL × 2). The washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 100:1) to obtain the title compound (6 g). MS m / z (ESI): 297.2 [M+H] + .

[0529] Step 2: Synthesis of N-(2-chlorophenyl)-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (Intermediate 56-4) Intermediate 56-3 (3 g) and bis(pinacolato)diboron (5.1 g) were dissolved in 1,4-dioxane (30 mL), to which potassium acetate (2.9 g) and Pd(dppf)Cl2 (738 mg) were added. Under nitrogen protection, the reaction mixture was stirred at 100 °C for 15 hours. After the reaction was completed, the mixture was cooled to room temperature, and water (200 mL) and ethyl acetate (90 mL) were added sequentially. The organic phase was washed with water (30 mL x 2) and then dried over an appropriate amount of anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent, and the residue was purified by preparative high-performance liquid chromatography (column: Gemini NX C18 5 μm x 10 x 150 mm; mobile phase: A: 0.05% TFA). v / v, B: acetonitrile; B%: 40% to 45%, 15 min), the title compound (800 mg) was obtained. MS m / z (ESI): 345.2[M+H] + .

[0530] Step 3: Synthesis of methyl 5-(2-((2-chlorophenyl)amino)-6-methylpyridin-3-yl)-1-methyl-1H-imidazole-4-carboxylate (Intermediate 56-5) Intermediate 56-4 (200 mg) and intermediate 15-4 (195 mg) were dissolved in dioxane (2 mL) and water (0.4 mL), and cesium fluoride (267 mg) and Pd(PPh)Cl (39 mg) were added. The reaction mixture was stirred at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, and water (30 mL) and ethyl acetate (40 mL) were added sequentially. The organic phase was washed with saturated brine (30 mL × 2). The washed organic phase was dried over anhydrous sodium sulfate and filtered. The organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:1) to give the title compound (70 mg). MS m / z (ESI): 357.2 [M+H] + .

[0531] Step 4: Synthesis of 5-(2-chlorophenyl)-1,7-dimethyl-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 56) Intermediate 56-5 (70 mg) was dissolved in acetonitrile (2 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (89 mg) was added. The reaction mixture was stirred at 25 °C for 16 h under nitrogen protection. After completion of the reaction, water (30 mL) and ethyl acetate (40 mL) were added sequentially to the reaction mixture. The organic phase was washed with saturated brine (30 mL × 2). The washed organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) [YMC-Actus Triart C18 column, 5 μm silica, 30 mm diameter, 150 mm length; eluting with a decreasing polarity mixture of water (containing 0.05% NH4HCO3) and acetonitrile, with an acetonitrile gradient of 40% to 75%, and elution time of 13 min] to obtain the title compound (4 mg).

[0532] MS m / z (ESI): 325.2 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.20 (d, J = 8.2 Hz, 1H), 7.82 (s, 1H), 7.61 - 7.54 (m, 1H), 7.48 - 7.39 (m, 2H), 7.37 - 7.31 (m, 1H), 7.09 (d, J = 8.1 Hz, 1H), 4.19 (s, 3H), 2.41 (s, 3H).

[0533] Example 57, 1-methyl-7-(trifluoromethyl)-5-(2-(trifluoromethyl)phenyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 57)

[0534] [ka]

[0535] Step 1: Synthesis of 3-bromo-6-(trifluoromethyl)-N-[2-(trifluoromethyl)phenyl]pyridin-2-amine (Intermediate 57-2) Intermediate 15-1 (200 mg) and reactant 57-1 (123.73 mg) were dissolved in anhydrous N,N-dimethylformamide (4 mL), sodium tert-butoxide (184.50 mg) was added, and the reaction mixture was stirred at 25 °C for 16 h. After completion of the reaction, water (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate. After filtration, the organic layer was concentrated to dryness under reduced pressure, and the residue was purified by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the title compound (61.6 mg). MS m / z (ESI): 384.9 [M+H] + .

[0536] Step 2: Synthesis of 1-methyl-7-(trifluoromethyl)-5-(2-(trifluoromethyl)phenyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 57) Intermediate 57-2 (60 mg) and Intermediate 20-1 (47.2 mg) were dissolved in xylene (1 mL), tetrakis(triphenylphosphine)palladium (18.0 mg) was added, and the reaction mixture was stirred at 140°C for 16 hours under nitrogen protection. After the reaction was completed, water (10 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (5 mL x 3 times). The combined organic phases were dried over anhydrous sodium sulfate.

[0537] After filtration, the organic layer was concentrated to dryness under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (Waters Xbridge BEH C18 100 × 25 mm × 5 μm column; mobile phase: A: water (0.225% formic acid v / v), B: acetonitrile; B%: 23% to 53%, 12 min). The product was also separated by supercritical fluid chromatography (DAICEL CHIRALCEL OD-H column (250 mm × 30 mm, 5 μm column); mobile phase: [A: carbon dioxide, B: 0.1% aqueous ammonia / ethanol]; B%: 35%) to give compound 57-P1 (1.9 mg, RT: 3.805 min) and compound 57-P2 (1.9 mg, RT: 4.112 min).

[0538] Compound 57-P1: MS m / z (ESI): 413.0 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ 8.90 (d, J = 8.3 Hz, 1H), 8.25 (s, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.89-7.84 (m, 1H), 7.80-7.75 (m, 2H), 7.48 (d, J = 7.9 Hz, 1H), 4.35 (s, 3H).

[0539] Compound 57-P2: MS m / z (ESI): 413.0 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ 8.78 (d, J = 8.3 Hz, 1H), 8.14 (s, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.77-7.72 (m, 1H), 7.68-7.61 (m, 2H), 7.36 (d, J = 7.9 Hz, 1H), 4.23 (s, 3H).

[0540] Example 58, 5-(2-chloro-4-(difluoromethoxy)phenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 58)

[0541] [ka]

[0542] Step 1: Synthesis of 2-chloro-4-(difluoromethoxy)aniline (Intermediate 58-2) At 25°C, reactant 58-1 (1 g) was dissolved in anhydrous acetonitrile (10 mL), N-chlorosuccinimide (839.13 mg) was added, and the reaction mixture was stirred at 80°C for 16 hours under nitrogen protection. After completion of the reaction, ethyl acetate (20 mL) and water (40 mL) were added to the reaction mixture, which was then washed with saturated aqueous sodium chloride (40 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (0-5% ethyl acetate / petroleum ether, 60 mL / min) to obtain the title compound (830 mg). MS m / z (ESI): = 193.8 [M+H] + .

[0543] Step 2: Synthesis of 3-bromo-N-(2-chloro-4-(difluoromethoxy)phenyl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 58-3) Intermediate 58-2 (730 mg) was dissolved in anhydrous N,N-dimethylformamide (9 mL) at 25 °C, the temperature was lowered to 0 °C, sodium hydride (301.66 mg) was slowly added, and the mixture was stirred for 30 minutes. Intermediate 15-1 (982.14 mg) was then dissolved in anhydrous N,N-dimethylformamide (2 mL) and added to the reaction mixture. The reaction mixture was stirred at 25 °C for 16 hours under nitrogen protection. After completion of the reaction, the temperature was lowered to 0 °C, water (5 mL) was added, and the reaction mixture was washed with saturated aqueous sodium chloride (2 x 40 mL). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure to give the title compound (1.5 g). MS m / z (ESI): = 417 [M+H] + .

[0544] Step 3: Synthesis of N-(2-chloro-4-(difluoromethoxy)phenyl)-6-(trifluoromethyl)-3-(trimethylstannyl)pyridin-2-amine (Intermediate 58-4) Intermediate 58-3 (300 mg) was dissolved in anhydrous xylene (3 mL) at 20 °C, and Pd(PPh3)4 (83.02 mg) and hexamethyldistannane (470.78 mg) were added to the reaction mixture. Under nitrogen protection, the reaction mixture was stirred at 140 °C for 16 hours. After completion of the reaction, the reaction mixture was quenched by adding saturated cesium fluoride solution (10 mL). Ethyl acetate (10 mL) and water (20 mL) were added, followed by extraction with ethyl acetate (20 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure, and the residue was purified by thin-layer chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain the title compound (80 mg). MS m / z (ESI): = 503.0 [M+H] + .

[0545] Step 4: Synthesis of 5-(2-chloro-4-(difluoromethoxy)phenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 58) Intermediate 58-4 (80 mg) was dissolved in anhydrous xylene (1 mL) at 20 °C, and Pd(PPh3)4 (18.43 mg) and intermediate 15-4 (34.94 mg, 159.53 μmol) were added to the reaction mixture. The mixture was stirred at 140 °C for 16 h under nitrogen protection. After completion of the reaction, ethyl acetate (10 mL) and water (20 mL) were added to the reaction mixture, followed by extraction with ethyl acetate (2 x 20 mL). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure, and the residue was purified by high-performance liquid chromatography (high-performance liquid chromatography, acidic conditions, column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: A: water (0.225% formic acid), B: acetonitrile; B%: 32% to 52%, 12 min). Further purification by supercritical fluid chromatography (basic conditions, column: Phenomenex-Cellulose-2 (250 mm × 30 mm, 10 μm); mobile phase: [0.1% aqueous ammonia], B: ethanol; B%: 40% to 40%) gave compound 58-P1 (1.5 mg, RT: 2.495 min) and compound 58-P2 (1.9 mg, RT: 3.176 min).

[0546] Compound 58-P1 1 H NMR (400MHz, METHANOL-d4) δ = 8.91 (d, J = 8.3 Hz, 1H), 8.26 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.53-7.46 (m, 2H), 7.34 (dd, J = 2.5, 8.8 Hz, 1H), 7.24-6.84 (m, 1H), 4.35 (s, 3H). MS m / z (ESI): = 445.0 [M+H] + .

[0547] Compound 58-P2 1H NMR (400MHz, METHANOL-d4) δ = 8.91 (d, J = 8.3 Hz, 1H), 8.26 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.53-7.46 (m, 2H), 7.34 (dd, J = 2.5, 8.8 Hz, 1H), 7.24-6.84 (m, 1H), 4.35 (s, 3H). MS m / z (ESI): = 445.0 [M+H] + .

[0548] Example 59, 5-(4-methoxyphenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 59)

[0549] [ka]

[0550] Step 1: Synthesis of 3-bromo-N-(4-methoxyphenyl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 59-2) Intermediate 59-1 (23.64 mg) was dissolved in anhydrous N,N-dimethylformamide (0.5 mL) at 25 °C. The temperature was lowered to 0 °C. Sodium hydride (15.36 mg) was slowly added and stirred for 30 min. Intermediate 15-1 (500 mg) was dissolved in anhydrous N,N-dimethylformamide (0.5 mL) and added to the reaction mixture. The reaction mixture was stirred at 25 °C for 16 h under nitrogen protection. After completion of the reaction, the temperature was lowered to 0 °C, and the sodium hydride was quenched with aqueous sodium hydride (1 mL). Ethyl acetate (10 mL) and water (20 mL) were added to the reaction mixture, followed by extraction twice with saturated aqueous sodium chloride (20 mL). The combined organic phases were dried over anhydrous sodium sulfate. After filtration, the organic layer was concentrated to dryness under reduced pressure. The residue was purified by silica gel preparative thin-layer chromatography (petroleum ether / tetrahydrofuran = 10 / 1) to give the title compound (40 mg). MS m / z (ESI): = 346.8 [M+H]+ .

[0551] Step 2: Synthesis of 5-(4-(methoxyphenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 59) Intermediate 59-2 (40 mg) was dissolved in anhydrous xylene (1 mL) at 20 °C, and Pd(PPh3)4 (13.32 mg) and intermediate 20-1 (34.91 mg) were added to the reaction mixture. The mixture was stirred at 140 °C for 16 hours under nitrogen protection. After completion of the reaction, ethyl acetate (10 mL) and water (20 mL) were added to the reaction mixture, followed by extraction with ethyl acetate (20 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by high-performance liquid chromatography (acidic conditions, column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: A: water (0.225% formic acid), B: acetonitrile; B%: 21% to 41%, 12 min) to obtain the title compound (2.2 mg).

[0552] 1 H NMR (400MHz, METHANOL-d4) δ = 8.87 (d, J = 8.3 Hz, 1H), 8.23 ​​(s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.24-7.16 (m, 2H), 7.15-7.07 (m, 2H), 4.34 (s, 3H), 3.92 (s, 3H). MS m / z (ESI): = 375.0 [M+H] + .

[0553] Example 60, 1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4(5H)-one (compound 60).

[0554] [ka]

[0555] Step 1: Synthesis of 3-bromo-N-(1-methyl-1H-pyrazol-5-yl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 60-2) Intermediate 60-1 (18.65 mg) was dissolved in anhydrous N,N-dimethylformamide (1 mL) at 25°C. After cooling to 0°C, sodium hydride (23.04 mg) was added to the reaction mixture. The reaction mixture was stirred at 0°C for 30 minutes under nitrogen protection, and then intermediate 15-1 (50 mg) was added to the reaction mixture. The mixture was stirred at 20°C for 16 hours under nitrogen protection. After completion of the reaction, the temperature was lowered to 0°C, water (20 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic layer was concentrated to dryness under reduced pressure, and the residue was purified by preparative thin-layer chromatography (petroleum ether:tetrahydrofuran = 1:1) to obtain the title compound (45 mg). MS m / z (ESI): = 320.8 [M+H] + .

[0556] Step 2: Synthesis of N-(1-methyl-1H-pyrazol-5-yl)-6-(trifluoromethyl)-3-(trimethylstannyl)pyridin-2-amine (Intermediate 60-3) Intermediate 60-2 (45 mg) was dissolved in anhydrous xylene (1 mL) at 25 °C, and Pd(PPh3)4 (16.19 mg) and hexamethyldistannane (91.83 mg) were added to the reaction mixture. The mixture was stirred at 140 °C for 16 hours under nitrogen protection. After completion of the reaction, saturated aqueous cesium fluoride solution (10 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (10 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure, and the residue was purified by preparative thin-layer chromatography (petroleum ether:tetrahydrofuran = 1:1) to obtain the title compound (40 mg). MS m / z (ESI): = 407.1 [M+H] + .

[0557] Step 3: Synthesis of 1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4(5H)-one (Compound 60) Intermediate 60-3 (28 mg) was added to anhydrous xylene (1 mL) at 25 °C, and Pd(PPh3)4 (7.99 mg) and intermediate 15-4 (22.71 mg) were added to the reaction mixture. The mixture was then reacted at 140 °C for 16 hours under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 17% to 27%, 12 min) to obtain the title compound (1.1 mg).

[0558] 1 H NMR (400MHz, METHANOL-d4) δ = 8.91 (d, J = 8.0 Hz, 1H), 8.27 (s, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 6.38 (d, J = 2.3 Hz, 1H), 4.35 (s, 3H), 3.60 (s, 3H). MS m / z (ESI): = 349.1 [M+H] + .

[0559] Example 61, 5-(2-chlorophenyl)-1-ethyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 61)

[0560] [ka]

[0561] Step 1: Synthesis of methyl 5-bromo-1-ethyl-1H-imidazole-4-formate (Intermediate 61-2) To a solution of intermediate 61-1 (300 mg) in N,N-dimethylformamide (4 mL), potassium carbonate (606.75 mg) was added at 20°C and the mixture was stirred for 0.5 h. Iodoethane (273.89 mg) was added, and the reaction mixture was stirred at 50°C for 16 h. After completion of the reaction, the mixture was filtered to obtain a filtrate, which was then concentrated to dryness under reduced pressure. The residue was pulped and slurried in tetrahydrofuran (10 mL), filtered again to obtain a filtrate, which was then concentrated to dryness under reduced pressure. The residue was purified by thin-layer chromatography (tetrahydrofuran:petroleum ether = 2:1) to obtain the title compound (130 mg). MS m / z (ESI): 233.0 [M+H] +

[0562] Step 2: Synthesis of 5-(2-chlorophenyl)-1-ethyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 61) Intermediate 61-2 (56 mg) and intermediate 50-6 (104.63 mg) were dissolved in xylene (5 mL), tetrakis(triphenylphosphine)palladium (27.77 mg) was added, and the mixture was stirred under a nitrogen atmosphere at 140 °C for 16 hours. The reaction mixture was then cooled to 20 °C, potassium tert-butoxide (40.44 mg) was added, and the mixture was reacted at 90 °C for 16 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by thin-layer chromatography (tetrahydrofuran:petroleum ether = 3:1) and then by high-performance liquid chromatography (formic acid conditions; column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 28% to 48%, 12 min) to obtain the title compound (1.6 mg).

[0563] MS m / z (ESI): 393.0 [M+H] + . 1HNMR (400MHz, METHANOL-d4) δ = 8.79 (d, J = 8.3 Hz, 1H), 8.33 (s, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.69-7.61 (m, 1H), 7.58-7.49 (m, 2H), 7.46-7.38 (m, 1H), 4.75 (q, J = 7.3 Hz, 2H), 1.67 (t, J = 7.3 Hz, 3H).

[0564] Example 62, 5-(2,4-dichlorophenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 62)

[0565] [ka]

[0566] Step 1: Synthesis of 3-bromo-N-(2,4-dichlorophenyl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 62-2) Reactant 62-1 (273.72 mg) was dissolved in N,N-dimethylformamide (6 mL). Under nitrogen protection, sodium hydride (122.86 mg) was added to the reaction mixture at 0°C and stirred for 30 minutes. A solution of intermediate 15-1 (400 mg) in N,N-dimethylformamide (2 mL) was added to the reaction mixture at 0°C and the mixture was stirred at 20°C for 16 hours. After completion of the reaction, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash column, gradient 0% ethyl acetate / petroleum ether @ 40 mL / min) to obtain the title compound (500 mg). MS m / z (ESI): 384.8 [M+H] + .

[0567] Step 2: Synthesis of N-(2,4-dichlorophenyl)-6-(trifluoromethyl)-3-(trimethylstannyl)pyridin-2-amine (Intermediate 62-3) Intermediate 62-2 (300 mg) was dissolved in xylene (3 mL), and Pd(PPh3)4 (89.81 mg) and hexamethyldistannane (1.02 g) were added at 20 °C. Under nitrogen protection, the reaction mixture was stirred at 140 °C for 1 hour. After completion of the reaction, the mixture was quenched with saturated aqueous cesium fluoride (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ISCO®; 20 g SepaFlash® Silica Flash column, petroleum ether @ 40 mL / min) to give the title compound (190 mg). MS m / z (ESI): 470.9 [M+H] + .

[0568] Step 3: Synthesis of 5-(2,4-dichlorophenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 62) Intermediate 62-3 (150 mg) and intermediate 15-4 (104.88 mg) were dissolved in xylene (2 mL), and Pd(PPh3)4 (55.33 mg) was added at 20 °C. The reaction mixture was stirred at 140 °C for 16 h under nitrogen protection. After completion of the reaction, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative thin-layer chromatography (petroleum ether:tetrahydrofuran = 10:1). Further purification by high-performance liquid chromatography (column: YMC-Actus Triart C18 150 × 30 mm × 5 μm; mobile phase: [A: water (0.05% ammonia water v / v), B: acetonitrile]; B%: 45% to 65%, 11 min) gave the title compound (10.2 mg).

[0569] 1 H NMR (400MHz, DMSO-d6) δ = 8.88 (d, J = 8.0 Hz, 1H), 8.35 (s, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.68-7.63 (m, 1H), 7.61-7.55 (m, 1H), 4.28 (s, 3H). MS m / z (ESI): 412.9 [M+H] + .

[0570] Example 63, 5-(3-fluorophenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 63)

[0571] [ka]

[0572] Step 1: Synthesis of 3-bromo-N-(3-fluorophenyl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 63-2) Reactant 63-1 (128.00 mg) was dissolved in N,N-dimethylformamide (3 mL). Under nitrogen protection, sodium hydride (69.11 mg) was added to the reaction solution at 0°C and stirred for 30 minutes. Intermediate 15-1 (300 mg) was added to the reaction solution at 0°C and the reaction was allowed to proceed with stirring at 20°C for 16 hours. After completion of the reaction, the reaction solution was quenched with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (ISCO®; 20 g SepaFlash® Silica Flash column, petroleum ether @ 60 mL / min) to obtain the title compound (117 mg). MS m / z (ESI): 334.8 [M+H] + .

[0573] Step 2: Synthesis of 5-(3-fluorophenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 63) Intermediate 63-2 (100 mg) and intermediate 20-1 (120.54 mg) were dissolved in xylene (8 mL), and Pd(PPh3)4 (34.48 mg) was added at 20 °C. The mixture was stirred at 140 °C for 16 hours under nitrogen protection. The reaction mixture was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane:methanol = 10:1). The residue was further purified by high-performance liquid chromatography (column: YMC-Actus Triart C18 150 × 30 mm × 5 μm; mobile phase: [A: water (0.225% formic acid v / v), B: acetonitrile]; B%: 38% to 58%, 11 min) to give the title compound (8.7 mg).

[0574] 1 H NMR (400MHz, DMSO-d6) δ = 8.84 (d, J = 8.1 Hz, 1H), 8.33 (s, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.59 (dt, J = 6.5, 8.1 Hz, 1H), 7.35 (dt, J = 1.8, 8.6 Hz, 1H), 7.28 (td, J = 2.1, 9.8 Hz, 1H), 7.18 (dd, J = 0.9, 7.8 Hz, 1H), 4.27 (s, 3H). MS m / z (ESI): 363.1 [M+H] + .

[0575] Example 64, 1-methyl-5-(pyridin-3-yl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 64)

[0576] [ka]

[0577] Step 1: Synthesis of 3-bromo-N-(pyridin-3-yl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 64-2) Potassium tert-butoxide (538.61 mg) was added to a solution of intermediate 15-1 (500 mg) and intermediate 64-1 (180.7 mg) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at 25 °C for 16 h. After completion of the reaction, water (200 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (100 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 10:1) to obtain the title compound (380.7 mg). MS m / z (ESI): =317.9 [M+H] + .

[0578] Step 2: Synthesis of N-(pyridin-3-yl)-6-(trifluoromethyl)-3-(trimethylstannyl)pyridin-2-amine (Intermediate 64-3) Intermediate 64-2 (380 mg) was dissolved in xylene (4 mL), and hexamethyldistannane (782.79 mg) and tetrakis(triphenylphosphine)palladium (138.05 mg) were added. The mixture was stirred at 140°C for 4 hours under nitrogen protection. After completion of the reaction, saturated potassium fluoride solution (5 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (5 mL x 3). The organic phase was concentrated to dryness under reduced pressure, and the residue was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the title compound (50 mg). MS m / z (ESI): = 403.9 [M+H] + .

[0579] Step 3: Synthesis of 1-methyl-5-(pyridin-3-yl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 64) Intermediate 64-3 (50 mg) was dissolved in xylene (2 mL), and intermediate 15-4 (27.24 mg) and tetrakis(triphenylphosphine)palladium (14.37 mg) were added. The mixture was stirred at 140 °C for 12 h under nitrogen protection. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 9% to 29%, 12 min) to obtain the title compound (16.6 mg).

[0580] MS m / z (ESI): = 346.0 [M+H] + . 1 H NMR (400MHz, METHANOL-d4) δ = 8.91 (d, J = 8.3 Hz, 1H), 8.70 (dd, J = 1.5, 5.0 Hz, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.26 (s, 1H), 7.94-7.89 (m, 1H), 7.83-7.77 (m, 1H), 7.71 (dd, J = 4.9, 8.1 Hz, 1H), 4.36 (s, 3H).

[0581] Example 65, 5-(2-chloro-3-fluorophenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4',5':4,5]pyrido[2,3-d]pyrimidin-4-one (Compound 65)

[0582] [ka]

[0583] Step 1: Synthesis of 5-bromo-2-(trifluoromethyl)pyrimidin-4(3H)-one (Intermediate 65-2) Intermediate 65-1 (5 g) was dissolved in N,N-dimethylformamide (50 mL), and N-bromosuccinimide (6.5 g) was added to the reaction mixture. The reaction mixture was stirred at 50 °C for 18 h. After the reaction mixture was cooled to room temperature, water (60 mL) and ethyl acetate (80 mL) were added sequentially. The organic phase was washed with water (30 mL × 2). The washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the title compound (5 g). MS m / z (ESI): 243.2 [M+H] +

[0584] Step 2: Synthesis of 5-bromo-N-(2-chloro-3-fluorophenyl)-2-(trifluoromethyl)pyrimidin-4-amine (Intermediate 65-4) Intermediate 65-2 (500 mg) and 2,6-dimethylpyridine (330 mg) were dissolved in anhydrous tetrahydrofuran (5 mL), and trifluoromethanesulfonic anhydride (697 mg) was added dropwise at -78 °C. The mixture was stirred at 0 °C for 2 h. Intermediate 65-3 (896 mg) was then added to the reaction mixture. The reaction mixture was stirred at 70 °C for 3 h. HO (20 mL) and ethyl acetate (20 mL × 3) were added sequentially to the reaction mixture, and the organic phase was washed with saturated brine (30 mL × 2). The washed organic phase was dried over anhydrous sodium sulfate and purified by preparative thin-layer chromatography (silica, petroleum ether:ethyl acetate = 100:0 to 50:50) to obtain the title compound (270 mg). MS m / z (ESI): 370.2 [M+H] +

[0585] Step 3: Synthesis of (4-((2-chloro-3-fluorophenyl)amino)-2-(trifluoromethyl)pyrimidin-5-yl)boronic acid (Intermediate 65-5) Intermediate 65-4 (300 mg) and bis(pinacolato)diboron (278 mg) were dissolved in 1,4-dioxane (3 mL), potassium acetate (211 mg) and Pd(dppf)Cl (46 mg) were added, and the reaction mixture was stirred at 100 °C for 15 hours under nitrogen protection. After cooling to room temperature, water (40 mL) and ethyl acetate (80 mL) were added sequentially. The organic phase was washed with water (30 mL × 2) and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give the title compound (200 mg). MS m / z (ESI): 336.1 [M+H] +

[0586] Step 4: Synthesis of 5-(2-chloro-3-fluorophenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4',5':4,5]pyrido[2,3-d]pyrimidin-4-one (compound 65) Intermediate 65-5 (200 mg) and intermediate 15-4 (195 mg) were dissolved in dioxane (2 mL) and water (0.4 mL), and cesium fluoride (267 mg) and Pd(dtbpf)Cl (39 mg) were added. The reaction mixture was stirred at 100 °C for 16 hours under nitrogen protection. After cooling to room temperature, water (30 mL) and ethyl acetate (40 mL) were added sequentially. The organic phase was washed with saturated brine (30 mL × 2). The washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (column: Gemini NX C18 5 μm × 10 × 150 mm; mobile phase: A: 0.05% TFA). v / v, B: acetonitrile; B%: 40% to 45%, 12 min), the title compound (13 mg) was obtained.

[0587] MS m / z (ESI): 398.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.42 (s, 1H), 7.69 - 7.60 (m, 2H), 7.47 (d, J = 7.3 Hz, 1H), 4.32 (s, 3H).

[0588] Example 66, 5-(2-chloro-3-fluorophenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one (Compound 66)

[0589] [ka]

[0590] Intermediate 45-3 (50 mg) and intermediate 66-1 (70 mg) were dissolved in anhydrous dioxane (1 mL), and cesium carbonate (163 mg), XantPhos (19 mg), and Pd(dba) (10 mg) were added. The reaction mixture was stirred at 100 °C for 12 h under nitrogen protection. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The concentrated residue was purified by preparative high-performance liquid chromatography (HPLC) using a YMC-Actus Triart C18 column (5 μm silica, 30 mm diameter, 150 mm length) with a decreasing polarity mixture of water (containing 0.05% NH4HCO3) and acetonitrile as the eluent, with a gradient of 55% to 75% acetonitrile, and a 12-minute elution time. The title compound (2 mg) was obtained.

[0591] MS m / z (ESI): 396.0 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.21 (d, J = 8.4 Hz, 1H), 7.89 (s, 1H), 7.57 - 7.50 (m, 2H), 7.43 - 7.41 (m, 1H), 7.26 - 7.21 (m, 1H), 6.88 (s, 1H), 4.28 (s, 3H).

[0592] Example 67, 5-(2-ethylpyridin-3-yl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 67)

[0593] [ka]

[0594] Step 1: Synthesis of 3-nitro-2-vinyl-pyridine (Intermediate 67-3) Under nitrogen protection, intermediate 67-1 (2.5 g) was added to dioxane (50 mL) and water (16 mL), and intermediate 67-2 (4.22 g), PdCl(dppf) (10.62 mg), and cesium carbonate (10.28 g) were added to the reaction mixture. Under nitrogen protection, the reaction mixture was stirred at 90 °C for 16 hours. After completion of the reaction, water (40 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (40 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent, and the residue was purified by flash chromatography (ISCO®; 20 g SepaFlash® Silica Flash chromatography column, gradient 0-12% ethyl acetate / petroleum ether @ 80 mL / min) to give the title compound (1.98 g). MS m / z (ESI): 150.9 [M+H] + .

[0595] Step 2: Synthesis of 2-ethylpyridin-3-amine (Intermediate 67-4) Under nitrogen protection, intermediate 67-3 (140.49 mg) was dissolved in anhydrous methanol (50 mL), and wet palladium-carbon (300 mg) was added to the reaction solution, followed by stirring under a hydrogen atmosphere at 45° C. for 16 hours. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent, yielding the title compound (1.22 g). MS m / z (ESI): 123.2 [M+H] + .

[0596] Step 3: Synthesis of 3-bromo-N-(2-ethylpyridin-3-yl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 67-5) Under nitrogen protection, intermediate 67-4 (140.49 mg) was dissolved in anhydrous N,N-dimethylformamide (3 mL) and cooled to 0 °C. Sodium hydride (69.00 mg) was added to the reaction mixture, and the mixture was stirred at 0 °C for 30 min. Intermediate 15-1 (300 mg) was dissolved in anhydrous N,N-dimethylformamide (2 mL) and added to the reaction mixture. The reaction mixture was stirred at 25 °C for 16 h under nitrogen protection. After completion of the reaction, water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent, and the residue was purified using a flash silica gel column (ISCO®; 12 g SepaFlash® Silica Flash chromatography column, gradient 0-13% ethyl acetate / petroleum ether @ 40 mL / min) to give the title compound (31.8 mg). MS m / z (ESI): 345.9 [M+H] + .

[0597] Step 4: Synthesis of 5-(2-ethylpyridin-3-yl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 67) Under nitrogen protection, intermediate 67-5 (31.8 mg) was added to anhydrous xylene (1 mL), and tetrakis(triphenylphosphine)palladium (10.62 mg) and intermediate 20-1 (27.83 mg) were added to the reaction mixture. The reaction mixture was then stirred at 140 °C for 16 hours under nitrogen protection. After completion of the reaction, water (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 100 x 25 mm x 5 μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 11% to 41%, 12 min) to obtain the title compound (7 mg). The solvent was removed by lyophilization, and the residue was purified by preparative supercritical fluid chromatography (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: [A: supercritical carbon dioxide, B: ethanol (0.1% aqueous ammonia)]; B%: 25% to 25%) to give compound 67-P1 (2.03 mg, RT: 4.35 min) and compound 67-P2 (2.02 mg, RT: 5.01 min).

[0598] Compound 67-P1 MS m / z (ESI): 374.1 [M+H] + . 1 H NMR (400MHz, METHANOL-d4) δ 8.93 (d, J = 8.0 Hz, 1H), 8.66 (d, J = 3.5 Hz, 1H), 8.28 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.52 (dd, J = 4.9, 7.9 Hz, 1H), 4.36 (s, 3H), 2.48 (q, J = 7.5 Hz, 2H), 1.08 (t, J = 7.5 Hz, 3H).

[0599] Compound 67-P2 MS m / z (ESI): 374.1 [M+H] + . 1 H NMR (400MHz, METHANOL-d4) δ 8.93 (d, J = 8.3 Hz, 1H), 8.66 (dd, J = 1.5, 5.0 Hz, 1H), 8.28 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.72 (dd, J = 1.5, 7.8 Hz, 1H), 7.52 (dd, J = 4.9, 7.9 Hz, 1H), 4.36 (s, 3H), 2.48 (q, J = 7.7 Hz, 2H), 1.08 (t, J = 7.5 Hz, 3H).

[0600] Example 68, 5-(2-methoxypyridin-3-yl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 68)

[0601] [ka]

[0602] Step 1: Synthesis of 3-bromo-N-(2-methoxypyridin-3-yl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 68-2) Under nitrogen protection, intermediate 68-1 (238.33 mg) was dissolved in anhydrous N,N-dimethylformamide (5 mL) and cooled to 0 °C. Sodium hydride (115.19 mg) was added to the reaction mixture and stirred at 0 °C for 30 min. Intermediate 15-1 (500 mg) was dissolved in anhydrous N,N-dimethylformamide (3 mL) and added to the reaction mixture. The reaction mixture was stirred at 25 °C for 16 h under nitrogen protection. After completion of the reaction, water (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified using a flash silica gel column (ISCO®; 12 g SepaFlash® Silica Flash chromatography column, gradient 0-5% ethyl acetate / petroleum ether @ 40 mL / min) to give the title compound (231.4 mg). MS m / z (ESI): 347.9 [M+H] + .

[0603] Step 2: Synthesis of 5-(2-methoxypyridin-3-yl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 68) Under nitrogen protection, intermediate 68-2 (231.4 mg) was added to anhydrous xylene (7 mL), and tetrakis(triphenylphosphine)palladium (76.81 mg) and intermediate 20-1 (201.37 mg) were added to the reaction mixture. Under nitrogen protection, the reaction mixture was stirred at 140°C for 16 hours. After completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure to remove the solvent. The residue was purified by thin-layer chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the crude product (20 mg). The crude product was added to anhydrous xylene (7 mL), and potassium tert-butoxide (30 mg) was added to the reaction mixture, and the reaction mixture was stirred at 100°C for 2 hours. After completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure to remove the solvent. The residue was purified by preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 23% to 43%, 12 min) to give the title compound (6.3 mg).

[0604] MS m / z (ESI): 376.1 [M+H] + . 1 H NMR (400MHz, METHANOL-d4) δ 8.89 (d, J = 8.1 Hz, 1H), 8.32 (dd, J = 1.7, 5.1 Hz, 1H), 8.25 (s, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.73 (dd, J = 1.8, 7.5 Hz, 1H), 7.20 (dd, J = 5.1, 7.4 Hz, 1H), 4.35 (s, 3H), 3.81 (s, 3H).

[0605] Example 69, 5-(5-(difluoromethoxy)pyridin-2-yl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 69)

[0606] [ka]

[0607] Step 1: Synthesis of 3-bromo-N-(5-(difluoromethoxy)pyridin-2-yl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 69-2) Reactant 69-1 (245.93 mg) was dissolved in N,N-dimethylformamide (10 mL), sodium hydride (92.14 mg) was added at 0°C, and the mixture was stirred for 30 minutes. Intermediate 15-1 (400 mg) was added at 0°C. The reaction mixture was stirred at 20°C for 16 hours under nitrogen protection. After completion of the reaction, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash column, gradient 0-5% ethyl acetate / petroleum ether @ 40 mL / min) to obtain the title compound (400 mg). MS m / z (ESI): 383.8 [M+H] + .

[0608] Step 2: Synthesis of 5-(5-(difluoromethoxy)pyridin-2-yl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 69) Intermediate 69-2 (100 mg) and intermediate 20-1 (119.50 mg) were dissolved in xylene (5 mL), and Pd(PPh3)4 (30.08 mg) was added at 20 °C. The reaction mixture was stirred at 140 °C for 16 hours under nitrogen protection. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane:methanol = 10:1). Further purification was performed by high-performance liquid chromatography (column: Phenomenex C18 150 × 30 mm × 5 μm; mobile phase: [A: water (aqueous ammonia + ammonium bicarbonate)], B: acetonitrile]; B%: 35% to 55%, 2 min) to obtain the title compound (46.3 mg).

[0609] 1H NMR (400MHz, DMSO-d6) δ = 8.86 (d, J = 8.2 Hz, 1H), 8.58 (d, J = 2.7 Hz, 1H), 8.35 (s, 1H), 7.95 (dd, J = 2.8, 8.6 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.50 (t, J = 73.2 Hz, 1H), 4.27 (s, 3H). MS m / z (ESI): 412.1 [M+H] + .

[0610] Example 70, 5-(3-fluoro-2-methoxyphenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 70)

[0611] [ka]

[0612] Step 1: Synthesis of 3-bromo-N-(3-fluoro-2-methoxyphenyl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 70-2) Under nitrogen protection, intermediate 70-1 (270.97 mg) was dissolved in anhydrous N,N-dimethylformamide (5 mL) and cooled to 0 °C. Sodium hydride (115.19 mg, active content 60%) was added to the reaction mixture, and the mixture was stirred at 0 °C for 30 min. Intermediate 15-1 (500 mg) was dissolved in anhydrous N,N-dimethylformamide (3 mL) and added to the reaction mixture. The reaction mixture was stirred at 25 °C for 16 h under nitrogen protection. After completion of the reaction, water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent, and the residue was purified using a flash silica gel column (ISCO®; 12 g SepaFlash® Silica Flash chromatography column, gradient 0-5% ethyl acetate / petroleum ether @ 40 mL / min) to give the title compound (231.4 mg). MS m / z (ESI): 365.0 [M+H] + .

[0613] Step 2: Synthesis of 5-(3-fluoro-2-methoxyphenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 70) Under nitrogen protection, intermediate 70-2 (100 mg) was added to anhydrous xylene (7 mL), and tetrakis(triphenylphosphine)palladium (41.96 mg) and intermediate 20-1 (110.00 mg) were added to the reaction solution. Under nitrogen protection, the reaction solution was stirred at 140°C for 16 hours. After completion of the reaction, the reaction solution was filtered and concentrated under reduced pressure to remove the solvent. The residue was purified by preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 24% to 44%, 12 min) and also by preparative supercritical fluid chromatography (column: DAICEL CHIRALCEL OD-H (250 mm × 30 mm, 5 μm); mobile phase: [A: supercritical carbon dioxide, B: ethanol (0.1% aqueous ammonia)]; B%: 40% to 40%) to give compound 70-P1 (3.5 mg, RT: 5.883 min) and compound 70-P2 (3.8 mg, RT: 6.298 min).

[0614] Compound 70-P1 MS m / z (ESI): 393.1 [M+H] + . 1 H NMR (400MHz, METHANOL-d4) δ 8.89 (d, J = 8.1 Hz, 1H), 8.26 (s, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.37-7.33 (m, 1H), 7.26 (dt, J = 5.5, 8.1 Hz, 1H), 7.10 (d, J = 7.9 Hz, 1H), 4.35 (s, 3H), 3.72 (d, J = 1.9 Hz, 3H).

[0615] Compound 70-P2 MS m / z (ESI): 393.1 [M+H] + . 1H NMR (400MHz, METHANOL-d4) δ 8.77 (d, J = 8.1 Hz, 1H), 8.13 (s, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.30-7.22 (m, 1H), 7.13 (dt, J = 5.3, 8.2 Hz, 1H), 6.98 (d, J = 7.9 Hz, 1H), 4.23 (s, 3H), 3.60 (d, J = 1.9 Hz, 3H).

[0616] Example 71, 5-[(4-(difluoromethoxy)-3-fluorophenyl]-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 71)

[0617] [ka]

[0618] Step 1: Synthesis of 3-bromo-N-[(4-(difluoromethoxy)-3-fluorophenyl]-6-(trifluoromethyl)pyridin-2-amine (Intermediate 71-2) Intermediate 15-1 (300 mg) and Intermediate 71-1 (203.69 mg) were dissolved in anhydrous N,N-dimethylformamide (5 mL), and potassium tert-butoxide (322.60 mg) was added to the reaction mixture. The reaction mixture was stirred at 25°C for 16 hours. After completion of the reaction, water (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified using a flash silica gel column (ISCO®; 12 g SepaFlash® Silica Flash chromatography column, gradient 0-10% ethyl acetate / petroleum ether @ 40 mL / min) to give the title compound (218.9 mg). MS m / z (ESI): 401.0 [M+H] + .

[0619] Step 2: Synthesis of 5-[4-(difluoromethoxy)-3-fluorophenyl]-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 71) Under nitrogen protection, intermediate 71-2 (100 mg) was added to anhydrous xylene (4 mL), and tetrakis(triphenylphosphine)palladium (28.81 mg) and intermediate 20-1 (75.53 mg) were added to the reaction mixture. The reaction mixture was then stirred at 140°C for 16 hours under nitrogen protection. After completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure to remove the solvent. The residue was purified by preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 100 x 25 mm x 5 μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 31% to 51%, 14 min) to obtain the title compound (25.8 mg).

[0620] MS m / z (ESI): 429.1 [M+H] + . 1 H NMR (400MHz, METHANOL-d4) δ 8.89 (d, J = 8.3 Hz, 1H), 8.25 (s, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.51 (t, J = 8.5 Hz, 1H), 7.34 (dd, J = 2.3, 10.9 Hz, 1H), 7.21 (s, 1H), 7.00 (t, J = 70.4 Hz, 1H), 4.35 (s, 3H).

[0621] Example 72, 1-(methyl-d3)-5-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 72)

[0622] [ka]

[0623] Step 1: Synthesis of N-(2-methylpyridin-3-yl)-6-(trifluoromethyl)-3-(trimethylstannyl)pyridin-2-amine Intermediate 20-3 (300 mg) was dissolved in xylene (8 mL), and hexamethyldistannane (591.88 mg) and tetrakis(triphenylphosphine)palladium (104.38 mg) were added. The mixture was sealed under nitrogen and heated to 140 °C for 1 h. After the reaction was completed, the mixture was cooled to 20 °C, quenched with potassium fluoride solution (20 mL), extracted with ethyl acetate (10 mL), and the organic phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel column (ISCO®; 12 g SepaFlash® silica gel column, eluent: 10-35% ethyl acetate / petroleum ether gradient @ 30 mL / min) to give the title compound (130 mg). MS m / z (ESI): 417.9 [M+H] + .

[0624] Step 2: Synthesis of 1-(methyl-d3)-5-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 72) Intermediate 72-1 (130 mg) and intermediate 44-2 (69.39 mg) were dissolved in xylene (5 mL), tetrakis(triphenylphosphine)palladium (36.11 mg) was added, and the mixture was stirred at 140 °C for 16 h under nitrogen protection. After the reaction was completed, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by thin-layer chromatography (tetrahydrofuran:dichloromethane = 1:1). The residue was also purified by preparative high-performance liquid chromatography (formic acid conditions; column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 4% to 34%, 12 min) to obtain the title compound (22.3 mg).

[0625] MS m / z (ESI): 363.0 [M+H] + . 1H NMR (400MHz, METHANOL-d4) δ = 8.91 (d, J = 8.3 Hz, 1H), 8.58 (d, J = 3.8 Hz, 1H), 8.25 (s, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.76-7.70 (m, 1H), 7.50 (dd, J = 5.0, 7.8 Hz, 1H), 2.19 (s, 3H).

[0626] Example 73, 2-chloro-3-(1-methyl-4-oxo-7-(trifluoromethyl)-1,4-dihydro-5H-imidazo[4,5-c][1,8]naphthyridin-5-yl)benzonitrile (Compound 73)

[0627] [ka]

[0628] Step 1: Synthesis of 3-amino-2-chlorobenzonitrile (Intermediate 73-2) Intermediate 73-1 (500 mg) was dissolved in absolute ethanol (9 mL) and water (3 mL) at 25°C, and iron powder (458.84 mg) and ammonium chloride (732.50 mg) were added to the reaction solution. Under nitrogen protection, the reaction solution was stirred at 70°C for 16 hours. After the reaction was completed, the temperature was lowered to 25°C, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent, yielding the title compound (375 mg). MS m / z (ESI): = 153.1 [M+H] + .

[0629] Step 2: Synthesis of 3-((3-bromo-6-(trifluoromethyl)pyridin-2-yl)amino)-2-chlorobenzonitrile (Intermediate 73-3) At 25°C, intermediate 73-2 (256.03 mg) was dissolved in N,N-dimethylformamide (5 mL). After cooling to 0°C, sodium hydride (117.96 mg, active content 60%) was added to the reaction mixture. Under nitrogen protection, the reaction mixture was stirred at 0°C for 0.5 hours, and intermediate 15-1 (150 mg) was added to the reaction mixture. After completion of the reaction, water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent, yielding the title compound (120 mg). MS m / z (ESI): = 375.7 [M+H] + .

[0630] Step 3: Synthesis of 2-chloro-3-(1-methyl-4-oxo-7-(trifluoromethyl)-1,4-dihydro-5H-imidazo[4,5-c][1,8]naphthyridin-5-yl)benzonitrile (Compound 73) Intermediate 73-3 (120 mg) was added to anhydrous xylene (5 mL) at 25 °C, and tetrakis(triphenylphosphine)palladium (36.82 mg) and intermediate 20-1 (144.81 mg) were added to the reaction mixture. The reaction mixture was then reacted at 140 °C for 16 hours under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure to remove the solvent. The residue was purified by preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 25% to 45%, 12 min) to obtain the title compound (65 mg).

[0631] Compound 73 was purified by preparative supercritical fluid chromatography (column: DAICEL CHIRALCEL OJ (250 mm × 30 mm, 10 μm); mobile phase: A: carbon dioxide, B: ethanol (0.1% aqueous ammonia)) to give compound 73-P1 (13.3 mg, RT: 3.105 min) and compound 73-P2 (11 mg, RT: 3.557 min).

[0632] Compound 73-P1 MS m / z (ESI): = 404.0 [M+H] + . 1 H NMR (400MHz, METHANOL-d4) δ = 8.93 (d, J = 8.0 Hz, 1H), 8.28 (s, 1H), 8.03 (dd, J = 1.5, 7.8 Hz, 1H), 7.86-7.80 (m, 2H), 7.77-7.71 (m, 1H), 4.36 (s, 3H). MS m / z (ESI): = 404.0 [M+H] + .

[0633] Compound 73-P2 1 H NMR (400MHz, METHANOL-d4) δ = 8.93 (d, J = 8.3 Hz, 1H), 8.28 (s, 1H), 8.03 (dd, J = 1.6, 7.7 Hz, 1H), 7.85-7.79 (m, 2H), 7.77-7.69 (m, 1H), 4.36 (s, 3H).

[0634] Example 74, 1-((1-methyl-1H-pyrazol-4-yl)methyl)-5-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 74)

[0635] [ka]

[0636] Step 1: Synthesis of 4-(chloromethyl)-1-methyl-1H-pyrazole (Intermediate 74-2) The reactant 74-1 (2 g) was dissolved in dichloromethane (23 mL), thionyl chloride (3.18 g) was added at 0° C., and the reaction mixture was stirred at 25° C. for 16 hours under nitrogen protection. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the title compound (3.02 g) as a crude product.

[0637] 1 H NMR (400MHz, DMSO-d6) δ = 7.79 (s, 1H), 7.48 (s, 1H), 4.68 (s, 2H), 3.81 (s, 3H)

[0638] Step 2: Synthesis of methyl 5-bromo-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-imidazole-4-formate (Intermediate 74-4) Intermediate 74-2 (300 mg) and intermediate 74-3 (471.01 mg) were dissolved in acetonitrile (10 mL), and sodium iodide (344.39 mg) and potassium carbonate (952.60 mg) were added at 25° C. The reaction mixture was stirred at 80° C. for 24 hours. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain the title compound (201 mg).

[0639] 1 H NMR (400MHz, DMSO-d6)δ NMR (400MHz, DMSO-48 (s, 1H), 4.68 (s, 2H), 3.81 (s, 3H) 3.79 (s, 3H), 3.75 (s, 3H). MS m / z (ESI): = 299.0 [M+H] + .

[0640] Step 3: Synthesis of 1-((1-methyl-1H-pyrazol-4-yl)methyl)-5-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 74) Intermediate 74-4 (100 mg) and intermediate 72-1 (139.08 mg) were dissolved in xylene (5 mL), and tetrakis(triphenylphosphine)palladium (38.63 mg) was added at 25°C under nitrogen protection. The mixture was stirred at 140°C for 16 hours under nitrogen protection. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) and further purified by high-performance liquid chromatography (column: C18-1 150 × 30 mm × 5 μm; mobile phase: [A: water (aqueous ammonia + ammonium bicarbonate), B: acetonitrile]; B%: 25% to 45%, 2 min) to obtain the title compound (29.4 mg).

[0641] 1 H NMR (400MHz, DMSO-d6) δ = 8.77 (d, J = 8.2 Hz, 1H), 8.56 (dd, J = J = 1.4, 4.8 Hz, 1H), 8.49 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.75 (s, 1H), 7.70 (dd, J = 1.4, 7.9 Hz, 1H), 7.50 (s, 1H), 7.43 (dd, J = 4.8, 7.9 Hz, 1H), 5.79 (s, 2H), 3.77 (s, 3H), 2.09 (s, 3H). MS m / z (ESI): = 440.2 [M+H] + .

[0642] Example 75, 1-methyl-5-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4',5':4,5]pyrido[2,3-d]pyrimidin-4-one (Compound 75)

[0643] [ka]

[0644] Step 1: Synthesis of 5-bromo-N-(2-methylpyridin-3-yl)-2-(trifluoromethyl)pyrimidin-4-amine (Intermediate 75-2) Intermediate 65-2 (500 mg) and 2,6-dimethylpyridine (330 mg) were dissolved in anhydrous tetrahydrofuran (5 mL), and trifluoromethanesulfonic anhydride (697 mg) was added dropwise at -78 °C. The mixture was allowed to react at 0 °C for 2 h. Intermediate 75-1 (667 mg) was then added to the reaction mixture. The reaction mixture was stirred at 70 °C for 3 h. HO (20 mL) and ethyl acetate (20 mL × 3) were added sequentially to the reaction mixture, and the organic phase was washed with saturated brine (30 mL × 2). The washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate and purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 100:0 to 50:50) to obtain the title compound (230 mg). MS m / z (ESI): 333.2 [M+H] + .

[0645] Step 2: Synthesis of (4-((2-methylpyridin-3-yl)amino)-2-(trifluoromethyl)pyrimidin-5-yl)boronic acid (Intermediate 75-3) Intermediate 75-2 (220 mg) and bis(pinacolato)diboron (252 mg) were dissolved in 1,4-dioxane (3 mL), and potassium acetate (194 mg) and Pd(dppf)Cl (42 mg) were added. Under nitrogen protection, the reaction mixture was stirred at 100 °C for 15 hours. After cooling to room temperature, water (40 mL) and ethyl acetate (80 mL) were added sequentially. The organic phase was washed with water (30 mL × 2). The washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain the title compound (160 mg). MS m / z (ESI): 299.1 [M+H] + .

[0646] Step 3: Synthesis of 1-methyl-5-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4',5':4,5]pyrido[2,3-d]pyrimidin-4-one (compound 75) Intermediate 75-3 (160 mg) and intermediate 15-4 (175 mg) were dissolved in dioxane (2 mL) and water (0.4 mL), and cesium fluoride (156 mg) and Pd(dtbpf)Cl (39 mg) were added. The reaction mixture was stirred at 100 °C for 16 hours under nitrogen protection. After cooling to room temperature, water (30 mL) and ethyl acetate (40 mL) were added sequentially. The organic phase was washed with saturated brine (30 mL × 2). The washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (column: Gemini NX C18 5 μm × 10 × 150 mm; mobile phase: A: 0.05% TFA). v / v, B: acetonitrile; B%: 40% to 45%, 12 min), the title compound (15 mg) was obtained.

[0647] MS m / z (ESI): 361.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.63 - 8.57 (m, 1H), 8.41 (s, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.46 (s, 1H), 4.31 (s, 3H), 2.12 (s, 3H).

[0648] Example 76, 1-methyl-5-(pyrimidin-5-yl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 76)

[0649] [ka]

[0650] Step 1: Synthesis of 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (Intermediate 76-3) Intermediate 76-1 (100 g) was dissolved in THF (1000 mL), and intermediate 76-2 (124 g) was added to the reaction mixture. Under nitrogen protection, the reaction mixture was stirred at -78 °C for 10 min. Lithium diisopropylamide (318 mL) was added in several portions, and the reaction mixture was stirred at 25 °C for 4 h. The reaction mixture was cooled to 0 °C, and aqueous HCl was added to adjust the pH to 4. The mixture was then extracted with ethyl acetate (1500 mL × 2). The combined organic phase was washed with brine (300 mL × 2). The washed organic phase was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and distilled under reduced pressure (90 °C) to obtain the title compound (130 g). MS m / z (ESI): 292.1 [M+H] + .

[0651] Step 2: Synthesis of methyl 5-(2-fluoro-6-(trifluoromethyl)pyridin-3-yl)-1-methyl-1H-imidazole-4-carboxylate (Intermediate 76-4) Intermediate 15-4 (29.0 g) and Intermediate 76-3 (58 g) were dissolved in 1,4-dioxane (250 mL) and water (25 mL). Cesium fluoride (60.25 g), Ruphos (6.2 g), and Ruphos Pd G3 (11.10 g) were added, and the reaction mixture was stirred at 100 °C for 4 h under nitrogen protection. After cooling to room temperature, 290 mL of 6 M K2CO3 aqueous solution was added, and the mixture was stirred at 25 °C for 0.5 h. The mixture was extracted with ethyl acetate (300 mL × 2). The combined organic phase was washed with brine (300 mL × 2). The washed organic phase was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by preparative thin-layer chromatography (silica, dichloromethane:methanol = 20:1) to give the title compound (22.3 g). MS m / z (ESI): 304.1 [M+H] + .

[0652] Step 3: Synthesis of 1-methyl-5-(pyrimidin-5-yl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 76) Intermediate 76-4 (100 mg) and intermediate 76-5 (31 mg) were dissolved in anhydrous tetrahydrofuran (2 mL), and lithium bis(trimethylsilyl)amide (LiHMDS) (1 mL, 1.0 N) was added dropwise at 0 °C. After the addition was complete, the mixture was stirred at 25 °C for 1 hour. After the reaction was complete, saturated aqueous ammonium chloride solution (8 mL) and ethyl acetate (8 mL × 3) were added sequentially to the reaction mixture. The organic phase was washed with water (8 mL × 2). The washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate and filtered. The organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative high-performance liquid chromatography (column: Gemini NX C18 5 μm × 10 × 150 mm; mobile phase: A: water (0.225% formic acid v / v), B: acetonitrile; B%: 30% to 50%) to obtain the title compound (6 mg).

[0653] MS m / z (ESI): 347.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.95 (s, 2H), 8.91 (d, J = 8.2 Hz, 1H), 8.38 (s, 1H), 7.89 (d, J = 8.2 Hz, 1H), 4.30 (s, 3H).

[0654] Example 77, Synthesis of 1-methyl-5-(pyrazin-2-yl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 77)

[0655] [ka]

[0656] Step 1: Synthesis of methyl 1-methyl-5-(2-(pyrazin-2-ylamino)-6-(trifluoromethyl)pyridin-3-yl)-1H-imidazole-4-carboxylate (Intermediate 77-1) Intermediate 76-4 (100 mg) and 2-aminopyrazine (31 mg) were dissolved in anhydrous tetrahydrofuran (2 mL). Lithium bis(trimethylsilyl)amide (1 mL) was added dropwise at 0 °C. After the addition was complete, the mixture was stirred at 25 °C for 1 h. After the reaction was complete, saturated aqueous ammonium chloride (8 mL) and ethyl acetate (8 mL × 3) were added sequentially. The organic phase was washed with water (8 mL × 2). The washed organic phase was dried over anhydrous sodium sulfate and filtered. The organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by flash chromatography (ISCO®; 20 g SepaFlash® Silica Flash chromatography column, gradient 0–5% methanol / dichloromethane, 80 mL / min) to give the title compound (60.0 mg). MS m / z (ESI): 379.0 [M+H] +

[0657] Step 2: Synthesis of 1-methyl-5-(pyrazin-2-yl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 77) Intermediate 77-2 (100 mg) was dissolved in anhydrous acetonitrile (3 mL), potassium phosphate (100 mg) was added, and the mixture was stirred at 80 °C for 4 hours. After the reaction was completed, saturated aqueous ammonium chloride (8 mL) and ethyl acetate (8 mL × 3) were added sequentially. The organic phase was washed with water (8 mL × 2). The washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate and filtered. The organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 33% to 50%, 12 min) to obtain the title compound (23.5 mg). MS m / z (ESI): 347.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.93 - 8.81 (m, 4H)8.38 (s, 1H), 7.88 (d, J = 8.2 Hz, 1H), 4.30 (s, 3H).

[0658] Example 78, 5-(2,3-difluorophenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 78)

[0659] [ka]

[0660] Intermediate 76-4 (50 mg) and intermediate 78-1 (22 mg, 0.17 mmol) were dissolved in tetrahydrofuran (1 mL), and the reaction mixture was stirred at 0 °C for 10 min under nitrogen protection. Lithium bis(trimethylsilyl)amide (0.34 mL) was added to the reaction mixture. The reaction mixture was stirred at 24 °C for 2 h. The temperature of the reaction mixture was lowered to 0 °C, and 5 mL of H2O was added to quench the reaction. Water (15 mL) and ethyl acetate (30 mL) were added sequentially, and the organic phase was washed with saturated brine (30 mL × 2). The washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate and concentrated under reduced pressure to obtain 50 mg of crude product. The crude product was purified by preparative high-performance liquid chromatography (column: Gemini NX C18 5 μm × 10 × 150 mm; mobile phase: A: 0.05% TFA). v / v, B: acetonitrile; B%: 40% to 45%, 12 min), the title compound (5 mg) was obtained.

[0661] MS m / z (ESI): 381.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J = 8.2 Hz, 1H), 8.36 (s, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.70 - 7.58 (m, 1H), 7.47 - 7.30 (m, 2H), 4.27 (s, 3H).

[0662] Example 79, 1-methyl-5-(4-methylpyrimidin-5-yl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 79)

[0663] [ka]

[0664] Step 1: Synthesis of 1-methyl-5-(4-methylpyrimidin-5-yl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 79) Intermediate 76-4 (80 mg) and intermediate 79-1 (29 g) were dissolved in tetrahydrofuran (2 mL), and lithium bis(trimethylsilyl)amide (1 mol / L in THF, 0.4 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 3 h. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by preparative high-performance liquid chromatography (column: Gemini NX C18 5 μm × 10 × 150 mm; mobile phase: A: water (0.225% formic acid v / v), B: acetonitrile; B%: 40% to 60%, 12 min) to give the title compound (31 mg).

[0665] MS m / z (ESI): 361.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.91 (d, J = 8.2 Hz, 1H), 8.74 (s, 1H), 8.38 (s, 1H), 7.89 (d, J = 8.2 Hz, 1H), 4.29 (s, 3H), 2.15 (s, 3H).

[0666] Example 80, 5-(2-chloro-3-ethynylphenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 80)

[0667] [ka]

[0668] Step 1: Synthesis of 2-chloro-3-((triisopropylsilyl)ethynyl)aniline (Intermediate 80-3) Intermediate 80-1 (316 mg), Intermediate 80-2 (562 mg), tetrakis(triphenylphosphine)palladium (707 mg), and cesium carbonate (998 mg) were dissolved in anhydrous tetrahydrofuran (8 mL) and reacted at 60 °C for 10 h. Saturated aqueous ammonium chloride solution (20 mL) and ethyl acetate (20 mL × 2) were added sequentially to the reaction mixture, and the organic phase was washed with saturated brine (20 mL × 2). The washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The residue was purified by preparative thin-layer chromatography (silica, petroleum ether:ethyl acetate = 4:1) to obtain the title compound (174 mg). MS m / z (ESI): 308.1 [M+H] + .

[0669] Step 2: Synthesis of 5-(2-chloro-3-((triisopropylsilyl)ethynyl)phenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Intermediate 80-4) Intermediate 80-3 (125 mg) and intermediate 76-4 (152 mg) were dissolved in anhydrous tetrahydrofuran (4 mL), and a THF solution of lithium bis(trimethylsilyl)amide (1 mol / L, 0.8 mL) was added dropwise thereto at 0° C. The reaction mixture was stirred for 2 h at 0° C. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by preparative thin-layer chromatography (silica, dichloromethane:methanol=20:1) to obtain the title compound (165 mg). MS m / z (ESI): 558.9 [M+H] + .

[0670] Step 3: Synthesis of 5-(2-chloro-3-ethynylphenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (compound 80) Intermediate 80-4 (160 mg, 0.3 mmol) and tetramethylammonium fluoride (56 mg, 0.6 mmol) were dissolved in tetrahydrofuran (2 mL) and reacted at 25 °C for 5 h. The reaction mixture was washed with water (15 mL) and extracted with ethyl acetate (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The residue was purified by preparative high-performance liquid chromatography (column: Gemini NX C18 5 μm × 10 × 150 mm; mobile phase: A: water (0.225% formic acid v / v), B: acetonitrile; B%: 30% to 50%, 11 min) to give the title compound (32 mg).

[0671] MS m / z (ESI): 403.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J = 8.2 Hz, 1H), 8.35 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.78-7.76 (m, 1H), 7.63-7.48 (m, 2H), 4.67 (s, 1H), 4.28 (s, 3H).

[0672] Compound 80 (46.5 mg) was separated and purified by supercritical fluid chromatography (column: DAICEL CHIRALPAK AD-H (250 mm × 30 mm, 5 μm); mobile phase: A: carbon dioxide, B: ethanol (0.1% aqueous ammonia); B%: 45%; flow rate: 70 mL / min) to give compound 80-P1 (6.4 mg, RT: 1.499 min) and compound 80-P2 (9.1 mg, RT: 1.893 min).

[0673] Compound 80-P1: 1 H NMR (400MHz, METHANOL-d4) δ = 8.93-8.87 (m, 1H), 8.25 (s, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.76-7.71 (m, 1H), 7.55-7.48 (m, 1H), 7.48-7.43 (m, 1H), 4.35 (s, 3H), 3.94 (s, 1H). MS m / z (ESI): 403.1[M+H] + .

[0674] Compound 80-P2: 1 H NMR (400MHz, METHANOL-d4) δ = 8.90 (d, J = 8.3 Hz, 1H), 8.25 (s, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.76-7.70 (m, 1H), 7.54-7.49 (m, 1H), 7.49-7.43 (m, 1H), 4.35 (s, 3H), 3.94 (s, 1H). MS m / z (ESI): 403.0 [M+H] + .

[0675] Example 81, 5-(2-cyclopropylpyridin-3-yl)-7-(trifluoromethyl)oxazolo[4,5-c][1,8]naphthyridin-4(5H)-one (Compound 81)

[0676] [ka]

[0677] Step 1: Synthesis of 2-((2-cyclopropylpyridin-3-yl)amino)-6-(trifluoromethyl)pyridine-3-formic acid (Intermediate 81-1) Intermediate 35-1 (300 mg) was dissolved in anhydrous tetrahydrofuran (4 mL), and LiHMDS (1 M, 5.0 mL) was added dropwise thereto at −78°C. After the addition was complete, the mixture was reacted at −78°C for 1 hour. Intermediate 42-4 (323 mg) was then added to the reaction mixture. The mixture was allowed to warm to room temperature and reacted for 3 hours. Saturated aqueous ammonium chloride solution (10 mL) and ethyl acetate (20 mL × 3) were added sequentially to the reaction mixture, and the organic phase was washed with water (20 mL × 2). The washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound (220 mg). MS m / z (ESI): 324.2 [M+H] + .

[0678] Step 2: Synthesis of ethyl 5-(2-((2-cyclopropylpyridin-3-yl)amino)-6-(trifluoromethyl)pyridin-3-yl)oxazole-4-carboxylate (Intermediate 81-2) Intermediate 81-1 (100 mg) and cesium carbonate (228 mg) were dissolved in N,N-dimethylformamide (1 mL), and diphenylphosphoryl azide (DPPA) (192 mg) was added at 0 °C. The mixture was allowed to react at room temperature for 1 h. Intermediate 35-3 (40 mg) was added at 0 °C, and the mixture was stirred at 25 °C for 2 h. Water (5 mL) and ethyl acetate (5 mL × 3) were added sequentially to the reaction mixture, and the organic phase was washed with saturated brine (5 mL × 2). The washed organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by preparative thin-layer chromatography (silica, petroleum ether:ethyl acetate = 100:0 to 50:50) to give the title compound (70 mg). MS m / z (ESI): 419.2 [M+H] + .

[0679] Step 3: Synthesis of 5-(2-cyclopropylpyridin-3-yl)-7-(trifluoromethyl)oxazolo[4,5-c][1,8]naphthyridin-4(5H)-one (compound 81) Intermediate 81-2 (70 mg) and cesium carbonate (149 mg) were dissolved in N,N-dimethylformamide (1 mL) and reacted at 70° C. for 2 h. The reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (column: Gemini NX C18 5 μm × 10 × 150 mm; mobile phase: A: water (0.225% formic acid v / v), B: acetonitrile; B%: 30% to 50%, 11 min) to give the title compound (15 mg).

[0680] MS m / z (ESI): 373.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.74 (d, J = 8.0 Hz, 1H), 8.56-8.53 (m, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.73-7.68 (m, 1H), 7.32-7.24 (m, 1H), 1.61-1.50 (m, 1H), 1.03-0.92 (m, 1H), 0.75-0.57 (m, 2H), 0.55-0.43 (m, 1H).

[0681] Compound 81 (13 mg) was separated and purified by supercritical fluid chromatography (column: (s,s) WHELK-01 (250 mm × 30 mm, 5 μm); mobile phase: A: carbon dioxide, B: ethanol (0.1% aqueous ammonia); B%: 50%; flow rate: 70 mL / min) to give compound 81-P1 (3.2 mg, RT: 1.570 min) and compound 81-P2 (4.9 mg, RT: 2.675 min).

[0682] Compound 81-P1 1H NMR (400MHz, METHANOL-d4) δ = 8.80 (s, 1H), 8.77 (d, J = 8.0 Hz, 1H), 8.56 (dd, J = 1.5, 5.0 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.70 (dd, J = 1.6, 7.9 Hz, 1H), 7.39 (dd, J = 4.9, 7.9 Hz, 1H), 1.66-1.58 (m, 1H), 1.17-1.09 (m, 1H), 0.94-0.86 (m, 1H), 0.83-0.75 (m, 1H), 0.68-0.59 (m, 1H). MS m / z (ESI): 373.1 [M+H] + .

[0683] Compound 81-P2 1 H NMR (400MHz, METHANOL-d4) δ = 8.80 (s, 1H), 8.77 (d, J = 8.0 Hz, 1H), 8.56 (dd, J = 1.5, 4.8 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.70 (dd, J = 1.5, 8.0 Hz, 1H), 7.39 (dd, J = 4.9, 7.9 Hz, 1H), 1.66-1.57 (m, 1H), 1.18-1.09 (m, 1H), 0.93-0.88 (m, 1H), 0.83-0.75 (m, 1H), 0.68-...

Claims

1. A compound of formula (I) or a pharma- ceutically acceptable salt thereof, [Formula 1] Among them, L is selected from a chemical bond, NH or O; R １ is halogen or optionally R １ａ C replaced by １ ~C １０ Alkyl group, C ３ ~C １０ cycloalkyl groups, and 3- to 10-membered heterocyclyl groups; X １ , X ２ are each independently selected from N or CH; Ring A is C ６ ~C １０ an aryl group, a 5- to 10-membered heteroaryl group, or a 4- to 7-membered heterocyclyl group; ６ ~C １０ The aryl group, the 5- to 10-membered heteroaryl group, or the 4- to 7-membered heterocyclyl group is optionally R ２ is replaced by X and Y are ring atoms of ring A, and X and Y are each independently selected from a C atom or an N atom, and when at least one of X and Y is selected from an N atom, X and Y are linked by a single bond, and when both of X and Y are selected from a C atom, X and Y are linked by a single bond or a double bond; R ２ is halogen, ═O, OH, CN, or optionally R ２ａ NH substituted by ２ , C １ ~C １０ Alkyl group, C ３ ~C １０ Cycloalkyl group, 3- to 10-membered heterocyclyl group, C １ ~C １０ Alkoxy group, C ３ ~C １０ a cycloalkyloxy group, a 3- to 10-membered heterocyclyloxy group, Ring Q is C ６ ~C １０an aryl group, or a 5- to 10-membered heteroaryl group; ６ ~C １０ The aryl group or the 5- to 10-membered heteroaryl group is optionally R ３ is replaced by R ３ is halogen, =O, OH, CN, NO ２ or optionally R ３ａ SH, NH replaced by ２ , C ２ ~C １０ Alkenyl group, C ２ ~C １０ Alkynyl group, C １ ~C １０ Alkyl group, C ３ ~C １０ Cycloalkyl group, 3- to 10-membered heterocyclyl group, C １ ~C １０ Alkoxy group, C ３ ~C １０ a cycloalkyloxy group, a 3- to 10-membered heterocyclyloxy group, Each R １ａ , R ２ａ , R ３ａ are independently a deuterium atom, F, Cl, Br, I, OH, CN, ═O, or optionally R ｂ NH substituted by ２ , C １ ~C ６ Alkyl group, C ３ ~C ６ Cycloalkyl groups, 4- to 7-membered heterocyclyl groups, 5- to 6-membered heteroaryl groups, C １ ~C ６ Alkoxy group, C ３ ~C ６ a cycloalkyloxy group, a 4- to 7-membered heterocyclyloxy group, Each R ｂ are independently F, Cl, Br, I, OH, CN, =O, NH ２ , S.H., C. １ ~C ６ Alkyl group, C ３ ~C ６ selected from a cycloalkyl group or a 4- to 7-membered heterocyclyl group; A compound of formula (I) or a pharma- ceutically acceptable salt thereof.

2. R １ is halogen or optionally R １ａ C replaced by １ ~C ３ Alkyl group, C ３ ~C ６ cycloalkyl groups, 4- to 7-membered heterocyclyl groups, and / or each R １ａ are independently F, Cl, Br, I, OH, CN, ═O, or optionally R ｂ NH substituted by ２ , C １ ~C ６ Alkyl group, C ３ ~C ６ Cycloalkyl group, 4- to 7-membered heterocyclyl group, C １ ~C ６ alkoxy groups; or R １ is halogen or optionally R １ａ C replaced by １ ~C ３ alkyl group, 4- to 7-membered heterocyclyl group, and / or each R １ａ are independently selected from F, Cl, Br, I; or R １ is halogen or optionally R １ａ and / or each R １ａ is independently selected from F, Cl, Br and I, or a pharma- ceutically acceptable salt thereof.

3.

2. Cl, CH ３ , C.F. ３ , O.C.H. ２ CH ３ 3. The compound of formula (I) according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, selected from:

4. X １ is N, and X ２ is CH, or X １ and X ２ are both CH, or X １ and X ２ The compound of formula (I) according to any one of claims 1 to 3, wherein both are N, or a pharma- ceutically acceptable salt thereof.

5. The compound of formula (I) according to any one of claims 1 to 4, wherein X and Y are both C and X and Y are linked by a single bond or a double bond, or one of X and Y is C and the other is N and X and Y are linked by a single bond, or a pharma- ceutically acceptable salt thereof.

6. Ring A is selected from a 5- to 6-membered heteroaryl group or a 5- to 7-membered heterocyclyl group, and the ring atoms of the 5- to 6-membered heteroaryl group or the 5- to 7-membered heterocyclyl group are N, O, S, S(O), ２ The 5- to 6-membered heteroaryl group or the 5- to 7-membered heterocyclyl group may optionally include R ２ or Ring A is optionally R ２ a pyrrolyl group, a pyrazolyl group, an imidazolyl group, an oxazolyl group, an isoxazolyl group, a triazolyl group substituted by [C3] or Ring A is optionally R ２ Replaced by [C4] The compound of formula (I) according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, selected from:

7. R ２ is ═O or optionally R ２ａ NH substituted by ２ , C １ ~C ６ Alkyl group, C ３ ~C ６ Cycloalkyl group, C １ ~C ６ alkoxy groups, and the R ２ａ is a deuterium atom, F, Cl, Br, I, C １ ~C ３ Alkyl group, optionally C １ ~C ３ NH substituted with an alkyl group ２ , or optionally C １ ~C ３ a 5- to 6-membered heteroaryl group substituted with an alkyl group; or R ２ is ═O, methyl group, ethyl group, CD ３ , C.H. ２ CH ２ N (CH ３ ) ２ , C.H. ２ CH ２ O.H., C.H. ２ CH ２ NH (CH ３ ), C.H. ２ CH ２ N.H. ２ , O.C.H. ３ , N.H.H. ３ , C.H.F. ２ , C.F. ３ , a cyclopropyl group or [C5] The compound of formula (I) according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, selected from:

8. Ring A is [C6] The compound of formula (I) according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, selected from:

9. Ring Q is selected from a phenyl group, a pyridyl group, a pyrazolyl group, a pyrimidinyl group, or a pyrazinyl group, and the phenyl group, the pyridyl group, the pyrazolyl group, the pyrimidinyl group, or the pyrazinyl group is optionally selected from R ３ The compound of formula (I) according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt thereof, wherein

10. R ３ is halogen, ═O, OH, CN, or optionally R ３ａSH, C replaced by ２ ~C ３ Alkynyl group, C １ ~C ６ Alkyl group, C ３ ~C ６ Cycloalkyl group, C １ ~C ６ Alkoxy group, C ３ ~C ６ cycloalkyloxy groups, and R ３ａ is halogen, CN, or C １ ~C ３ alkyl groups, or R ３ is halogen, CN, C ３ ~C ６ Cycloalkyl group, C ２ ~C ３ Alkynyl group, optionally substituted with halogen １ ~C ６ C optionally substituted with an alkyl group or halogen １ ~C ６ alkoxy groups; or R ３ is F, Cl, Br, CN, SH, an isopropyl group, a cyclopropyl group, a methyl group, an ethyl group, a trifluoromethyl group, an ethynyl group, and OCHF ２ 10. The compound of formula (I) according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, wherein R is selected from the group consisting of , ...

11. Ring Q is selected from a phenyl group, a pyridyl group, a pyrazolyl group, a pyrimidinyl group, or a pyrazinyl group, and the phenyl group, the pyridyl group, the pyrazolyl group, the pyrimidinyl group, or the pyrazinyl group is optionally selected from R ３ and each R ３ are independently halogen, CN, C ３ ~C ６ Cycloalkyl group, C ２ ~C ３ Alkynyl group, optionally substituted with halogen １ ~C ６ C optionally substituted with an alkyl group or halogen １ ~C ６ alkoxy groups; or Ring Q is selected from a phenyl group, a pyridyl group, a pyrazolyl group, a pyrimidinyl group, or a pyrazinyl group, and the phenyl group, the pyridyl group, the pyrazolyl group, the pyrimidinyl group, or the pyrazinyl group is optionally selected from R ３ and each R ３ are independently F, Cl, Br, CN, an isopropyl group, a cyclopropyl group, a methyl group, an ethyl group, a trifluoromethyl group, an ethynyl group, or OCHF ２ or a methoxy group; Ring Q is [C7] The compound of formula (I) according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, selected from:

12. The compound represented by formula (I) or a pharma- ceutically acceptable salt thereof is a compound represented by formula (Ia) or a pharma- ceutically acceptable salt thereof, [C8] Among them, ring A, ring Q, and X １ , X ２ , L, R １ 2. A compound of formula (I) as defined in claim 1, or a pharma- ceutically acceptable salt thereof.

13. The compound of claim 1, wherein the compound is selected from one of the following structures: [C9] [C10] [C11] [C12] [C13] [C14] [C15] [C16] [C17] [C18] [C19] [C20]

14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

15. The compound according to any one of claims 1 to 13 or a pharma- ceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14, for the prevention or treatment of a tumor having reduced MTAP activity or in which MTAP is deficient.