Tricyclic compounds and uses thereof

Abstract

Provided are compounds represented by Formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical compositions thereof, and methods of making the same, and uses thereof as MAT2A inhibitors. In Formula (I), ring A, ring Q, X, Y, X1, X2, L, and R 1 As defined in the specification.

Description

[0001] Cross-references to related applications

[0002] This application claims Chinese patent applications filed with the China National Intellectual Property Administration (CNIPA) on December 31, 2020, with patent application number 202011637193.3, entitled "Tricyclic Compounds and Their Uses"; Chinese patent applications filed with the CNIPA on February 26, 2021, with patent application number 202110213607.8, also entitled "Tricyclic Compounds and Their Uses"; and Chinese patent applications filed with the CNIPA on April 29, 2021, with patent application number 20211... The priority and interests of the following Chinese patent applications are hereby declared: 0477136.1, entitled "Tricyclic Compounds and Uses"; 202110780130.1, filed with the China National Intellectual Property Administration on July 9, 2021, entitled "Tricyclic Compounds and Uses"; and 202110998242.4, filed with the China National Intellectual Property Administration on August 27, 2021, entitled "Tricyclic Compounds and Uses". The entire contents of the above patent applications are incorporated herein by reference. Technical Field

[0003] This application belongs to the pharmaceutical field and specifically relates to a novel tricyclic compound or a pharmaceutically acceptable salt thereof, pharmaceutical compositions containing them, and their use as MAT2A inhibitors. Background Technology

[0004] Methionine adenosyltransferase (MAT), also known as S-adenosylmethionine synthase, is a class of enzymes that catalyze the reaction of methionine (Met) with ATP to produce S-adenosyl-L-methionine (SAM). SAM serves as a major methyl donor for methyltransferases in the body, regulating gene expression, transcription, and translation through transmethylation reactions, thereby significantly impacting cell growth, death, and differentiation. Protein arginine N-methyltransferase 5 (PRMT5) is a methyltransferase that uses SAM as a substrate and plays a crucial regulatory role in tumor cell proliferation.

[0005] There are three isoforms of MAT enzymes, MAT1A, MAT2A and MAT2B. MAT1A is mainly present in normal hepatocytes, while MAT2A is widely distributed in extrahepatic cells. The two isoforms differ in catalytic efficiency and regulation. MAT2B does not have the ability to synthesize SAM, but as a regulatory subunit of MAT2A, it forms a complex with MAT2A to regulate the catalytic activity of MAT2A.

[0006] It was found that cancer cell lines with methylthioadenosine phosphorylase (MTAP) deletion are sensitive to MAT2A inhibition (Cell Reports 15(3) (2016) 574-587). MTAP is widely expressed in normal tissue cells. This enzyme can catalyze the conversion of methylthioadenosine (5'methylthioadenosine, MTA) to 5-methylthioribose-1-phosphate and adenine. This process is also an important compensatory pathway for methionine in the human body. When MTAP is deleted, the metabolic pathway of MTA is inhibited, resulting in the accumulation of MTA in the body. The accumulation of MTA will partially inhibit the activity of PRMT5, thereby causing the sensitivity of PRMT5 to changes in the level of SAM in the body to increase; therefore, in tumors with MTAP deletion, by inhibiting MAT2A to reduce the level of SAM in the body, the activity of PRMT5 will be further inhibited, resulting in a synthetic lethal effect.

[0007] The gene encoding human MTAP is located in the chr9p21 region of chromosome 9p21, and the frequency of homozygous deletion in all tumors is about 15%, and the deletion frequency varies in different tumors. The tumor species with higher deletion frequency 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, non-Hodgkin's lymphoma, etc.

[0008] In the chr9p21 region of human chromosome 9p21, in addition to the gene encoding MTAP, the region also contains tumor suppressor genes p16INK4A (also known as CDKN2A) and p15INK4B. In 80%-90% of tumors with CDKN2A deletion, MTAP is also in a deleted state.

[0009] Given that the expression level of MAT2A is abnormally elevated in multiple types of tumors, including gastric cancer, colon cancer, liver cancer and pancreatic cancer, etc., and selective inhibition of MAT2A can reduce the proliferation activity of MTAP-deleted cancer cells. Therefore, selective inhibition of MAT2A can be used as an effective tumor treatment method.

[0010] Patent documents such as WO2018039972, WO2018045071, WO2019191470 and WO2020123395 disclose heterocyclic MAT2A inhibitors for treating tumors. DETAILED DESCRIPTION

[0012] The present application provides a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0013]

[0014] wherein,

[0015] L is selected from a chemical bond, NH or O;

[0016] R 1 selected from halogen or the following group optionally substituted by R 1a C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclyl;

[0017] X1, X2are each independently selected from N or CH;

[0018] Ring A is selected from C6-C 10 aryl, 5-10 membered heteroaryl or 4-7 membered heterocyclyl, said C6-C 10 aryl, 5-10 membered heteroaryl or 4-7 membered heterocyclyl optionally substituted by R 2 ;

[0019] X, Y are ring atoms of ring A, X, Y are each independently selected from C atom or N atom, and when at least one of X, Y is selected from N atom, X, Y are connected by a single bond; when X, Y are both selected from C atom, X, Y can be connected by a single bond or a double bond;

[0020] R 2 selected from halogen, =O, OH, CN or the following group optionally substituted by R 2a NH2, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclyl, C1-C 10 alkoxy, C3-C 10 cycloalkyloxy, 3-10 membered heterocyclyloxy;

[0021] Ring Q is selected from C6-C 10 aryl or 5-10 membered heteroaryl, said C6-C 10 aryl or 5-10 membered heteroaryl optionally substituted by R 3 ;

[0022] R 3Selected from halogens, =O, OH, CN, NO2, or optionally R 3a The following groups are substituted: SH, NH2, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic, C1-C 10 Alkoxy, C3-C 10 Cycloalkyloxy groups, 3-10 membered heterocyclic alkyloxy groups;

[0023] Each R 1a R 2a R 3a Independently selected from deuterium, F, Cl, Br, I, OH, CN, =O, or arbitrarily selected by R b The following groups are substituted: NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, 5-6 membered heteroaryl, C1-C6 alkoxy, C3-C6 cycloalkyloxy, 4-7 membered heterocyclic oxy;

[0024] Each R b It is independently selected from F, Cl, Br, I, OH, CN, =O, NH2, SH, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic groups.

[0025] In some implementation schemes, R 3 Selected from halogens, =O, OH, CN, or optionally R 3a The following groups are substituted: NH2, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic, C1-C 10 Alkoxy, C3-C 10 Cycloalkyloxy, 3-10 membered heterocyclic alkyloxy; each R 1a R 2a R 3a Independently selected from deuterium, F, Cl, Br, I, OH, CN, =O, or arbitrarily selected by R b The following groups are substituted: NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic, C1-C6 alkoxy, C3-C6 cycloalkyloxy, 4-7 membered heterocyclic oxy; each R b It is independently selected from F, Cl, Br, I, OH, CN, =O, NH2, SH, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic groups.

[0026] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is a compound of Formula (la) or a pharmaceutically acceptable salt thereof:

[0027]

[0028] wherein,

[0029] L is selected from a bond, NH, or O;

[0030] R 1 is selected from halogen or the following groups optionally substituted with R 1a : C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclyl;

[0031] X1, X2are each independently selected from N or CH;

[0032] Ring A is selected from C6-C 10 aryl, 5-10 membered heteroaryl, or 4-7 membered heterocyclyl, said C6-C 10 aryl, 5-10 membered heteroaryl, or 4-7 membered heterocyclyl is optionally substituted with R 2 ;

[0033] R 2 is selected from halogen, =0, OH, CN, or the following groups optionally substituted with R 2a : NH2, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclyl, C1-C 10 alkoxy, C3-C 10 cycloalkyloxy, 3-10 membered heterocyclyloxy;

[0034] Ring Q is selected from C6-C 10 aryl or 5-10 membered heteroaryl, said C6-C 10 aryl or 5-10 membered heteroaryl is optionally substituted with R 3 ;

[0035] R 3 is selected from halogen, =0, OH, CN, or the following groups optionally substituted with R 3a : NH2, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclyl, C1-C 10 alkoxy, C3-C 10 cycloalkyloxy, 3-10 membered heterocyclyloxy;

[0036] each R1a 2a 3a independently selected from F, CI, Br, I, OH, CN, =0, or optionally R b substituted with R

[0037] each R b independently selected from F, CI, Br, I, OH, CN, =0, NH2, SH, C1-C6 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclyl.

[0038] In some embodiments, the 3-10 membered heterocyclyl contains 1-3 or 1-5 heteroatoms or heteroatom groups independently selected from N, O, S, P, B, -S(=0)2-, -S(=0)-, -P(=0)2-, -P(=0)-, -NH-, -S(=0)(=NH)-, -C(=0)NH-, or -NHC(=0)NH-.

[0039] In some embodiments, the 3-10 membered heterocyclyl contains 1-3 heteroatoms or heteroatom groups independently selected from N, O, S, -S(=0)2-, or -NH-. In some embodiments, the 4-7 membered heterocyclyl contains 1-3 heteroatoms or heteroatom groups independently selected from N, O, S, -S(=0)2-, or -NH-. In some embodiments, the 4-7 membered heterocyclyl contains 1, 2, or 3 heteroatoms independently selected from N, O, or S.

[0040] In some embodiments, the 5-10 membered heteroaryl contains 1-3 or 1-5 heteroatoms independently selected from N, O, and S. In some embodiments, the 5-6 membered heteroaryl contains 1-3 heteroatoms independently selected from N, O, and S.

[0041] In some embodiments, X and Y are ring atoms, and both X and Y are C, X and Y are connected with a single bond or a double bond; or one of X and Y is C, and the other is N, X and Y are connected with a single bond.

[0042] In some embodiments, both X and Y are C, X and Y are connected with a single bond or a double bond; X1 is N, and X2 is CH or N; or both X1 and X2 are CH. In some embodiments, both X and Y are C, X and Y are connected with a double bond; X1 is N, and X2 is CH; or both X1 and X2 are CH; or both X1 and X2 are N.

[0043] In some embodiments, L is selected from NH, R​​1 selected from F, CI, Br, I, OH, CN, =0, NH2, NH(Ci-C3alkyl), N(Ci-C3alkyl)2, Ci-C3alkyl, or Ci-C3alkoxy.

[0044] In some embodiments, L is selected from NH, R 1 selected from F, CI, Br, I, OH, CN, =0, NH2, NH(Ci-C3alkyl), N(Ci-C3alkyl)2, Ci-C3alkyl, or Ci-C3alkoxy.

[0045] In some embodiments, L is selected from NH, X1is selected from N, and X2is selected from CH.

[0046] In some embodiments, L is selected from a bond or O.

[0047] In some embodiments, L is selected from a bond.

[0048] In some embodiments, L is selected from O.

[0049] In some embodiments, R 1 selected from F, CI, Br, I, OH, CN, =0, NH2, NH(Ci-C3alkyl), N(Ci-C3alkyl)2, Ci-C3alkyl, or Ci-C3alkoxy. 1a selected from F, CI, Br, I, OH, CN, =0, NH2, NH(Ci-C3alkyl), N(Ci-C3alkyl)2, Ci-C3alkyl, or Ci-C3alkoxy.

[0050] In some embodiments, R 1 selected from F, CI, Br, I, OH, CN, =0, NH2, NH(Ci-C3alkyl), N(Ci-C3alkyl)2, Ci-C3alkyl, or Ci-C3alkoxy. 1a selected from F, CI, Br, I, OH, CN, =0, NH2, NH(Ci-C3alkyl), N(Ci-C3alkyl)2, Ci-C3alkyl, or Ci-C3alkoxy.

[0051] In some embodiments, R 1 selected from F, CI, Br, I, OH, CN, =0, NH2, NH(Ci-C3alkyl), N(Ci-C3alkyl)2, Ci-C3alkyl, or Ci-C3alkoxy. 1a selected from F, CI, Br, I, OH, CN, =0, NH2, NH(Ci-C3alkyl), N(Ci-C3alkyl)2, Ci-C3alkyl, or Ci-C3alkoxy.

[0052] In some embodiments, R 1 selected from F, CI, Br, I, OH, CN, =0, NH2, NH(Ci-C3alkyl), N(Ci-C3alkyl)2, Ci-C3alkyl, or Ci-C3alkoxy. 1a selected from F, CI, Br, I, OH, CN, =0, NH2, NH(Ci-C3alkyl), N(Ci-C3alkyl)2, Ci-C3alkyl, or Ci-C3alkoxy.

[0053] In some embodiments, R 1 selected from F, CI, Br, I, OH, CN, =0, NH2, NH(Ci-C3alkyl), N(Ci-C3alkyl)2, Ci-C3alkyl, or Ci-C3alkoxy. 1a selected from F, CI, Br, I, OH, CN, =0, NH2, NH(Ci-C3alkyl), N(Ci-C3alkyl)2, Ci-C3alkyl, or Ci-C3alkoxy.

[0054] In some embodiments, R 1 selected from F, CI, Br, I, OH, CN, =0, NH2, NH(Ci-C3alkyl), N(Ci-C3alkyl)2, Ci-C3alkyl, or Ci-C3alkoxy. 1a selected from F, CI, Br, I, OH, CN, =0, NH2, NH(Ci-C3alkyl), N(Ci-C3alkyl)2, Ci-C3alkyl, or Ci-C3alkoxy.

[0055] In some embodiments, each R 1a is independently selected from F, CI, Br, I, OH, CN, =0, or optionally substituted methyl. bsubstituted with one or more of the following groups: F, CI, Br, I, OH, CN, =0, NH2, NH(Ci-C3alkyl), N(Ci-C3alkyl)2, Ci-C3alkyl, and Ci-C3alkoxy.

[0056] In some embodiments, each R 1a is independently selected from F, CI, Br, I.

[0057] In some embodiments, each R 1a is independently selected from F.

[0058] In some embodiments, R 1 is selected from CI, CH3, CF3, ethyl, or oxetanyl.

[0059] In some embodiments, R 1 is selected from CF3, ethyl, or oxetanyl.

[0060] In some embodiments, R 1 is selected from CI, CH3, CF3, or ethyl.

[0061] In some embodiments, R 1 is selected from CI, CF3, or ethyl.

[0062] In some embodiments, R 1 is selected from CF3, or ethyl.

[0063] In some embodiments, R 1 is selected from CF3.

[0064] In some embodiments, L is a bond, R 1 is selected from halogen, Ci-C6alkyl, C3-C6cycloalkyl, or 4-7 membered heterocyclyl, said Ci-C6alkyl, C3-C6cycloalkyl, or 4-7 membered heterocyclyl optionally substituted with F, CI, Br, I, OH, CN, =0, NH2, NH(Ci-C3alkyl), N(Ci-C3alkyl)2, Ci-C3alkyl, and Ci-C3alkoxy.

[0065] In some embodiments, L is a bond, R 1 is selected from halogen or Ci-C3alkyl optionally substituted with R 1a ; each R 1a is independently selected from F, CI, Br, I.

[0066] In some embodiments, L is O, R 1selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclyl, said C1-C6 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclyl being optionally substituted with F, CI, Br, I, OH, CN, =0, NH2, NH(C1-C3 alkyl), N(C1-C3 alkyl)2, C1-C3 alkyl, and C1-C3 alkoxy.

[0067] In some embodiments, L is O, R 1 selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclyl, said C1-C6 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclyl being optionally substituted with F, CI, Br, I, OH, CN, =0, NH2, NH(C1-C3 alkyl), N(C1-C3 alkyl)2, C1-C3 alkyl, and C1-C3 alkoxy.

[0068] In some embodiments, structural unit selected from the group consisting of CI, CH3, CF3, OCH2CH3, NHCH2CH3, or

[0069] In some embodiments, structural unit selected from the group consisting of CF3, OCH2CH3, NHCH2CH3, or

[0070] In some embodiments, structural unit selected from the group consisting of CI, CH3, CF3, or OCH2CH3.

[0071] In some embodiments, structural unit selected from the group consisting of CI, CF3, or OCH2CH3.

[0072] In some embodiments, structural unit selected from the group consisting of CF3, or OCH2CH3.

[0073] In some embodiments, structural unit selected from the group consisting of CF3.

[0074] In some embodiments, X1is selected from N.

[0075] In some embodiments, X1is selected from CH.

[0076] In some embodiments, X2is selected from CH.

[0077] In some embodiments, X1is N and X2is CH. In some embodiments, X1and X2are both CH. In some embodiments, X1and X2are both N.

[0078] In some embodiments, X1is selected from N or CH and X2is selected from CH.

[0079] In some embodiments, ring A is selected from 5-6 membered heteroaryl or 4-7 membered heterocyclyl, said 5-6 membered heteroaryl or 4-7 membered heterocyclyl being optionally substituted with R 2 substituted.

[0080] In some embodiments, ring A is selected from a 5-6 membered heteroaryl or a 5-7 membered heterocyclyl, containing at least one heteroatom or heteroatom group selected from N, O, S, S(O)2, in the ring atoms of said 5-6 membered heteroaryl or 5-7 membered heterocyclyl, said 5-6 membered heteroaryl or 5-7 membered heterocyclyl being optionally substituted with R 2 substituted.

[0081] In some embodiments, ring A is selected from a pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, 2 substituted.

[0082] In some embodiments, ring A is selected from a pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, 2 substituted.

[0083] In some embodiments, ring A is selected from a pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, 2 substituted.

[0084] In some embodiments, ring A is selected from an imidazolyl, oxazolyl, said imidazolyl, oxazolyl, optionally substituted with R 2 substituted.

[0085] In some embodiments, ring A is selected from a pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, said pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, optionally substituted with R 2 substituted.

[0086] In some embodiments, ring A is selected from a pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, 2 substituted.

[0087] In some embodiments, ring A is selected from an imidazolyl or a pyrazolyl, said imidazolyl or pyrazolyl being optionally substituted with R 2 substituted.

[0088] In some embodiments, R 2 is selected from =O or from NH2, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, optionally substituted. 2a substituted.

[0089] In some embodiments, R is selected from a deuterium atom, F, Cl, Br, I, OH, C1-C3 alkyl, NH2 optionally substituted with C1-C3 alkyl, or 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl. 2 is selected from =0 or C1-C3 alkyl optionally substituted with R 2a is selected from =0 or C1-C3 alkyl optionally substituted with R

[0090] In some embodiments, R is selected from a deuterium atom, F, Cl, Br, I, OH, C1-C3 alkyl, NH2 optionally substituted with C1-C3 alkyl, or 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl. 2 is selected from =0 or C1-C3 alkyl optionally substituted with R 2a is selected from =0 or C1-C3 alkyl optionally substituted with R

[0091] In some embodiments, R is selected from a deuterium atom, F, Cl, Br, I, OH, C1-C3 alkyl, NH2 optionally substituted with C1-C3 alkyl, or 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl. 2a is selected from a deuterium atom, F, Cl, Br, I, OH, C1-C3 alkyl, NH2 optionally substituted with C1-C3 alkyl, or 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl.

[0092] In some embodiments, R is selected from a deuterium atom, F, Cl, Br, I, OH, C1-C3 alkyl, NH2 optionally substituted with C1-C3 alkyl, or 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl. 2a is selected from a deuterium atom, F, Cl, Br, I, OH, C1-C3 alkyl, NH2 optionally substituted with C1-C3 alkyl, or 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl.

[0093] In some embodiments, R is selected from a deuterium atom, F, Cl, Br, I, OH, C1-C3 alkyl, NH2 optionally substituted with C1-C3 alkyl, or 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl. 2a is selected from a deuterium atom, F, Cl, Br, I, OH, C1-C3 alkyl, NH2 optionally substituted with C1-C3 alkyl, or 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl.

[0094] In some embodiments, R is selected from a deuterium atom, F, Cl, Br, I, OH, C1-C3 alkyl, NH2 optionally substituted with C1-C3 alkyl, or 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl. 2a is selected from a deuterium atom, F, Cl, Br, I, OH, C1-C3 alkyl, NH2 optionally substituted with C1-C3 alkyl, or 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl.

[0095] In some embodiments, R is selected from a deuterium atom, F, Cl, Br, I, OH, C1-C3 alkyl, NH2 optionally substituted with C1-C3 alkyl, or 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl. 2a is selected from a deuterium atom, F, Cl, Br, I, OH, C1-C3 alkyl, NH2 optionally substituted with C1-C3 alkyl, or 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl.

[0096] In some embodiments, R is selected from a deuterium atom, F, Cl, Br, I, OH, C1-C3 alkyl, NH2 optionally substituted with C1-C3 alkyl, or 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl. 2a is selected from a deuterium atom, F, Cl, Br, I, OH, C1-C3 alkyl, NH2 optionally substituted with C1-C3 alkyl, or 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl.

[0097] In some embodiments, R is selected from a deuterium atom, F, Cl, Br, I, OH, C1-C3 alkyl, NH2 optionally substituted with C1-C3 alkyl, or 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl. 2 is selected from =0, methyl, ethyl, CD3, CH2CH2N(CH3)2, CH2CH2OH, CH2CH2NH(CH3), CH2CH2NH2, OCH3, NHCH3, CHF2, CF3, cyclopropyl, or

[0098] In some embodiments, R is selected from a deuterium atom, F, Cl, Br, I, OH, C1-C3 alkyl, NH2 optionally substituted with C1-C3 alkyl, or 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl. 2 is selected from =0, methyl, CD3, CH2CH2N(CH3)2, OCH3, NHCH3, CF3, or cyclopropyl.

[0099] In some embodiments, R is selected from a deuterium atom, F, Cl, Br, I, OH, C1-C3 alkyl, NH2 optionally substituted with C1-C3 alkyl, or 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl. 2 is selected from =0, methyl, CD3, or OCH3.

[0100] In some embodiments, R 2 is selected from =0, methyl, or CH2CH2N(CH3)2.

[0101] In some embodiments, R 2 is selected from =0, methyl, or methoxy.

[0102] In some embodiments, ring A is selected from the following groups optionally substituted with R 2 R 2 is selected from =0, methyl, CD3, OCH3, or CF3.

[0103] In some embodiments, ring A is selected from the following groups optionally substituted with R 2 R 2 is selected from =0, methyl, ethyl, CD3, CH2CH2N(CH3)2, CH2CH2OH, CH2CH2NH(CH3), CH2CH2NH2, OCH3, NHCH3, CHF2, CF3, cyclopropyl, or

[0104] In some embodiments, ring A is selected from

[0105] In some embodiments, ring A is selected from

[0106] In some embodiments, ring A is selected from

[0107] In some embodiments, ring A is selected from

[0108] In some embodiments, ring A is selected from

[0109] In some embodiments, ring A is selected from In some embodiments, ring A is selected from

[0110] In some embodiments, ring A is selected from

[0111] In some embodiments, ring A is selected from ​​

[0112] In some embodiments, ring A is selected from

[0113] In some embodiments, ring Q is selected from phenyl or 5-6 membered heteroaryl, optionally substituted with R 3 .

[0114] In some embodiments, ring Q is selected from phenyl, pyridyl, pyrazolyl, pyrimidinyl, or pyrazinyl, optionally substituted with R 3 .

[0115] In some embodiments, ring Q is selected from phenyl or pyridyl, optionally substituted with R 3 .

[0116] In some embodiments, ring Q is selected from phenyl, optionally substituted with R 3 .

[0117] In some embodiments, R 3 is selected from halogen, =0, OH, CN, or the following groups optionally substituted with R 3a : SH, C2-C3 alkynyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyloxy.

[0118] In some embodiments, R 3 is selected from halogen, =0, OH, CN, or the following groups optionally substituted with R 3a : C2-C3 alkynyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy.

[0119] In some embodiments, R 3 is selected from halogen, =0, OH, CN, or the following groups optionally substituted with R 3a : ethynyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyloxy.

[0120] In some embodiments, R 3 is selected from halogen, =0, OH, CN, or the following groups optionally substituted with R 3a : C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyloxy.

[0121] In some embodiments, R 3a is selected from halogen, CN, or C1-C3 alkyl.

[0122] In some embodiments, R 3aselected from halogen, e.g. F.

[0123] In some embodiments, R is selected from halogen, CN, C3-C6cycloalkyl, C2-C3alkynyl, C1-C6alkyl optionally substituted with halogen or C1-C6alkoxy optionally substituted with halogen. 3a selected from halogen, e.g. F.

[0124] In some embodiments, R is selected from halogen, CN, C3-C6cycloalkyl, C2-C3alkynyl, C1-C6alkyl optionally substituted with halogen or C1-C6alkoxy optionally substituted with halogen. 3 selected from halogen, CN, C3-C6cycloalkyl, C2-C3alkynyl, C1-C6alkyl optionally substituted with halogen or C1-C6alkoxy optionally substituted with halogen.

[0125] In some embodiments, R is selected from halogen, CN, C3-C6cycloalkyl, C2-C3alkynyl, C1-C6alkyl optionally substituted with halogen or C1-C6alkoxy optionally substituted with halogen. 3 selected from halogen, CN, C3-C6cycloalkyl, C2-C3alkynyl, C1-C6alkyl optionally substituted with halogen or C1-C6alkoxy optionally substituted with halogen.

[0126] In some embodiments, R is selected from halogen, CN, C3-C6cycloalkyl, C2-C3alkynyl, C1-C6alkyl optionally substituted with halogen or C1-C6alkoxy optionally substituted with halogen. 3 selected from halogen, CN, C3-C6cycloalkyl, C2-C3alkynyl, C1-C6alkyl optionally substituted with halogen or C1-C6alkoxy optionally substituted with halogen.

[0127] In some embodiments, R is selected from halogen, CN, C3-C6cycloalkyl, C2-C3alkynyl, C1-C6alkyl optionally substituted with halogen or C1-C6alkoxy optionally substituted with halogen. 3 selected from halogen, CN, C3-C6cycloalkyl, C2-C3alkynyl, C1-C6alkyl optionally substituted with halogen or C1-C6alkoxy optionally substituted with halogen.

[0128] In some embodiments, R is selected from halogen, CN, C3-C6cycloalkyl, C2-C3alkynyl, C1-C6alkyl optionally substituted with halogen or C1-C6alkoxy optionally substituted with halogen. 3 selected from halogen, CN, C3-C6cycloalkyl, C2-C3alkynyl, C1-C6alkyl optionally substituted with halogen or C1-C6alkoxy optionally substituted with halogen.

[0129] In some embodiments, R is selected from halogen, CN, C3-C6cycloalkyl, C2-C3alkynyl, C1-C6alkyl optionally substituted with halogen or C1-C6alkoxy optionally substituted with halogen. 3 selected from halogen, CN, C3-C6cycloalkyl, C2-C3alkynyl, C1-C6alkyl optionally substituted with halogen or C1-C6alkoxy optionally substituted with halogen.

[0130] In some embodiments, R is selected from halogen, CN, C3-C6cycloalkyl, C2-C3alkynyl, C1-C6alkyl optionally substituted with halogen or C1-C6alkoxy optionally substituted with halogen. 3 selected from halogen, CN, C3-C6cycloalkyl, C2-C3alkynyl, C1-C6alkyl optionally substituted with halogen or C1-C6alkoxy optionally substituted with halogen.

[0131] In some embodiments, R is selected from halogen, CN, C3-C6cycloalkyl, C2-C3alkynyl, C1-C6alkyl optionally substituted with halogen or C1-C6alkoxy optionally substituted with halogen. 3 selected from halogen, CN, C3-C6cycloalkyl, C2-C3alkynyl, C1-C6alkyl optionally substituted with halogen or C1-C6alkoxy optionally substituted with halogen.

[0132] In some embodiments, R is selected from halogen, CN, C3-C6cycloalkyl, C2-C3alkynyl, C1-C6alkyl optionally substituted with halogen or C1-C6alkoxy optionally substituted with halogen. 3 selected from halogen, CN, C3-C6cycloalkyl, C2-C3alkynyl, C1-C6alkyl optionally substituted with halogen or C1-C6alkoxy optionally substituted with halogen.

[0133] In some embodiments, R is selected from halogen, CN, C3-C6cycloalkyl, C2-C3alkynyl, C1-C6alkyl optionally substituted with halogen or C1-C6alkoxy optionally substituted with halogen. 3 selected from halogen, CN, C3-C6cycloalkyl, C2-C3alkynyl, C1-C6alkyl optionally substituted with halogen or C1-C6alkoxy optionally substituted with halogen.

[0134] In some embodiments, R is selected from halogen, CN, C3-C6cycloalkyl, C2-C3alkynyl, C1-C6alkyl optionally substituted with halogen or C1-C6alkoxy optionally substituted with halogen. 3 selected from halogen, CN, C3-C6cycloalkyl, C2-C3alkynyl, C1-C6alkyl optionally substituted with halogen or C1-C6alkoxy optionally substituted with halogen.

[0135] In some embodiments, R3 selected from halogen or methoxy optionally substituted with F.

[0136] In some embodiments, R 3 selected from F, CI, Br, CN, isopropyl, cyclopropyl, methyl, ethyl, trifluoromethyl, ethynyl, OCHF2, or methoxy.

[0137] In some embodiments, R 3 selected from F, CI, Br, CN, isopropyl, cyclopropyl, methyl, ethyl, trifluoromethyl, ethynyl, OCHF2, or methoxy.

[0138] In some embodiments, R 3 selected from F, CI, Br, CN, isopropyl, cyclopropyl, methyl, ethyl, trifluoromethyl, OCHF2, or methoxy.

[0139] In some embodiments, R 3 selected from F, CI, Br, CN, methyl, isopropyl, OCHF2, or methoxy.

[0140] In some embodiments, R 3 selected from F, CI, methyl, isopropyl, OCHF2, or methoxy.

[0141] In some embodiments, R 3 selected from CI, Br, CN, methyl, OCHF2, or methoxy.

[0142] In some embodiments, R 3 selected from CI or OCHF2.

[0143] In some embodiments, ring Q is selected from phenyl or pyridyl, optionally substituted with R 3 each R 3 is independently selected from halogen, CN, isopropyl, cyclopropyl, methyl optionally substituted with halogen (e.g., F), or methoxy optionally substituted with halogen (e.g., F).

[0144] In some embodiments, ring Q is selected from phenyl or pyridyl, optionally substituted with R 3 each R 3 is independently selected from F, CI, Br, CN, isopropyl, cyclopropyl, methyl, trifluoromethyl, OCHF2, or methoxy.

[0145] In some embodiments, ring Q is selected from phenyl, pyridyl, pyrazolyl, pyrimidinyl, or pyrazinyl, optionally substituted with R 3 each R 3independently selected from halogen, CN, C3-C6cycloalkyl, C2-C3alkynyl, C1-C6alkyl optionally substituted with halogen (e.g., F), or C1-C6alkoxy optionally substituted with halogen (e.g., F).

[0146] In some embodiments, ring Q is selected from phenyl, pyridyl, pyrazolyl, pyrimidinyl, or pyrazinyl, optionally substituted with R 3 each R 3 is independently selected from F, Cl, Br, CN, isopropyl, cyclopropyl, methyl, ethyl, trifluoromethyl, ethynyl, OCHF2, or methoxy.

[0147] In some embodiments, ring Q is selected from

[0148] In some embodiments, ring Q is selected from

[0149] In some embodiments, ring Q is selected from

[0150] In some embodiments, ring Q is selected from

[0151] In some embodiments, ring Q is selected from

[0152] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is selected from the following compounds or a pharmaceutically acceptable salt thereof:

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164] 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.

[0165] Further, the present application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the preparation of an antitumor medicament.

[0166] Further, the present application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the preparation of a medicament for the prevention or treatment of a tumor with reduced or absent MTAP activity.

[0167] Further, the present application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the preparation of an antitumor medicament.

[0168] Further, the present application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the preparation of a medicament for the prevention or treatment of a tumor with reduced or absent MTAP activity.

[0169] Further, the present application relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of a tumor.

[0170] Further, the present application relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the prevention or treatment of a tumor with reduced or absent MTAP activity.

[0171] The present application also relates to a method for the treatment of a tumor, comprising administering to a patient a therapeutically effective amount of a pharmaceutical preparation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described herein.

[0172] The present application also relates to a method for the treatment of a tumor with reduced or absent MTAP activity, comprising administering to a patient a therapeutically effective amount of a pharmaceutical preparation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described herein.

[0173] The present application also relates to a method for the treatment of a tumor, comprising administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described herein.

[0174] The present application also relates to a method for the treatment of a tumor with reduced or absent MTAP activity, comprising administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described herein.

[0175] In some embodiments, the tumor is a gastric cancer, a colon cancer, a liver cancer, or a pancreatic cancer.

[0176] Definitions and explanations of terms

[0177] Unless otherwise indicated, the definitions of groups and terms in the specification and claims hereof include definitions that are in effect as examples, illustrative, preferred, recited in tables, specific compounds in the examples, etc., can be combined and incorporated with each other in any manner. Such combined and incorporated group definitions and compound structures shall be within the scope of the specification. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0178] Herein, a bond depicted by a solid line and a dashed line represents a single bond or a double bond.

[0179] Herein represents a point of attachment.

[0180] Herein, the graphical representation of a racemate or enantiomerically pure compound is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, a wedge and a dashed wedge represents the absolute configuration of a stereocenter, a solid and a dashed bond represents the relative configuration of a stereocenter (e.g., the cis or trans configuration of an alicyclic compound).

[0181] The term "tautomer" refers to isomers of a molecule that differ only in the position of a proton. Compounds of the present application can exhibit tautomerism. Compounds that tautomerize can exist in two or more interconvertible forms. Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture having physical and chemical properties consistent with mixtures of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates; in phenols, the enol form predominates. The present application encompasses all tautomeric forms of the compounds.

[0182] The term "stereoisomer" refers to isomers that have the same molecular formula but different spatial arrangement of atoms. Stereoisomers include enantiomers and diastereomers.

[0183] The compounds of the present application can have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms, or asymmetric double bonds, and therefore the compounds of the present application can exist in particular geometric or stereoisomeric forms. The particular geometric or stereoisomeric forms can be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)-isomers, (L)-isomers, atropisomers, as well as racemic mixtures or other mixtures thereof, such as enantiomeric or diastereomeric mixtures that are enriched in one enantiomeric or diastereomeric form, all of which are within the scope of the compounds of the present application. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms, or asymmetric phosphorus atoms can be present in a substituent group, and all such isomers and mixtures thereof are included within the scope of the compounds of the present application. The compounds of the present application containing an asymmetric atom can be isolated in optically active form or as racemic mixtures, and the optically active forms can be obtained, for example, by resolution of a racemic mixture or by synthesis from an optically active starting material or reagent.

[0184] The compounds of the present application can exist in atropisomeric forms, which are stereoisomers that arise when rotation about a single bond is hindered or greatly slowed. If the rotational barrier about a single bond is sufficiently high and the interconversion between isomers is sufficiently slow, then a single isomer can be isolated by methods known in the art, such as crystallization or chiral chromatography, or obtained by resolution, for example. Atropisomers of the compounds of the present application can be represented in the “P” or “M” configuration, or in other ways commonly known in the art. For further information on atropisomers, see Andrew Clark, Introduction to Stereochemistry, 147-148 (2020, 1st ed.).

[0185] The term “substituted” means that any one or more hydrogen atoms on the particular atom is replaced with a substituent group, which can be a heavy hydrogen and hydrogen variant, provided that the valency of the particular atom is normal and that the substituted compound is stable. When the substituent group is oxo (i.e., =0), it means that two hydrogen atoms are replaced, and oxo cannot occur on an aromatic group.

[0186] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and thus the description includes instances where the event or circumstance occurs and instances where it does not. For example, ethyl "optionally" substituted with halogen means that the ethyl group can be unsubstituted (CH2CH3), mono-substituted (e.g., CH2CH2F, CH2CH2C1, etc.), poly-substituted (e.g., CHFCH2F, CH2CHF2, CHFCH2C1, CH2CHC12, etc.), or fully substituted (CF2CF3, CF2CC13, CC12CC13, etc.). It will be understood by those skilled in the art that, for any group containing one or more substituents, such group does not include any substitution or substitution pattern that is not

[0187] When any variable (e.g., R a , R b ) occurs more than one time in a compound, its definition in each occurrence is independent of its definition at every other occurrence. b For example, if a group is substituted with 2 R b groups, then each R 1 group is independently selected.

[0188] When the number of occurrences of a linking group is zero, such as -(CH2)0-, it means that the linking group is a bond.

[0189] When one of the variables is selected from a bond or nothing, it means that the two groups to which it is attached are directly connected, such as when L represents a bond in A-L-Z, it means that the structure is actually A-Z.

[0190] When a linking group is referred to herein without specifying the direction of attachment, then the direction of attachment is arbitrary. For example, when L 1 in structural unit is selected from "C1-C3alkylene-O", then L 1 can either attach ring Q and R 1 to form "ring Q-C1-C3alkylene-O-R 1 ", or it can attach ring Q and R 1 to form "ring Q-O-C1-C3alkylene-R 1 ".

[0191] When a substituent is bonded to two atoms of a ring, the substituent can be bonded to either atom of the ring. For example, structural unit indicates that R 5 can be substituted at any position on the phenyl ring.

[0192] C m -C nThis refers to having an integer number of carbon atoms in the range mn. For example, "C1-C 10 "" means that the group can have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.

[0193] The term "alkyl" refers to a compound with the general formula C1. n H 2n+1 The alkyl group can be straight-chain or branched. The term "C1-C" refers to a hydrocarbon group. 10 "Alkyl" should be understood to mean a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Specific examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2- Dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, etc. The term "C1-C6 alkyl" can be understood as referring to an alkyl group having 1 to 6 carbon atoms, specific examples including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc. The term "C1-C3 alkyl" can be understood as referring to a straight-chain or branched saturated alkyl group having 1 to 3 carbon atoms. The "C1-C3"... 10 "alkyl" can include the range of "C1-C6 alkyl" or "C1-C3 alkyl", and the "C1-C6 alkyl" can further include "C1-C3 alkyl".

[0194] The term "alkoxy" refers to a group formed by the loss of a hydrogen atom from a hydroxyl group in straight-chain or branched alcohols; it can be understood as "alkyloxy" or "alkyl-O-". The term "C1-C"... 10 "Alkoxy" can be understood as "C1-C 10 "alkyloxy" or "C1-C" 10 Alkyl-O-"; the term "C1-C6 alkoxy" can be understood as "C1-C6 alkyloxy" or "C1-C6 alkyl-O-". The "C1-C" 10 "Alkoxy" can include the range of "C1-C6 alkoxy" and "C1-C3 alkoxy", and the "C1-C6 alkoxy" can further include "C1-C3 alkoxy".

[0195] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms and having at least one double bond. The term "C2-C"... 10 "Alkenyl" can be understood as representing a straight-chain or branched unsaturated hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, "C2-C". 10 The term "alkenyl" is preferably "C2-C6 alkenyl", more preferably "C2-C4 alkenyl", and even more preferably C2 or C3 alkenyl. It should be understood that when the alkenyl group contains more than one double bond, the double bonds may be separable or conjugated. 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.

[0196] The term "alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms and having at least one triple bond. The term "C2-C"... 10 "Alkyne" can be understood as representing a straight-chain or branched unsaturated hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. "C2-C" 10 Examples of "alkynyl" include, but are not limited to, ethynyl (-C≡CH), propynyl (-C≡CCH3, -CH2C≡CH), buty-1-alkynyl, buty-2-alkynyl, or buty-3-alkynyl. "C2-C 10 "Alynyl" can include "C2-C3 alkynyl", and examples of "C2-C3 alkynyl" include ethynyl (-C≡CH), propynyl-1-alkynyl (-C≡CCH3), and propynyl-2-alkynyl (-CH2C≡CH).

[0197] The term "cycloalkyl" refers to a fully saturated carbocyclic group that exists in the form of a monocyclic, fused, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 10-membered ring. For example, the term "C3-C..." 10 "Cycloalkyl" refers to a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9, or 10 cyclic carbon atoms. Specific examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decane, etc. The term "C3-C" is used in this context. 10"Cycloalkyl" can include "C3-C6cycloalkyl", the term "C3-C6cycloalkyl" means a cycloalkyl group having 3, 4, 5, or 6 ring carbon atoms, specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0198] The term "cycloalkyloxy" can be understood as "cycloalkyl-O-". Preferably, "C3-C6cycloalkyloxy" can include "C3-C6cycloalkyl-O-". 10 "Cycloalkyloxy" can include "C3-C6cycloalkyloxy".

[0199] The term "heterocyclyl" refers to a monocyclic, fused, spiro, or bridged ring radical that is completely saturated or partially saturated, having from 1 to 5 heteroatoms or heteroatom groups (i.e., an atom group containing a heteroatom) in the ring atoms, including, but not limited to, nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), -S(=0)2-, -S(=0)-, -P(=0)2-, -P(=0)-, -NH-, -S(=0)(=NH)-, -C(=0)NH-, or -NHC(=0)NH-, and the like, in the ring atoms. The term "3-10 membered heterocyclyl" means a heterocyclyl having a number of ring atoms that is 3, 4, 5, 6, 7, 8, 9, or 10, and having from 1 to 5 heteroatoms or heteroatom groups independently selected from the above-mentioned heteroatoms or heteroatom groups in the ring atoms. The "heterocyclyl" is overall non-aromatic. The term "3-10 membered heterocyclyl" can include 1, 2, or 3 heteroatoms or heteroatom groups. For example, the heteroatoms can be selected from nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), or boron (B); and the heteroatom groups can be selected from -S(=0)2-, -S(=0)-, -P(=0)2-, -P(=0)-, -NH-, -S(=0)(=NH)-, -C(=0)NH-, or -NHC(=0)NH-. The "4-7 membered heterocyclyl" and "5-7 membered heterocyclyl" can each include 1, 2, or 3 heteroatoms or heteroatom groups. Preferably, the "3-10 membered heterocyclyl" includes the ranges of "4-10 membered heterocyclyl", "4-7 membered heterocyclyl", "5-7 membered heterocyclyl", and the like, wherein examples of 4-membered heterocyclyl include, but are not limited to, azetidinyl, oxetanyl; examples of 5-membered heterocyclyl include, but are not limited to, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazole, or 2,5-dihydro-lH-pyrrolyl; examples of 6-membered heterocyclyl include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl, or 4H-[l,3,4]thiadiazinyl; examples of 7-membered heterocyclyl include, but are not limited to, diazepanyl. The heterocyclyl can also be a bicyclic radical, wherein specific examples of 5,5 membered bicyclic radicals include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(lH)-yl; specific examples of 5,6 membered bicyclic radicals include, but are not limited to, hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl, 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazinyl, or 5,6,7,8-tetrahydroimidazo[l,5-a]pyrazinyl. Optionally, the heterocyclyl can be a benzo-fused ring radical of the above-mentioned 4-7 membered heterocyclyl, examples include, but are not limited to, dihydroisoquinolinyl, and the like.Preferably, "3-10 membered heterocyclyl" can include the range of "4-7 membered heterocyclyl", "5-7 membered heterocyclyl", "5-6 membered heterocyclyl", "4-7 membered heterocycloalkyl", "5-7 membered heterocycloalkyl", "5-6 membered heterocycloalkyl", and the like, and "4-7 membered heterocyclyl" can further include the range of "5-7 membered heterocyclyl", "5-6 membered heterocyclyl", "5-7 membered heterocycloalkyl", "5-6 membered heterocycloalkyl", and the like. Although some of the bicyclic heterocyclyl groups contain a benzene ring or a heteroaromatic ring partially, the heterocyclyl groups are still non-aromatic as a whole in the present application.

[0200] The term "heterocyclyloxy" can be understood as "heterocyclyl-O-", and the term "3-10 membered heterocyclyloxy" can be understood as "3-10 membered heterocyclyl-O-".

[0201] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and exists in the form of a monocyclic, fused ring, bridged ring, or spirocyclic, etc., having 1-5 heteroatoms or heteroatomic groups (i.e., an atom group containing a heteroatom) in its ring of ring atoms, including but 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)2-, -S(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH-, or -NHC(=O)NH-, etc. The term "3-10 membered heterocycloalkyl" can include 1, 2, or 3 heteroatoms or heteroatomic 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 heteroatomic 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-. The "4-7 membered heterocycloalkyl" and "5-7 membered heterocycloalkyl" can each include 1, 2, or 3 heteroatoms or heteroatomic groups. The term "3-10 membered heterocycloalkyl" means a heterocycloalkyl group having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, and having 1-5 ring atoms independently selected from the above-mentioned heteroatoms or heteroatomic groups. Preferably, the "3-10 membered heterocycloalkyl" includes "4-7 membered heterocycloalkyl", wherein examples of 4-membered heterocycloalkyl groups include but are not limited to azetidinyl, oxetanyl, thietanyl, examples of 5-membered heterocycloalkyl groups include but are not limited to tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, 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, 1,4-dithianyl, and examples of 7-membered heterocycloalkyl groups include but are not limited to azepanyl, oxepanyl, thiepanyl.

[0202] The term "heterocycloalkyloxy" can be understood as "heterocycloalkyl-O-".

[0203] The term "heteroaryl" refers to an aromatic monocyclic or fused polycyclic system containing at least one ring atom selected from N, O, or S, with the remaining ring atoms being C aromatic cyclic groups. The term "5-10-membered heteroaryl" should be understood as a monovalent monocyclic or bicyclic aromatic ring system having 5, 6, 7, 8, 9, or 10 ring atoms, particularly 5, 6, 9, or 10 ring atoms, and containing 1-5, preferably 1-3, heteroatoms independently selected from N, O, and S; and, in each case, may be benzofused. Specifically, "5-10-membered heteroaryl" is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl and their benzo[derivatives], such as benzofuranyl, benzothienyl, benzothiazolyl, benzooxazolyl, benzoisooxazolyl, benzoimidazolyl, benzotriazolyl, indazole, indolyl, isindolyl and others; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and their benzo[derivatives], such as quinolinyl, quinazolinyl, isoquinolinyl and others.

[0204] The term "5-6 membered heteroaryl" should be understood as a monovalent aromatic ring system having 5 or 6 ring atoms, and containing 1-3 heteroatoms independently selected from N, O, and S. Specifically, it is selected from thiophene, furanyl, pyrrole, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.

[0205] The term "heteroaryloxy" can be understood as "heteroaryl-O-".

[0206] The term "aryl" refers to an aromatic ring group consisting of an all-carbon monocyclic or fused polycyclic aromatic ring with a conjugated π-electron system. The term "C6-C"... 10 "Aryl" should be understood to preferably represent a monovalent aromatic or partially aromatic hydrocarbon ring having 6 to 10 carbon atoms. In particular, a ring with 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring with 9 carbon atoms ("C9 aryl"), such as indenyl or indenyl; or a ring with 10 carbon atoms ("C9 aryl"). 10 Aryl), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.

[0207] The term "aryloxy group" can be understood as "aryl-O-".

[0208] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0209] The term “prevention” means the prevention of the occurrence of a disease or disease state in mammals, especially when such mammals are susceptible to the disease state but have not yet been diagnosed with it.

[0210] The term "treatment" means the administration of a compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0211] (i) inhibiting the disease or condition, i.e., arresting its development;

[0212] (i) relieving the disease or condition, i.e., causing regression of the disease or condition.

[0213] The term "therapeutically effective amount" means an amount of a compound of the application that (i) treats a particular disease, condition, or disorder, (ii) delays or reduces the symptoms of a particular disease, condition, or disorder, or (iii) delays onset of a particular disease, condition, or disorder as described herein. The amount of a compound of the application that will constitute a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the manner of administration, and the age of the mammal to be treated, but can be determined routinely by the skilled practitioner as an initial consideration.

[0214] The term "pharmaceutically acceptable excipient" means an excipient that is not biologically or otherwise undesirable, i.e., the excipient can be administered to an organism without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.

[0215] The words "comprise," "comprises," or "comprising" and variations thereof, such as "comprises" or "comprising," when used in this disclosure and claims shall be understood to specify the presence of the stated features, integers, steps or components but not to preclude the presence or addition of one or more other features, integers, steps, components, or groups thereof.

[0216] The compounds of the application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by a combination of the specific embodiments set forth below with other chemical synthetic methods well known in the art, and equivalents thereof as appreciated by those skilled in the art, preferred embodiments including but not limited to the examples of the application.

[0217] The application also includes isotopically-labeled compounds of the application which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be present in compounds of the application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, iodine, and chlorine, such as 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, and the like.

[0218] Certain isotopically-labeled compounds of the present application (for example, those 3 H and 14 C) can be used in compound and / or substrate tissue distribution analysis. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes such as 15 O, 13 N, 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically-labeled compounds of the present application can generally be prepared by

[0219] Furthermore, substitution with heavier isotopes such as deuterium (i.e., 2 H, D) can afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence can be preferred in some circumstances. Deuterium substitutions can be partial or total, with partial deuterium substitution meaning at least one hydrogen is replaced by at least one deuterium.

[0220] Pharmaceutical compositions of the present application can be prepared by combining a compound of the present application with a suitable pharmaceutically acceptable excipient, such as can be formulated into solid, semi-solid, liquid, or gaseous dosage forms, such as tablets, pills, capsules, powders, granules, ointments, creams, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols and the like.

[0221] Typical routes of administering a compound of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, include, but are not limited to, oral, rectal, topical, inhalant, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

[0222] The pharmaceutical compositions of the present application can be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, lyophilizing processes, and so on.

[0223] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by combining the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, dragees, sugar-coated tablets, capsules, liquids, gels, slurries, suspensions, and the like, for oral administration to a patient.

[0224] Solid oral compositions can be prepared by conventional mixing or compaction methods. For example, the active compounds can be mixed with a solid excipient, optionally ground, and if necessary, with other suitable excipients, and then processed into granules, which are filled into tablets or sugar-coated tablets. Suitable excipients include, but are not limited to, binding agents, diluents, disintegrating agents, lubricants, glidants, sweetening or flavoring agents, and the like.

[0225] The pharmaceutical composition can also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.

[0226] In all methods of administration of the compounds of general formula (I) described herein, the daily dose is from 0.01 to 100 mg / kg of body weight, preferably from 0.05 to 50 mg / kg of body weight, and more preferably from 0.1 to 30 mg / kg of body weight, in single or divided doses.

[0227] The chemical reactions of the specific embodiments of the present application are performed in solvents appropriate to the reagents and materials employed and suitable for the chemical changes being effected. In the synthetic schemes and examples that follow, all substituents unless otherwise indicated, are as previously described. It is understood that enantiomers and racemates of the compounds of the present application can be prepared from the corresponding enantiomeric or racemic starting materials, by employing enantiomeric or racemic synthetic procedures. DETAILED DESCRIPTION

[0228] The application is described in detail below by way of examples, but it is not meant to be limited by any of them. The present application has been described in detail by making specific reference only to certain embodiments thereof which are exemplary. Changes in form and substitution of equivalents are contemplated as circumstances can suggest themselves to those skilled in the art without departing from the spirit and scope of the application. All reagents used in the present application are commercially available and used without further purification.

[0229] Unless otherwise indicated, the proportions stated in the mixture of solvents are volume proportions.

[0230] Unless otherwise indicated, % means wt%.

[0231] Compounds are named by hand or by software. Commercially available compounds are named using the vendor catalog name.

[0232] The structure of the compounds is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The unit of NMR shift is 10 -6 (ppm). The solvent for NMR determination is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC 50 " refers to the half maximal inhibitory concentration, which refers to the concentration at which the maximum inhibitory effect is halved.

[0233] Explanation of terms or abbreviations:

[0234] Me: methyl

[0235] Et: ethyl

[0236] Ph: phenyl

[0237] t-Bu: tert-butyl

[0238] DMF: N,N-dimethylformamide

[0239] LCMS / LC-MS: liquid chromatography mass spectrometry

[0240] DCE: 1,2-dichloroethane

[0241] t-BuONO: tert-butyl nitrite

[0242] THF: tetrahydrofuran

[0243] NBS: N-bromosuccinimide

[0244] DPPA: diphenyl phosphorous azide

[0245] TEA: triethylamine

[0246] toluene: toluene

[0247] DCM: dichloromethane

[0248] SEMCl: 2-(trimethylsilyl)ethoxymethyl chloride

[0249] SEM: 2-(trimethylsilyl)ethoxymethyl

[0250] Pd(dppf)Cl2 / PdCl2(dppf): [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride

[0251] dioxane: dioxane

[0252] ​Pd(dtbpf)Cl2: 1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium

[0253] DMSO: Dimethyl sulfoxide

[0254] Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium

[0255] XantPhos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

[0256] Pin2B2: Bis(pinacolato)diboron

[0257] NMP: N-methylpyrrolidone

[0258] TFA: Trifluoroacetic acid

[0259] LiHMDS: Lithium bis(trimethylsilyl)amide

[0260] BrettPhos: Dicyclohexyl(2,4,6-triisopropyl-3,6-dimethoxy-[1,1- biphenyl]-2-yl)phosphine

[0261] BrettPhos Pd G3: (2-Dicyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)palladium(II) mesylate

[0262] t-AmylOH: Tert-amyl alcohol

[0263] HATU: O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0264] DIEA: Diisopropylethylamine

[0265] xylene: Xylenes

[0266] DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene

[0267] ACN: Acetonitrile

[0268] CD3I: Deuterated iodomethane

[0269] Methanol: Methanol

[0270] -OTBS: (Tert-butyldimethylsilyl)oxy

[0271] MsCl: Methanesulfonyl chloride

[0272] NCS: N-Chlorosuccinimide

[0273] EtI: Ethyl iodide

[0274] O(Tf)2: Trifluoromethanesulfonic anhydride

[0275] Lutidine: 2,6-Dimethylpyridine

[0276] Chloroform

[0277] Pd(PPh3)4: Tetra(triphenylphosphine)palladium

[0278] SOCl2: thionyl chloride

[0279] LDA: Lithium diisopropylamino

[0280] Ruphos: 2-Bicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl

[0281] Ruphos Pd G3: (2-Dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II)methanesulfonate

[0282] LiHMDS: Lithium bis(trimethylsilylamine)

[0283] TMAF: Tetramethylammonium fluoride

[0284] BTMPO: N,N'-bis(2,4,6-trimethoxyphenyl)oxalamide

[0285] acetone: Acetone

[0286] Example 1: 5-(2-chlorophenyl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]diazanaphth-4-one (Compound 1)

[0287]

[0288] Step 1: Synthesis of 2-((2-chlorophenyl)amino)-6-(trifluoromethyl)-3-cyanopyridine (intermediates 1-2)

[0289] Chloroaniline (7.20 g, 56.46 mmol) was dissolved in DMF (100 mL), and sodium hydride (9.68 g, 242.07 mmol, 60% active content) was added at 0 °C under nitrogen protection. The reaction was kept at 0 °C for 1 h, and then a solution of the reactant 1-1 (10 g, 48.41 mmol) in DMF (20 mL) was added dropwise at 0 °C. The reaction was stirred at 25 °C for 16 h. LCMS showed that the reaction was completed. The reaction mixture was quenched with 200 mL of water at 0 °C, and then diluted with 200 mL of ethyl acetate. The reaction mixture was extracted with ethyl acetate (200 mL*3) three times. The organic phase was washed with brine (400 mL*3) three times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated solution was separated by column chromatography (silica gel, eluent: 0-2% ethyl acetate / petroleum ether, gradient @ 100 mL / min) to give the title compound (5.16 g). 120 g 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 title compound (11.64 g).

[0290] MS m / z (ESI): 297.9 [M+H] + .

[0291] 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)

[0292] 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 malonic acid dimethyl ester (6.87 g, 52.01 mmol) was added at 25 °C under nitrogen protection. The reaction was heated to 70 °C and stirred at 70 °C for 16 h. Then tin tetrachloride (2.23 g, 8.56 mmol) and malonic acid dimethyl ester (1.15 g, 8.70 mmol) were added at 25 °C under nitrogen protection. The reaction was heated to 70 °C and stirred at 70 °C for 4 h. LC-MS showed that the reaction was completed. The reaction was quenched with water (150 mL), diluted with ethyl acetate (150 mL), and extracted with ethyl acetate (150 mL*3) three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. The concentrated solution was separated by column chromatography (silica gel, eluent: 0-100% ethyl acetate / petroleum ether, gradient @ 100 mL / min; eluent: 0-20% methanol / ethyl acetate, gradient @ 100 mL / min) to give the title compound (11.64 g). 120 g 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 title compound (11.64 g).

[0293] MS m / z (ESI): 389.0 [M+H] + .

[0294] Step 3: Synthesis of 4-amino-l-(2-chlorophenyl)-7-(trifluoromethyl)-l,8- naphthyridin-2(lH)-one (Intermediate 1-4)

[0295] Intermediate 1-3 (11.64 g, 29.27 mmol) was dissolved in methanol (115 mL), and aqueous sodium hydroxide solution (10 M, 87.80 mL) was added dropwise at 0 °C. The temperature of the reaction system was raised to 25 °C and stirred at 25 °C for 16 hours. Then, the temperature of the reaction system was raised to 50 °C and stirred at 50 °C for 70 hours. LC-MS showed that the reaction was completed. The reaction solution was concentrated under reduced pressure to remove methanol, and the concentrated solution was diluted with water (150 mL) and extracted with ethyl acetate (200 mL*4) four times. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to dryness. The title compound (4.5 g) was obtained by column chromatography (eluent: 0-4% methanol / dichloromethane, gradient @ 100 mL / min). 80 g Fast silica gel column, eluent: 0-4% methanol / dichloromethane, gradient @ 100 mL / min.

[0296] MS m / z (ESI): 340.1 [M+H] + .

[0297] Step 4: Synthesis of 4-amino-l-(2-chloro-4-nitrophenyl)-3-nitro-7- (trifluoromethyl)-l,8-naphthyridin-2(lH)-one (Intermediate 1-5)

[0298] 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 solution was stirred at 25 °C for 0.5 hours. LC-MS monitoring showed that the starting material had completely reacted and the target product had been formed. The reaction solution was slowly poured into water (20 mL) at 0 °C, followed by adjusting the pH to 8 with saturated aqueous sodium bicarbonate solution, and extracting with ethyl acetate three times. The organic layer was concentrated under reduced pressure to dryness. The title compound was obtained as a crude product (135 mg).

[0299] MS m / z (ESI): 430.1 [M+H] + .

[0300] Step 5: Synthesis of 3,4-diamino-l-(4-amino-2-chlorophenyl)-7- (trifluoromethyl)-l,8-naphthyridin-2(lH)-one (Intermediate 1-6)

[0301] Intermediate 1-5 (110 mg, 256.00 μmol) was dissolved in methanol (4 mL), iron powder (220.00 mg), ammonium chloride (109.55 mg, 2.05 mmol) and water (1 mL) were added. The reaction was stirred at 90 °C for 16 h. LC-MS monitoring showed that the starting material had been completely reacted and the target product was formed. The reaction was concentrated under reduced pressure, extracted with ethyl acetate three times, and the organic layer was concentrated to dryness under reduced pressure. The title compound was obtained as a crude product (94 mg).

[0302] MS m / z (ESI): 370.1 [M+H] + .

[0303] Step 6: Synthesis of 5-(4-amino-2-chlorophenyl)-7-(trifluoromethyl)-1,5- dihydro-4H-imidazo[4,5-c][1,8]naphthridin-4-one (Intermediate 1-7)

[0304] Intermediate 1-6 (90 mg, 243.42 μmol) was dissolved in triethyl orthoformate (2.45 g, 16.56 mmol). The reaction was stirred at 120 °C for 4 h under nitrogen protection. LC-MS monitoring showed that the starting material had been completely reacted and the target product was formed. The triethyl orthoformate was removed by concentrating the reaction under reduced pressure to obtain the title compound as a crude product (92 mg).

[0305] MS m / z (ESI): 379.9 [M+H] + .

[0306] Step 7: Synthesis of 5-(2-chlorophenyl)-7-(trifluoromethyl)-1,5-dihydro-4H- imidazo[4,5-c][1,8]naphthridin-4-one (Compound 1)

[0307] 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 was stirred at 70 °C for 1 h. LC-MS monitoring showed that the starting material had been completely reacted and the target product was formed. The tetrahydrofuran was removed by concentrating the reaction under reduced pressure, and the residue was purified by high performance liquid chromatography ((column: YMC Triart C18 150*30mm*5μm; mobile phase: [A: 0.05% ammonia water (v / v), B: acetonitrile]; B%: 30%-50%, 11 min)) to obtain the title compound (7.2 mg).

[0308] 1H NMR (400 MHz, DMSO-d6) d = 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);

[0309] MS m / z (ESI): 365.0 [M+H] + .

[0310] Example 2, 5-(2-chlorophenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H- imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 2)

[0311]

[0312] Step 1: Synthesis of 4-amino-3-bromo-1-(2-chlorophenyl)-7- (trifluoromethyl)-1,8-naphthyridin-2(1H)-one (Intermediate 2-1)

[0313] Intermediate 1-4 (400 mg, 1.18 mmol) was dissolved in acetonitrile (8 mL), N- bromosuccinimide (209.58 mg, 1.18 mmol) was added at 25 °C, the reaction solution was stirred at 25 °C for 0.1 h. LC-MS monitoring showed that the raw material had been completely reacted, and the target product was formed. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 48%~100%) to give the title compound (488.0 mg).

[0314] MS m / z (ESI): 420.1 [M+H] + .

[0315] Step 2: Synthesis of 1-(2-chlorophenyl)-4-(methylamino)-7-(trifluoromethyl)-1,8- naphthyridin-2(1H)-one (Intermediate 2-2)

[0316] Intermediate 2-1 (488.0 mg, 1.17 mmol) was dissolved in THF (10 mL), and sodium hydride (93.59 mg, 2.34 mmol, 60% active content) was added under nitrogen protection at 0 °C. The reaction was stirred at 0 °C for 0.5 h, and iodomethane (166.07 mg, 1.17 mmol) was added at 0 °C. The reaction solution was stirred at 20 °C for 16 h. LC-MS monitoring showed that the raw material had been completely reacted, and the target product was formed. The reaction solution was quenched with water (10 mL) at 0 °C, and extracted with ethyl acetate three times. 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: 12 g Mobile phase: ethyl acetate / petroleum ether; ethyl acetate %: 0~74%); to give the title compound (109 mg).

[0317] MS m / z (ESI): 353.9 [M+H] + .

[0318] Step 3: Synthesis of 1-(2-chloro-4-nitrophenyl)-4-(methylamino)-3-nitro-7- (trifluoromethyl)-1,8-naphthyridin-2(1H)-one (Intermediate 2-3)

[0319] Intermediate 2-2 (109 mg, 308.15 μmol) was dissolved in sulfuric acid (0.3 mL), nitric acid (38.83 mg, 616.30 μmol) was added dropwise at 0 °C, and the reaction was allowed to react at 0 °C for 1 hour. LC-MS monitoring showed that the raw material had completely reacted and the target product was formed. The reaction solution was diluted with water (50 mL) at 0 °C, the pH was adjusted to 8 with a saturated aqueous sodium carbonate solution, and extracted with ethyl acetate three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to give the title compound (129 mg).

[0320] MS m / z (ESI): 444.0 [M+H] + .

[0321] Step 4: Synthesis of 3-amino-1-(4-amino-2-chlorophenyl)-4-(methylamino)-7- (trifluoromethyl)-1,8-naphthyridin-2(1H)-one (Intermediate 2-4)

[0322] Intermediate 2-3 (129 mg, 290.72 μmol) was dissolved in methanol (2 mL), 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, and the reaction was allowed to react at 90 °C for 16 hours. LC-MS monitoring showed that the raw material had completely reacted and the target product was formed. The reaction solution was filtered, the methanol was removed by concentration under reduced pressure, extracted with ethyl acetate three times, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to give the title compound (97 mg).

[0323] MS m / z (ESI): 384.0 [M+H] + .

[0324] 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)

[0325] 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 was stirred at 120 °C for 4 h. LC-MS monitoring showed that the starting material had been completely reacted and the target product was formed. The reaction was concentrated to dryness under reduced pressure to give the title compound (110 mg).

[0326] MS m / z (ESI): 393.9 [M+H] + .

[0327] Step 6: Synthesis of 5-(2-chlorophenyl)-l-methyl-7-(trifluoromethyl)-l,5- dihydro-4H-imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 2)

[0328] 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 was stirred at 70 °C for 1 h. LC-MS monitoring showed that the starting material had been completely reacted and the target product was formed. The reaction was concentrated to dryness under reduced pressure, and the residue was purified by high performance liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: [A: water (with 0.05% ammonia water v / v), B: acetonitrile]; B%: 38%-58%, 11 min) to give the title compound (3.1 mg).

[0329] 1 H NMR (400 MHz, 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);

[0330] MS m / z (ESI): 379.0 [M+H] + .

[0331] Example 3, 5-(2-chlorophenyl)-3-methyl-7-(trifluoromethyl)-3,5-dihydro-4H- imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 3)

[0332]

[0333] Compound 1 (117 mg, 320.80 μmol) was dissolved in N,N-dimethylformamide (1.5 mL), sodium hydride (25.66 mg, 641.61 μmol, 60% active content) was added at 0 °C, the reaction solution was reacted at 0 °C for 0.1 hour. Iodomethane (45.53 mg, 320.80 μmol) was added dropwise to the reaction system at 0 °C, and the reaction solution was reacted at 0 °C for 0.9 hour. LC-MS was used to monitor the formation of the target product. The reaction solution was quenched with water, diluted with methanol (1.5 mL), and purified by high performance liquid chromatography ((column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: [A: water (0.05% ammonia water v / v), B: acetonitrile]; B%: 40%-60%, 11 min)) to give the title compound (5.2 mg).

[0334] 1 H NMR (400 MHz, 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);

[0335] MS m / z (ESI): 379.0 [M+H] + .

[0336] Example 4, 5-(2-chlorophenyl)-7-(trifluoromethyl)-3,5-dihydro-1H-imidazo[4,5- c][1,8]naphthyridine-2,4-dione (Compound 4)

[0337]

[0338] Step 1: synthesis of intermediate 4-1

[0339] Intermediate 1-3 (1 g, 2.51 mmol) was dissolved in methanol, and aqueous sodium hydroxide solution (10 M) was added, and the reaction solution was stirred at 25 °C for 16 hours. LC-MS was used to monitor that the starting material had completely reacted and the target product was formed. Hydrochloric acid (6 M) was added to the reaction solution to adjust pH = 7, and the reaction solution was extracted with ethyl acetate three times, and the organic layer was concentrated to dryness under reduced pressure to give the crude title compound (590 mg).

[0340] MS m / z (ESI): 384.0 [M+H] + .

[0341] Step 2: Synthesis of 5-(2-chlorophenyl)-7-(trifluoromethyl)-3,5-dihydro-lH- imidazo[4,5-c][l,8]naphthyridine-2,4-dione (Compound 4)

[0342] Intermediate 4-1 (50 mg, 130.31 pmol) was dissolved in toluene, triethylamine (19.78 mg, 195.46 pmol) and diphenyl phosphorazide (39.45 mg, 143.34 pmol) were added and the reaction was stirred at 100 °C for 16 h. LC-MS monitoring showed that the starting material had completely reacted and the target product was formed. 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 then by high performance liquid chromatography (column: YMC-Actus Triart C18 150*30 mm*5 pm; mobile phase: [A: water (0.05% ammonia water v / v), B: acetonitrile]; B%: 20%-40%, 11 min) to give the title compound (3.4 mg)

[0343] MS m / z (ESI): 381.1 [M+H] + .

[0344] 1 H NMR (400 MHz, Methanol-d4) d 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).

[0345] Example 5, 5-(2-chlorophenyl)-2-methoxy-7-(trifluoromethyl)-l,5-dihydro-4H- imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 5)

[0346]

[0347] Compound 4 (60 mg, 157.60 pmol) was dissolved in dichloromethane, trimethyl oxonium tetrafluoroborate (46.62 mg, 315.20 pmol) was added and the reaction was stirred at 40 °C for 16 h. LC-MS monitoring showed that the starting material had completely reacted and the target product was formed. 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 pm; mobile phase: [A: water (0.225% formic acid v / v), B: acetonitrile]; B%: 25%-55%, 12 min) to give the title compound (3.7 mg).

[0348] MS m / z (ESI): 395.0 [M+H] + .

[0349] 1 H NMR (400 MHz, DMSO-d6) δ 13.48 (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).

[0350] Example 6, 5-(2-chlorophenyl)-7-(trifluoromethyl)-3,5-dihydro-4H-pyrazolo[3,4- c] [ 1,8] naphthyridin-4-one (Compound 6)

[0351]

[0352] Step 1: Synthesis of ethyl 4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazole-3-carboxylate (Intermediate 6-2)

[0353] Intermediate 6-1 (1 g, 3.75 mmol) was dissolved in THF (15 mL), the reaction was cooled to 0 °C, sodium hydride (300 mg, 7.51 mmol, 60% active content) was added, the reaction was stirred at 25 °C for 0.5 h, 2- (trimethylsilyl)ethoxymethyl chloride (936 mg, 5.63 mmol) was added to the reaction under ice water bath, the reaction was stirred at 25 °C for 15 h under nitrogen protection. LC-MS detection showed that the reaction was completed. After the reaction was cooled to room temperature, it was quenched slowly with ice water (10 mL), then extracted with ethyl acetate (30 mL*3), the combined organic phase was washed with brine (50 mL*3), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by preparative thin layer chromatography (silica, petroleum ether: ethyl acetate = 10:3) to give the title compound (700 mg).

[0354] MS m / z (ESI): 397 [M+H] + .

[0355] 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)

[0356] Intermediate 6-2 (700 mg, 1.76 mmol) and bis-pinacolborate (897 mg, 3.53 mmol) were dissolved in anhydrous dimethyl sulfoxide (10 mL). Potassium acetate (345 mg, 3.53 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (Pd(dppf)Cl2) (128 mg, 0.17 mmol) were added to the solution. The reaction mixture was stirred at 100 °C for 15 h under nitrogen protection. The reaction was detected by LC-MS. After the reaction was cooled 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 an appropriate amount of anhydrous sodium sulfate. The title compound (500 mg) was obtained by preparative thin-layer chromatography (silica, dichloromethane:methanol = 10:1).

[0357] MS m / z(ESI): 397 [M+H] + .

[0358] Step 3: Synthesis of ethyl 4-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylic acid (intermediate 6-5)

[0359] 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 to the solution. The reaction mixture was stirred at 100 °C for 16 h under nitrogen protection. The reaction was confirmed by LC-MS. After the reaction was cooled to room temperature, water (30 mL) and ethyl acetate (40 mL) were added sequentially. The organic phase was washed with water (30 mL x 2) and dried over an appropriate amount of anhydrous sodium sulfate. The title compound (300 mg) was obtained by preparative thin-layer chromatography (silica, dichloromethane:methanol = 5:1).

[0360] MS m / z(ESI): 450 [M+H] + .

[0361] Step 4: Synthesis of 5-(2-chlorophenyl)-7-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2,5-dihydro-4H-pyrazolo[3,4-c][1,8]naphthidium-4-one (intermediates 6-7)

[0362] Intermediate 6-5 (150 mg, 0.33 mmol) and intermediate 6-6 (85 mg, 0.66 mmol) were dissolved in N-methylpyrrolidone (4 mL), to which was added 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), and the reaction was stirred at 100 °C under nitrogen protection for 15 h. LC-MS detection showed that the reaction was completed. After the reaction was cooled to room temperature, water (15 mL) and ethyl acetate (20 mL) were added in turn, the organic phase was washed with water (30 mL*2), and the washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate. Concentration under reduced pressure gave the title compound (160 mg) as a crude product.

[0363] MS m / z (ESI): 495 [M+H] + .

[0364] Step 5: Synthesis of 5-(2-chlorophenyl)-7-(trifluoromethyl)-3,5-dihydro-4H-pyrazolo[3,4-c][1,8]naphthyridin-4-one (Compound 6)

[0365] Intermediate 6-7 (160 mg) was dissolved in dichloromethane (3 mL). To this was added trifluoroacetic acid (1.5 mL), and the reaction was stirred at 25 °C for 0.5 h. After TLC monitoring showed that the reaction was complete, saturated aqueous sodium bicarbonate solution (20 mL) was added to adjust the pH to 8, and dichloromethane (20 mL*3) was used for extraction. The organic phase was washed with water (30 mL*2), dried over an appropriate amount of anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and 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%-45%, 12 min) to give the title compound (2.3 mg).

[0366] MS m / z (ESI): 365 [M+H] + .

[0367] 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).

[0368] Example 7, 5-(2-chlorophenyl)-7-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[4,3- c][1,8]naphthyridin-4-one (Compound 7)

[0369]

[0370] Step 1: Synthesis of ethyl 5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4- carboxylate (Intermediate 7-2)

[0371] Intermediate 7-1 (4.0 g, 15.04 mmol) was dissolved in tetrahydrofuran solution (40 mL), sodium hydride (60% active content) (820 mg, 20.5 mmol) was added at 0-5 °C, the reaction solution 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 solution, and stirring was performed at room temperature for 12 h. After the reaction was completed by LC-MS detection, the reaction solution was slowly poured into saturated aqueous ammonium chloride solution (50 mL), extracted with ethyl acetate (60 mL*2), the combined organic phase was washed with saturated brine (100 mL), and the washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to dryness, and the residue was subjected to preparative thin layer chromatography (silica, petroleum ether: ethyl acetate = 10:1) to give the title compound (2.7 g).

[0372] MS m / z (ESI): 397.0 [M+H] + .

[0373] 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)

[0374] 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)Cl2 (297 mg, 0.46 mmol) were added, and the reaction solution was stirred at 80 °C under nitrogen protection for 2 h. After the reaction was completed by LC-MS detection, water (15 mL) and ethyl acetate (15 mL) were sequentially added after the reaction solution was cooled to room temperature, the organic phase was washed with water (15 mL*2), and the washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to dryness, and the residue was subjected to preparative thin layer chromatography (silica, petroleum ether: ethyl acetate = 10:1) to give the title compound (800 mg).

[0375] MS m / z (ESI): 450.0 [M+H] + .

[0376] Step 3: Synthesis of 5-(2-chlorophenyl)-7-(trifluoromethyl)-1,5-dihydro-4H- pyrazolo[4,3-c][1,8]naphthyridin-4-one (Compound 7)

[0377] Intermediate 7-4 (250.0 mg, 0.56 mmol) was dissolved in N-methylpyrrolidine (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 Pd2(dba)3(50.9 mg, 0.06 mmol) were added. The reaction was stirred at 100 °C under nitrogen for 12 h. The reaction was checked by LC-MS. The reaction was filtered and 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; a mixture of water (containing 0.05% NH4HCO3) and acetonitrile of decreasing polarity as eluents; acetonitrile gradient ratio 55-80%, elution time 13 min] to give the title compound (2 mg).

[0378] MS m / z (ESI): 365.0 [M+H] + .

[0379] 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).

[0380] Example 8, 5-(2-chlorophenyl)-7-(trifluoromethyl)oxazolo[4,5-c][1,8]naphthyridin- 4(5H)-one (Compound 8)

[0381]

[0382] Step 1: Synthesis of 2-((2-chlorophenyl)amino)-6-(trifluoromethyl)pyridine-3- carboxylic acid (Intermediate 8-3)

[0383] Intermediate 8-1 (1.0 g, 4.5 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and lithium bis(trimethylsilyl)amide (LiHMDS) in THF (1 M, 9.76 ml, 9.76 mmol) was added dropwise at -78 °C. After the addition was completed, the reaction was allowed to react at -78 °C for 1 h, and then intermediate 8-2 (840.66 mg, 5.3 mmol) was added. The reaction was allowed to warm to room temperature and react for 3 h. Saturated ammonium chloride (10 mL) and ethyl acetate (10 mL*3) were added to the reaction solution in sequence, 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 concentrated. Purification 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%-50%, 11 min) gave the title compound (400 mg).

[0384] MS m / z (ESI): 317.1 [M+H] + .

[0385] Step 2: Synthesis of ethyl 5-(2-((2-chlorophenyl)amino)-6- (trifluoromethyl)pyridin-3-yl)oxazole-4-carboxylate (Intermediate 8-5)

[0386] Intermediate 8-3 (200 mg, 631.59 μmol) and cesium carbonate (412 mg, 1.26 mmol) were dissolved in N,N-dimethylformamide (4 mL), and diazophosphoryl diphenyl phosphate (DPPA) (347.63 mg, 1.26 mmol) was added at 0 °C. After the addition was completed, the reaction was allowed to react at room temperature for 1 h, and then intermediate 8-4 (71.4 mg, 631.59 μmol) was added at 0 °C. The reaction was allowed to stir at 25 °C for 2 h. Water (5 mL) and ethyl acetate (5 mL*3) were added to the reaction solution in sequence, and the organic phase was washed with saturated brine (5 mL*2). The washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate, and purified by preparative thin-layer chromatography (silica, petroleum ether: ethyl acetate = 100:0-50:50) to give the title compound (90 mg).

[0387] MS m / z (ESI): 411.9 [M+H] + .

[0388] Step 3: Synthesis of 5-(2-chlorophenyl)-7-(trifluoromethyl)oxazolo[4,5- c][1,8]naphthyridin-4(5H)-one (Compound 8)

[0389] Intermediate 8-5 (80 mg, 194.29 pmol) and cesium carbonate (190 mg, 582.86 pmol) were dissolved in N,N-dimethylformamide (1 mL) and reacted at 60 °C for 3 h. The reaction solution was filtered and purified by preparative high performance liquid chromatography (column: Gemini NXC18 5 pm*10*150 mm; mobile phase: A: water (0.225% formic acid v / v), B: acetonitrile; B%: 30%-50%, 11 min) to give the title compound (30 mg).

[0390] MS m / z (ESI): 366.1 [M+H] + .

[0391] 1 H NMR (400 MHz, DMSO-d6) d 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).

[0392] Example 9, 5-(2-chlorophenyl)-2,7-bis(trifluoromethyl)-1,5-dihydro-4H- imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 9)

[0393]

[0394] 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)

[0395] Intermediate 1-6 (58 mg, 156.87 pmol) was added to trifluoroacetic acid and the reaction solution was stirred at 70 °C for 16 h. LCMS showed the formation of the target product. The reaction solution was concentrated to dryness under reduced pressure to give the title compound (60 mg).

[0396] MS m / z (ESI): 448.0 [M+H] + .

[0397] 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)

[0398] Intermediate 9-1 (60 mg, 134.01 μmol) was dissolved in N,N-dimethylformamide and tetrahydrofuran, and tert-butyl nitrite (62.19 mg, 603.05 μmol) was added. The reaction solution was stirred at 70 °C for 1 h. LCMS showed that the target product was formed. The reaction solution was concentrated to dryness under reduced pressure, and purified by preparative liquid chromatography (column: Waters Xbridge BEH C18 100*25mm*5μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 39%-59%, 12 min) to give the title compound (13.9 mg).

[0399] MS m / z (ESI): 433.0 [M+H] + .

[0400] 1 H NMR (400 MHz, 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)

[0401] Example 10, 5-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3,5-dihydro-1H-imidazo[4,5- c][1,8]naphthyridine-2,4-dione (Compound 10)

[0402]

[0403] Step 1: Synthesis of 2-chloro-6-ethoxy-3-cyanopyridine (Intermediate 10-2)

[0404] Intermediate 10-1 (10 g, 57.80 mmol) was dissolved in N,N-dimethylformamide (200 mL) at 25 °C, and sodium ethoxide (3.93 g, 57.80 mmol) was added. The reaction solution was stirred at 25 °C for 16 h under nitrogen protection. LCMS showed that the target product had been formed. After the reaction was completed, ethyl acetate (200 mL) and water (400 mL) were added to the reaction solution, and the organic phase was extracted twice with aqueous lithium chloride solution (500 mL), and then combined and 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.

[0405] MS m / z (ESI): 183.1 [M+H] + .

[0406] Step 2: Synthesis of 2-((4-(difluoromethoxy)phenyl)amino)-6-ethoxy-3-cyanopyridine (Intermediate 10-3)

[0407] Intermediate 10-2 (7.7 g, 42.17 mmol) was dissolved in tert-amyl alcohol (120 mL) at 20 °C, 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)methanesulfonic acid palladium(II) methylsulfonate (BrettPhos Pd G3) (1.91 g, 2.11 mmol) and p-difluoromethoxyaniline (8.05 g, 50.60 mmol) were added. The reaction was stirred at 100 °C for 16 h under nitrogen atmosphere. LCMS showed the target product was generated. After reaction, the organic phase was concentrated by removing the solvent under reduced pressure. Ethyl acetate (50 mL) and water (100 mL) were added to the residue, which was extracted with water (100 mL) twice. The organic phase was combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated by removing the solvent under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 9 / 1) to give the title compound (6 g).

[0408] MS m / z (ESI): 305.9 [M+H] + .

[0409] Step 3: Synthesis of ethyl 4-amino-1-(4-(difluoromethoxy)phenyl)-7-ethoxy-2-oxo-1,2- dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 10-4)

[0410] Intermediate 10-3 (5.2 g, 17.03 mmol) was dissolved in ethanol (60 mL) at 20 °C, sodium ethoxide (4.64 g, 68.13 mmol) and diethyl malonate (8.18 g, 51.10 mmol) were added. The reaction was stirred at 90 °C for 16 h under nitrogen atmosphere. LCMS showed the target product was generated. After reaction, the organic phase was concentrated by removing the solvent under reduced pressure. Ethyl acetate (100 mL) and water (200 mL) were added to the residue, which was extracted with water (200 mL) twice. The organic phase was combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated by removing the solvent under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give the title compound (4.5 g).

[0411] MS m / z (ESI): 420.1 [M+H] + .

[0412] 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)

[0413] 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 solution. The reaction solution was stirred at 50 °C for 16 hours under nitrogen protection. LCMS showed that the target product was generated. 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 thereto, and water (60 mL) was used for extraction twice, and the organic phase was combined and 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.

[0414] MS m / z (ESI): 392.0 [M+H] + .

[0415] 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)

[0416] Intermediate 10-5 (900 mg, 2.30 mmol) was dissolved in toluene (8 mL) at 20 °C, and diphenyl phosphorazide (1.27 g, 4.60 mmol) and triethylamine (349.08 mg, 3.45 mmol) were added to the reaction solution. The reaction solution was stirred at 100 °C for 16 hours. LCMS showed that the target product was generated. After the reaction was completed, ethyl acetate (20 mL) and water (40 mL) were added to the reaction solution, and water (40 mL) was used for extraction twice, and the organic phase was combined and 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 obtain the title compound (700 mg). The title compound (50 mg) was purified by high performance liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: A: water (0.05% ammonia water), B: acetonitrile; B%: 25%-45%, 11 minutes) to obtain the title compound (6.5 mg).

[0417] MS m / z (ESI): 389.1 [M+H] + .

[0418] 1H NMR (400 MHz, Methanol-d4) d = 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).

[0419] 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)

[0420]

[0421] Compound 10 (100 mg, 257.52 pmol) was dissolved in dichloromethane (1 mL) at 20 °C, and trimethyl oxonium tetrafluoroborate (76.18 mg, 515.03 pmol) was added to the reaction solution. The reaction solution was stirred at 40 °C for 16 hours. LCMS showed that the target product was generated. After the reaction was completed, dichloromethane (5 mL) and water (10 mL) were added to the reaction solution, and water (10 mL) was used for extraction twice, and the organic phase was combined 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 high performance liquid chromatography (column: Waters Xbridge BEH C18 100*25mm*5pm; mobile phase: A: water (0.225% formic acid), B: acetonitrile; B%: 25%-55%, 12 minutes) to obtain the title compound (7.9 mg).

[0422] 1 H NMR (400 MHz, Methanol-d4) d = 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).

[0423] MS m / z (ESI): 403.1 [M+H] + .

[0424] 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)

[0425]

[0426] Step 1: Synthesis of ethyl 4-iodo-1-methyl-1H-pyrazole-3-carboxylate (Intermediate 12-2)

[0427] 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 solution. The reaction solution was stirred at 25 °C for 18 h under nitrogen protection. Water (50 mL) and ethyl acetate (100 mL) were added in turn, the organic phase was washed with water (30 mL*2), the washed organic phase was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and subjected to preparative thin-layer chromatography (silica, petroleum ether: ethyl acetate = 10:3) to give the title compound (2 g).

[0428] MS m / z (ESI): 281.0 [M+H] + .

[0429] 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)

[0430] 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), and potassium acetate (1.04 g, 10.67 mmol) and Pd(dppf)Cl2 (387 mg, 0.53 mmol) were added thereto. The reaction solution was stirred at 100 °C for 15 h under nitrogen protection. After the reaction was cooled to room temperature, water (60 mL) and ethyl acetate (80 mL) were added in turn, the organic phase was washed with water (30 mL*2), and the washed organic phase was dried over anhydrous sodium sulfate. Preparative thin-layer chromatography (silica, dichloromethane:methanol = 10:1) was performed to give the title compound (750 mg).

[0431] MS m / z (ESI): 281.0 [M+H] + .

[0432] Step 3: Synthesis of ethyl 4-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-1-methyl-1H-pyrazole-3-carboxylate (Intermediate 12-4)

[0433] 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), to which potassium phosphate (534 mg, 2.51 mmol) and Pd(dtbpf)Cl2 (81.98 mg, 0.12 mmol) were added, and the reaction was stirred at 100 °C under nitrogen protection for 16 h. After the reaction was cooled to room temperature, water (30 mL) and ethyl acetate (40 mL) were added in sequence, the organic phase was washed with water (30 mL*2), and the washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate. The title compound (300 mg) was obtained by preparative thin layer chromatography (silica, dichloromethane:methanol = 5:1).

[0434] MS m / z (ESI): 334.1 [M+H] + .

[0435] 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)

[0436] Intermediate 12-4 (70 mg, 0.21 mmol) and intermediate 12-5 (50 mg, 0.31 mmol) were dissolved in N-methylpyrrolidone (2 mL), to which sodium tert-butoxide (40 mg, 0.42 mmol) and Pd2(dba)3 (1.9 mg, 0.02 mmol) were added, and the reaction was stirred at 100 °C under nitrogen protection for 15 h. After the reaction was cooled to room temperature, water (15 mL) and ethyl acetate (30 mL) were added in sequence, the organic phase was washed with water (30 mL*2), and the washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate and concentrated under reduced pressure. The title compound (2.5 mg) was obtained by TLC purification (dichloromethane:methanol = 10:1) and preparative high performance liquid chromatography purification (column: Gemini NX C18 5 μm*10*150 mm; mobile phase: A: 0.05% trifluoroacetic acid v / v, B: acetonitrile; B%: 40%-45%, 12 min).

[0437] MS m / z (ESI): 411.0 [M+H] + .

[0438] 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).

[0439] Example 13, 5-(4-(Difluoromethoxy)phenyl)-7-ethoxy-2-methyl-2,5-dihydro-4H- pyrazolo[3,4-c][l,8]naphthyridin-4-one (Compound 13)

[0440]

[0441] Step 1: Synthesis of ethyl 4-(6-ethoxy-2-fluoropyridin-3-yl)-l-methyl-lH-pyrazole-3- carboxylate (Intermediate 13-2)

[0442] 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), to which was added potassium phosphate (534 mg, 2.51 mmol) and Pd(dtbpf)Cl2 (81.98 mg, 0.12 mmol), and the reaction was stirred at 100 °C under nitrogen for 16 h. After the reaction was cooled 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 the washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate. The title compound (250 mg) was obtained by preparative thin layer chromatography (silica, dichloromethane:methanol = 5:1).

[0443] MS m / z (ESI): 294.0 [M+H] + .

[0444] Step 2: Synthesis of 5-(4-(difluoromethoxy)phenyl)-7-ethoxy-2-methyl-2,5-dihydro-4H- pyrazolo[3,4-c][l,8]naphthyridin-4-one (Compound 13)

[0445] Intermediate 13-2 (70 mg, 0.23 mmol) and Intermediate 12-5 (50 mg, 0.31 mmol) were dissolved in N-methylpyrrolidone (2 mL), to which was added sodium tert-butoxide (40 mg, 0.46 mmol) and Pd2(dba)3 (1.9 mg, 0.02 mmol), and the reaction was stirred at 100 °C under nitrogen for 15 h. After the reaction was cooled to room temperature, water (15 mL) and ethyl acetate (30 mL) were added sequentially, the organic phase was washed with water (30 mL*2), and the washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate and concentrated under reduced pressure. The title compound (5.2 mg) was obtained by purification of the residue by TLC (dichloromethane:methanol = 10:1) and then by preparative high performance liquid chromatography (column: Gemini NX C18 5 μm*10*150 mm; mobile phase: A: 0.05% trifluoroacetic acid v / v, B: acetonitrile; B%: 40%-48%, 12 min).

[0446] MS m / z (ESI): 387.0 [M+H] + .

[0447] 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).

[0448] Example 14, 5-(4-(Difluoromethoxy)phenyl)-7-ethoxy-l-methyl-l,5-dihydro-4H- imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 14)

[0449]

[0450] Step 1: Synthesis of 3-bromo-6-ethoxy-2-fluoropyridine (Intermediate 14-2)

[0451] 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 and the reaction was stirred at 100 °C for 16 h. The reaction was allowed to cool to room temperature and water (10 mL) was added. The reaction was extracted with ethyl acetate (3 x 10 mL) and the organic layers combined and concentrated to dryness under reduced pressure. The residue was purified by flash silica gel column chromatography (0-12% ethyl acetate in petroleum ether) to give the title compound (600 mg). 12g Silica gel column eluent gradient 0-12% ethyl acetate in petroleum ether, 30 mL / min.

[0452] MS m / z (ESI): 387.0 [M+H] + .

[0453] Step 2: Synthesis of 6-ethoxy-2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine (Intermediate 14-3)

[0454] 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, PdCl2(dppf) (49.88 mg, 68.17 μmol) was added under nitrogen protection, and the reaction was stirred at 90 °C for 2 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to obtain the title compound (364 mg).

[0455] Step 3: Synthesis of methyl 5-(6-ethoxy-2-fluoropyridin-3-yl)-1-methyl-1H-imidazole-4- carboxylate (Intermediate 14-4)

[0456] Intermediate 14-3 (360 mg, 1.35 mmol) and methyl 5-bromo-1-methyl-1H-imidazole-4- carboxylate (206.65 mg, 943.45 μmol, which can be synthesized according to the method reported in patent document WO 2017218960) were dissolved in dioxane (3 mL) and water (0.5 mL), Pd(dtbpf)Cl2 (87.84 mg, 134.78 μmol) and potassium phosphate (286.10 mg, 1.35 mmol) were added under nitrogen protection, and the reaction was stirred at 50 °C for 16 h. After the reaction was completed, it was cooled to 20 °C, extracted with ethyl acetate (10 mL) twice, and the organic phase was concentrated to dryness under reduced pressure. The residue was purified by preparative thin layer chromatography (silica, petroleum ether: ethyl acetate = 3:1). The obtained title compound (0.5 g).

[0457] MS m / z (ESI): 280.0 [M+H] + .

[0458] Step 4: Synthesis of 5-(6-ethoxy-2-fluoropyridin-3-yl)-1-methyl-1H-imidazole-4-carboxylic acid (Intermediate 14-5)

[0459] 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 was stirred at 60 °C for 2 h. After the reaction was completed, it was concentrated to dryness under reduced pressure. The obtained title compound (161 mg).

[0460] MS m / z (ESI): 265.9 [M+H] + .

[0461] 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)

[0462] Intermediate 14-5 (161 mg, 607.00 μmol) was dissolved in N,N- dimethylformamide (2 mL) with 4-(difluoromethoxy)aniline (193.19 mg, 1.21 mmol), followed by the addition of 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), and the reaction was stirred at 20 °C for 16 hours. Upon completion of the reaction, lithium hydroxide monohydrate (76.42 mg, 1.82 mmol) was added, and the reaction was stirred at 100 °C for 5 hours. Upon completion of the reaction, the reaction mixture was filtered, and the filtrate was purified by preparative high performance liquid chromatography (column: Boston Prime C18 150*30mm*5μm; mobile phase: [A: water (0.05% ammonia water + 10 mM ammonium bicarbonate), B: acetonitrile]; B%: 36%-66%, 10 min), and the residue was further purified by high performance liquid chromatography (formic acid condition, column: Waters Xbridge BEH C18 100*25mm*5μm; mobile phase: [A: water (0.225% formic acid); B: acetonitrile]; B%: 20%-50%, 12 min) to give the title compound (14.8 mg).

[0463] MS m / z (ESI): 387.0 [M+H] + .

[0464] 1 H NMR (400 MHz, 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).

[0465] Example 15: 5-(4-(Difluoromethoxy)phenyl)-1-methyl-7-(trifluoromethyl)-1H- imidazo[4,5-c][1,8]naphthyridin-4(5H)-one (Compound 15)

[0466]

[0467] Step 1: Synthesis of 3-bromo-N-(4-(difluoromethoxy)phenyl)-6- (trifluoromethyl)pyridin-2-amine (Intermediate 15-2)

[0468] To a solution of 4-(difluoromethoxy)aniline (611.02 mg, 3.84 mmol) in N,N- dimethylformamide (15 mL) was added sodium hydride (60% active content, 230.38 mg, 5.76 mmol) at 0 °C. The reaction was stirred at 0 °C for 2 h. Intermediate 15-1 (1 g, 3.84 mmol) was dissolved in N,N-dimethylformamide (3 mL) and added dropwise to the reaction. The reaction was stirred at 0 °C for 12 h. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (10 mL*3). The organic layer was washed with saturated brine and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10: 1) to give the title compound (300 mg).

[0469] MS m / z (ESI): 384.9 [M+H] + .

[0470] 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)

[0471] 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), Pd(dppf)Cl2(9.55 mg, 13.05 μmol) were added. The reaction was stirred at 80 °C for 2 h under nitrogen protection. The title compound was used directly in the next step.

[0472] MS m / z (ESI): 431.1 [M+H] + .

[0473] 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).

[0474] A solution of intermediate 15-3 (100 mg, 232.46 pmol) in dioxane was added to water (1 mL), intermediate 15-4 (152.75 mg, can be synthesized according to the method reported in patent document WO 2017218960), potassium carbonate (48.21 mg, 697.39 pmol), Pd(dtbpf)Cl2(15.15 mg, 23.25 pmol). The reaction was stirred at 100 °C for 1 hour under nitrogen protection. The reaction was concentrated to dryness and purified by preparative high performance liquid chromatography (column: Boston Prime C18 150*30mm*5pm); mobile phase: (A: water (0.05% ammonia water + 10 mM ammonium bicarbonate), B: acetonitrile; B%: 37%-67%, 10 minutes). The title compound (13.1 mg) was obtained.

[0475] MS m / z (ESI): 411.0 [M+H] + .

[0476] 1 H NMR (400 MHz, Methanol-d4) d = 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)

[0477] Example 16, 5-(4-(Difluoromethoxy)phenyl)-7-(trifluoromethyl)oxazolo[4,5- c][l,8]naphthyridin-4(5H)-one (Compound 16)

[0478]

[0479] Step 1: Synthesis of 2-((4-(difluoromethoxy)phenyl)amino)-6- (trifluoromethyl)pyridine-3-carboxylic acid (Intermediate 16-1)

[0480] Intermediate 8-1 (1.0 g, 4.5 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and lithium bis(trimethylsilyl)amide in THF (1 M, 9.76 ml, 9.76 mmol) was added dropwise at -78 °C. After the addition was completed, the reaction was allowed to react at -78 °C for 1 h, and then intermediate 12-5 (842.7 mg, 5.3 mmol) was added. The temperature was raised to room temperature, and the reaction was allowed to react for 3 h. Saturated aqueous ammonium chloride solution (10 mL) and ethyl acetate (10 mL*3) were sequentially 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 concentrated. Purification 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%-50%) gave the title compound (900.0 mg).

[0481] MS m / z (ESI): 349.1 [M+H] + .

[0482] Step 2: Synthesis of ethyl 5-(2-((4-(difluoromethoxy)phenyl)amino)-6- (trifluoromethyl)pyridin-3-yl)oxazole-4-carboxylate (Intermediate 16-2)

[0483] Intermediate 16-1 (150 mg, 430.76 μmol) and cesium carbonate (281 mg, 861.51 μmol) were dissolved in N,N-dimethylformamide (4 mL), and diazophosphoryl diphenyl phosphate (DPPA) (209.52 mg, 861.51 mmol) was added at 0 °C. After the addition was completed, the reaction was allowed to react at room temperature for 1 h, and then intermediate 8-4 (48.72 mg, 430.76 μmol) was added at 0 °C. The reaction was allowed to stir at 25 °C for 2 h. Water (5 mL) and ethyl acetate (5 mL*3) were sequentially added to the reaction mixture, and the organic phase was washed with saturated brine (5 mL*2). The washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate, and purified by preparative thin-layer chromatography (silica, petroleum ether: ethyl acetate = 100:0-50:50) to give the title compound (90 mg).

[0484] MS m / z (ESI): 433.1 [M+H] + .

[0485] Step 3: Synthesis of 5-(4-(difluoromethoxy)phenyl)-7-(trifluoromethyl)oxazolo[4,5- c][1,8]naphthyridin-4(5H)-one (Compound 16)

[0486] Intermediate 16-2 (100 mg, 225.57 pmol) and cesium carbonate (220.47 mg, 676.71 pmol) were dissolved in N,N-dimethylformamide (4 mL) and reacted at 60 °C for 3 h. The reaction solution was filtered and purified by preparative high performance liquid chromatography (column: Gemini NX C18 5 pm*10*150 mm; mobile phase: A: water (0.225% formic acid v / v), B: acetonitrile; B%: 30%-50%, 11 min) to give the title compound (24.0 mg).

[0487] MS m / z (ESI): 398.1 [M+H] + .

[0488] 1 H NMR (400 MHz, DMSO-d6) d 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).

[0489] Example 17, 5-(2-chlorophenyl)-7-ethoxy-l-methyl-l,5-dihydro-4H-imidazo[4,5- c] [ 1,8] naphthyridin-4-one (Compound 17)

[0490]

[0491] Intermediate 14-4 (130 mg, 465.51 pmol) and 2-chloroaniline (59.39 mg, 465.51 pmol) were dissolved in N,N-dimethylformamide (3 mL) and sodium tert-butoxide (134.21 mg, 1.40 mmol) was added. The reaction was stirred at 80 °C for 1 h. After the reaction was completed, the filtrate was obtained by filtration and purified by preparative high performance liquid chromatography (column: Waters Xbridge BEH C18 100*25 mm*5 pm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 19%-49%, 12 min) to give the title compound (6.4 mg).

[0492] MS m / z (ESI): 355.2 [M+H] + .

[0493] 1H NMR (400 MHz, Methanol-d4) d = 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)

[0494] Example 18, 5-(4-(Difluoromethoxy)phenyl)-7-(trifluoromethyl)oxazolo[5,4- c][l,8]naphthyridin-4(5H)-one (Compound 18)

[0495]

[0496] Step 1: Synthesis of 3-bromo-N-(4-(difluoromethoxy)phenyl)-6- (trifluoromethyl)pyridin-2-amine (Intermediate 18-1)

[0497] 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 completed, the reaction was allowed to react at -78 °C for 1 h, and then Intermediate 12-5 (1.23 g, 7.72 mmol) was added. The reaction was allowed to warm to room temperature and react for 3 h. Saturated aqueous ammonium chloride solution (20 mL) and ethyl acetate (20 mL*3) were sequentially added to the reaction, and the organic phase was washed with water (20 mL). The washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate, and concentrated. The title compound was obtained by preparative thin-layer chromatography (silica, petroleum ether: ethyl acetate = from 100:0 to 50:50) (900 mg)

[0498] MS m / z (ESI): 383.1 [M+H] + .

[0499] Step 2: Synthesis of 5-(4-(difluoromethoxy)phenyl)-7-(trifluoromethyl)oxazolo[5,4- c][l,8]naphthyridin-4(5H)-one (Compound 18)

[0500] Intermediate 18-1 (350 mg, 916.23 μmol) and bis-pinacol boronic acid ester (348 mg, 1.37 mmol) were dissolved in dioxane (5 mL). Potassium acetate (179 mg, 1.83 mmol) and Pd(dppf)Cl2 (66.85 mg, 91.36 μmol) were added to the solution. 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)Cl2 (59.0 mg, 90.66 μmol) were added to the solution. The reaction mixture was stirred at 90 °C for 5 h under nitrogen protection. The reaction solution was filtered, concentrated to dryness under reduced pressure, and purified by preparative high performance liquid chromatography (column: Gemini NX C18 5μm*10*150mm; mobile phase: A: water (0.225% formic acid v / v), B: acetonitrile; B%: 30%-50%, 11 min) to obtain the title compound (50.0 mg).

[0501] MS m / z(ESI): 398.1 [M+H] + .

[0502] 1 H NMR (400MHz, DMSO-d6) δ9.23 (s, 1H), 8.82 (d, J = 7.9Hz, 1H), 7.92 (d, J = 8.0Hz, 1H), 7.61–7.21 (m, 5H).

[0503] Example 19, 5-(4-chlorophenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthidin-4-one (Compound 19)

[0504]

[0505] Step 1: Synthesis of 3-bromo-N-(4-chlorophenyl)-6-(trifluoromethyl)pyridine-2-amine (intermediate 19-1)

[0506] 4-chloroaniline (244.92 mg, 1.92 mmol) was dissolved in N,N-dimethylformamide (5 mL), sodium hydride (60% active content, 115.18 mg, 2.88 mmol) was added at 0 °C, stirred for 30 min at 0 °C, a solution of intermediate 15-1 (500 mg, 1.92 mmol) in N,N-dimethylformamide was added, the reaction was stirred at 20 °C for 16 h, sodium hydride (60% active content, 76.79 mg, 1.92 mmol) was added again, stirred for 30 min at 40 °C. Cooled to 0 °C, quenched with water (5 mL), extracted with ethyl acetate (30 mL), washed with brine, the organic phase was concentrated to dryness under reduced pressure, the residue was purified by flash silica gel column chromatography (silica gel, 0~15% ethyl acetate / petroleum ether gradient elution @ 20 mL / min) to give the title compound (250 mg). 4g silica gel column, 0~15% ethyl acetate / petroleum ether gradient elution @ 20 mL / min) to give the title compound (250 mg).

[0507] MS m / z (ESI): 352.7 [M+H] + .

[0508] Step 2: Synthesis of N-(4-chlorophenyl)-6-(trifluoromethyl)-3- (trimethylstannyl)pyridin-2-amine (intermediate 19-2)

[0509] Intermediate 19-1 (250 mg, 711.14 µmol), hexamethyldistannane (465.97 mg, 1.42 mmol), tetrakis(triphenylphosphine)palladium (82.18 mg, 71.11 µmol) were dissolved in durene (5 mL) successively, stirred at 140 °C for 5 h under nitrogen protection. The reaction was cooled to 20 °C after completion of the reaction, filtered, the filtrate was concentrated to dryness under reduced pressure, the residue was purified by silica gel column chromatography (silica gel, 0~10% ethyl acetate / petroleum ether gradient elution @ 30 mL / min) to give the title compound (240 mg). 12g silica gel column, 0~10% ethyl acetate / petroleum ether gradient elution @ 30 mL / min) to give the title compound (240 mg).

[0510] MS m / z (ESI): 436.9 [M+H] + .

[0511] 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)

[0512] 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). The mixture was stirred at 140 °C for 16 hours under nitrogen protection. After the reaction was complete, the reaction solution 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*25mm*5μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 26%-46%, 12 min) to give the title compound (47.1 mg).

[0513] MS m / z(ESI): 379.0 [M+H] + ;

[0514] 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).

[0515] Example 20: 1-Methyl-5-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthidin-4-one (Compound 20)

[0516]

[0517] Step 1: Synthesis of methyl 1-methyl-5-(trimethylstanyl)-1H-imidazolium-4-carboxylate (intermediate 20-1)

[0518] Intermediate 15-4 (1 g) was dissolved in xylene (6 mL), and tetrakis(triphenylphosphine)palladium (11.44 mg, 9.90 μmol) and hexamethyldistinane (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 the reaction was completed, the reaction mixture was added dropwise to a saturated potassium fluoride solution (10 mL) and stirred for 2 h. Then water (200 mL) was added, and the mixture was extracted with ethyl acetate (100 mL * 3 times). The organic phases were combined and 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 give the title compound (470 mg).

[0519] MS m / z (ESI): 304.9 [M+H] + .

[0520] Step 2: Synthesis of 3-bromo-N-(2-methylpyridin-3-yl)-6-(trifluoromethyl)pyridin-2- amine (Intermediate 20-3)

[0521] Under nitrogen protection, intermediate 20-2 (207.61 mg, 1.92 mmol) was dissolved in anhydrous N,N-dimethylformamide (8 mL), and sodium hydride (60% active content, 153.57 mg, 3.84 mmol) was added to the reaction solution when the temperature dropped to 0 °C. The reaction solution was stirred at 0 °C for 30 min. Then intermediate 15-1 (500 mg, 1.92 mmol) was added, and the reaction solution was stirred at 20 °C for 16 h under nitrogen protection. After the reaction was completed, water (200 mL) was added to the reaction solution, which was extracted with ethyl acetate (100 mL*3 times), and 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: ethyl acetate = 1:0 to 50:1) to give the title compound (320 mg).

[0522] MS m / z (ESI): 331.7 [M+H] + .

[0523] 1 H NMR (400 MHz, Methanol-d4) d 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).

[0524] 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)

[0525] 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 solution. Then the reaction solution was stirred at 140 °C for 16 h under nitrogen protection. After the reaction was completed, the reaction was filtered, and the solvent was removed by concentration under reduced pressure. The residue was purified by preparative high performance liquid chromatography (column: Waters Xbridge BEH C18 100*25mm*5μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 0%-30%, 12 min) to give the title compound (10 mg, racemate).

[0526] 1 H NMR (400 MHz, 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).

[0527] MS m / z (ESI): 360.1 [M+H] + .

[0528] Compound 20 (80 mg) was prepared by supercritical fluid chromatography (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 pm); mobile phase: A: carbon dioxide; B: 35% ethanol (0.1% ammonia water); 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).

[0529] Compound 20-P1:

[0530] 1 H NMR (400 MHz, 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).

[0531] MS m / z (ESI): 360.1 [M+H] + .

[0532] Compound 20-P2:

[0533] 1 H NMR (400 MHz, 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).

[0534] MS m / z (ESI): 360.1 [M+H] + .

[0535] Example 21, 1 -Methyl-5-phenyl-7-(trifluoromethyl)-1,5-dihydro-4H-imidazo[4,5- c][1,8]naphthyridin-4-one (Compound 21)

[0536]

[0537] Compound 19 (50 mg, 132.02 μmol) was dissolved in methanol (10 mL), wet palladium on carbon (7.02 mg, 6.60 μmol, 10% purity) was added, hydrogen was bubbled through and the reaction was stirred at 50 °C for 24 hours. Upon completion of the reaction, it was filtered through celite 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*25mm*5μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 22%-42%, 12 min) to give the title compound (10.2 mg).

[0538] MS m / z (ESI): 345.0 [M+H] + .

[0539] 1 H NMR (400 MHz, Methanol-d4) d = 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).

[0540] Example 22, 5-(3-Chlorophenyl)-1 -methyl-7-(trifluoromethyl)-1,5-dihydro-1 H- imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 22)

[0541]

[0542] Step 1 : Synthesis of 3-Bromo-N-(3-chlorophenyl)-6-(trifluoromethyl)pyridin-2- amine (Intermediate 22-2)

[0543] Intermediate 22-1 (244.92 mg, 1.92 mmol) was dissolved in N,N-dimethylformamide (5 mL), sodium hydride (60% active content, 153.57 mg, 3.84 mmol) was added at 0 °C, stirred at 0 °C for 30 min, and a solution of intermediate 15-1 (500 mg, 1.92 mmol) in N,N-dimethylformamide was added. The reaction was stirred at 20 °C for 16 h. After the reaction was completed, water (5 mL) was added at 0 °C to quench the reaction, and ethyl acetate (30 mL) was added to extract the product. The organic phase was concentrated to dryness under reduced pressure, and the residue was purified by flash silica gel column chromatography (0-5% ethyl acetate / petroleum ether gradient elution @ 20 mL / min) to give the title compound (420 mg). 4g silica gel column, 0-5% ethyl acetate / petroleum ether gradient elution @ 20 mL / min.

[0544] MS m / z (ESI): 352.8 [M+H] + .

[0545] Step 2: Synthesis of N-(3-chlorophenyl)-6-(trifluoromethyl)-3- (trimethylstannyl)pyridin-2-amine (intermediate 22-3)

[0546] 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 sequentially dissolved in xylene (5 mL), and the reaction was stirred at 140 °C for 5 h. After the reaction was completed, the reaction was cooled to 20 °C and filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (0-10% ethyl acetate / petroleum ether gradient elution @ 30 mL / min) to give the title compound (270 mg). 12g silica gel column, 0-5% ethyl acetate / petroleum ether gradient elution @ 20 mL / min.

[0547] MS m / z (ESI): 436.7 [M+H] + .

[0548] 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)

[0549] Intermediate 22-3 (270 mg, 620.04 pmol), intermediate 15-4 (135.81 mg) and tetrakis(triphenylphosphine)palladium (71.65 mg, 62.00 pmol) were dissolved in xylene (4 mL) and stirred at 140 °C for 16 h under nitrogen protection. After reaction, the reaction solution was filtered, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (column: Waters Xbridge BEH C18 100*25mm*5 pm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 26%-46%, 12 min) to give the title compound (78.2 mg).

[0550] MS m / z (ESI): 379.0 [M+H] + .

[0551] 1 H NMR (400 MHz, Methanol-d4) d = 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).

[0552] Example 23, 5-(2-fluorophenyl)-l-methyl-7-(trifluoromethyl)-l,5-dihydro-4H- imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 23)

[0553]

[0554] Step 1: Synthesis of 3-bromo-N-(2-fluorophenyl)-6-(trifluoromethyl)pyridin-2- amine (Intermediate 23-2)

[0555] The reactant 23-1 (213.33 mg, 1.92 mmol, 185.50 pL) was dissolved in N,N- dimethylformamide (5 mL). Sodium hydride (60% active content, 153.57 mg, 3.84 mmol) was added to the reaction solution at 0 °C under nitrogen protection, and stirred for 30 min. The reaction solution was added to a solution of intermediate 15-1 (500 mg, 1.92 mmol) in N,N-dimethylformamide (2 mL) at 0 °C, and the reaction solution was stirred at 20 °C for 16 h. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (20 mL) three times, and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1) to give the title compound (Intermediate 23-2) (300 mg, 1.02 mmol, 53.20% yield). 12g Silica Flash column, gradient 0-100% ethyl acetate / petroleum ether @ 40 mL / min) to give the title compound (440 mg).

[0556] MS m / z (ESI): 334.9 [M+H] + .

[0557] Step 2: Synthesis of N-(2-fluorophenyl)-6-(trifluoromethyl)-3-(trimethylstannyl)pyridin-2-amine (Intermediate 23-3)

[0558] Intermediate 23-2 (150 mg, 447.63 pmol) was dissolved in xylene (2 mL), Pd(PPh3)4 (51.73 mg, 44.76 pmol) and hexamethyldistannane (586.63 mg, 1.79 mmol, 371.28 pL) were added at 20 °C. The reaction was stirred at 140 °C under nitrogen atmosphere for 1 h. The reaction was quenched with aqueous cesium fluoride solution (20 mL), extracted with ethyl acetate (20 mL) for three times, the organic phase was concentrated under reduced pressure, the residue was purified by preparative thin layer chromatography (silica, petroleum ether: ethyl acetate = 15: 1) to give the title compound (170 mg).

[0559] MS m / z (ESI): 419.0 [M+H] + .

[0560] Step 3: Synthesis of 5-(2-fluorophenyl)-l-methyl-7-(trifluoromethyl)-l,5-dihydro-4H- imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 23)

[0561] Intermediate 23-3 (170 mg, 405.72 pmol) and Intermediate 15-4 (133.30 mg) were dissolved in xylene (2 mL), Pd(PPh3)4 (70.33 mg, 60.86 pmol) was added at 20 °C. The reaction was stirred at 140 °C under nitrogen atmosphere for 16 h. The reaction was diluted with water, extracted with ethyl acetate (20 mL) for three times, the organic phase was concentrated under reduced pressure, the residue was purified by preparative thin layer chromatography (silica, petroleum ether: ethyl acetate = 15: 1). Further purification by high performance liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5pm; mobile phase: [A: water (0.05% ammonia water v / v), B: acetonitrile]; B%: 42%-62%, 11 min) to give the title compound (25.5 mg)

[0562] MS m / z (ESI): 363.1 [M+H] + .

[0563] 1 H NMR (400 MHz, DMSO-d6) d = 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)

[0564] 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)

[0565]

[0566] Step 1: Synthesis of 3-bromo-N-(2-chloro-5-fluorophenyl)-6- (trifluoromethyl)pyridin-2-amine (Intermediate 24-2)

[0567] Intermediate 24-1 (558.96 mg, 3.84 mmol) was dissolved in anhydrous N,N- dimethylformamide (10 mL) at 25 °C, sodium hydride (60% active content, 230.38 mg, 5.76 mmol) was added to the reaction solution when the temperature dropped to 0 °C, the reaction solution was stirred at 0 °C for 30 minutes under nitrogen protection, and intermediate 15-1 (1 g, 3.84 mmol) was added to the reaction solution. The reaction solution was stirred at 20 °C for 16 hours under nitrogen protection. LCMS detection showed that the reaction was completed. Water (10 mL) was added when the temperature dropped to 0 °C, extracted twice with ethyl acetate (10 mL), and the 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 (mobile phase: petroleum ether: ethyl acetate = 0-5%, flow rate: 40 milliliters / minute) to obtain the title compound (1 g).

[0568] MS m / z (ESI): 368.8 [M+H] + .

[0569] Step 2: Synthesis of N-(2-chloro-5-fluorophenyl)-6-(trifluoromethyl)-3- (trimethylstannyl)pyridin-2-amine (Intermediate 24-3)

[0570] Intermediate 24-2 (50 mg, 135.30 pmol) was dissolved in anhydrous xylene (1 mL) at 25 °C, Pd(PPh3)4 (15.64 mg, 13.53 pmol) and hexamethyldistannane (44.33 mg, 135.30 pmol) were added to the reaction. The reaction was stirred at 140 °C for 16 h under nitrogen. LCMS showed the formation of the desired product. After the reaction was completed, cesium fluoride (10 mL) was added to the reaction, extracted with ethyl acetate (10 mL) twice, the organic phase was combined and 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).

[0571] MS m / z (ESI): 455.0 [M+H] + .

[0572] Step 3: Synthesis of 5-(2-chloro-5-fluorophenyl)-l-methyl-7-(trifluoromethyl)- 1,5-dihydro-4H-imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 24)

[0573] Intermediate 24-3 (35.00 mg, 77.19 pmol) was added to anhydrous xylene (1 mL) at 25 °C, Pd(PPh3)4 (8.92 mg, 7.72 pmol) and intermediate 15-4 (25.36 mg) were added to the reaction, the reaction was stirred at 140 °C for 16 h under nitrogen. After the reaction was completed, the reaction 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*25mm*5pm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 30%-40%, 12 min) to give the title compound (2.2 mg).

[0574] MS m / z (ESI): 397.0 [M+H] + .

[0575] 1 H NMR (400 MHz, Methanol-d4) d = 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).

[0576] Example 25, 5-(2-chloro-3-fluorophenyl)-l-methyl-7-(trifluoromethyl)-l,5- dihydro-4H-imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 25)

[0577]

[0578]

[0579] Step 1: Synthesis of 3-bromo-N-(2-chloro-3-fluorophenyl)-6- (trifluoromethyl)pyridin-2-amine (Intermediate 25-2)

[0580] The reactant 25-1 (279.45 mg, 1.92 mmol) was dissolved in N,N- dimethylformamide (5 mL). Sodium hydride (60% active content, 153.57 mg, 3.84 mmol) was added to the reaction solution under nitrogen protection at 0 °C and stirred for 30 minutes. Then the reactant 15-1 (500 mg, 1.92 mmol) was dissolved in N,N-dimethylformamide (2 mL) and added dropwise to the reaction solution, which was stirred at 20 °C for 16 hours. The reaction solution was quenched with water (20 mL) and extracted with ethyl acetate (20 mL*3 times), and the combined organic phase was dried and concentrated under reduced pressure. The residue was purified by column chromatography (Silica Flash column, gradient 0-100% ethyl acetate / petroleum ether @ 40 mL / min) to give the title compound (580 mg). 12g Silica Flash column, gradient 0-100% ethyl acetate / petroleum ether @ 40 mL / min) to give the title compound (580 mg).

[0581] MS m / z (ESI): 368.9 [M+H] + .

[0582] 1 H NMR (400 MHz, 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).

[0583] Step 2: Synthesis of N-(2-chloro-3-fluorophenyl)-6-(trifluoromethyl)-3- (trimethylstannyl)pyridin-2-amine (Intermediate 25-3)

[0584] Intermediate 25-2 (150 mg, 405.91 μmol) was dissolved in xylene (2 mL), Pd(PPh3)4 (46.91 mg, 40.59 μmol) and hexamethyldistannane (531.95 mg, 1.62 mmol) were added at 20 °C, and the reaction was stirred at 140 °C under nitrogen protection for 1 h. The reaction was quenched with saturated aqueous cesium fluoride solution, extracted with ethyl acetate (20 mL*3 times), and 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 give the title compound (165 mg).

[0585] MS m / z (ESI): 454.9 [M+H] + .

[0586] 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)

[0587] Intermediate 25-3 (160 mg, 352.85 μmol) and intermediate 15-4 (115.93 mg) were dissolved in xylene (2 mL), Pd(PPh3)4 (61.16 mg, 52.93 μmol) was added at 20 °C, and the reaction was stirred at 140 °C under nitrogen protection for 16 h. After the reaction was completed, the reaction was diluted with water (20 mL), extracted with ethyl acetate (20 mL*3 times), and the combined organic phase was dried over anhydrous sodium sulfate. After filtration, it was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 15:1), followed by further purification by high performance liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: [A: water (0.05% ammonia water v / v), B: acetonitrile]; B%: 40%-60%, 11 min) to give the title compound (24.7 mg, racemate).

[0588] MS m / z (ESI): 397.0 [M+H] + .

[0589] 1 H NMR (400 MHz, DMSO-d6) d 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).

[0590] Compound 25 (26 mg) was prepared by supercritical fluid chromatography (column: DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 μm); mobile phase: A: carbon dioxide; B: isopropanol (0.1% ammonia water); B%: 50%; flow rate: 80 mL / min) to give Compound 25-P1 (7.7 mg, RT: 1.688 min) and Compound 25-P2 (3.9 mg, RT: 2.349 min).

[0591] Compound 25-P1:

[0592] 1 H NMR (400 MHz, 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).

[0593] MS m / z (ESI): 397.1 [M+H] + .

[0594] Compound 25-P2:

[0595] 1 H NMR (400 MHz, 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).

[0596] MS m / z (ESI): 397.1 [M+H] + .

[0597] 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)

[0598]

[0599] Step 1: Synthesis of 3-bromo-N-(2-chloro-6-fluorophenyl)-6- (trifluoromethyl)pyridin-2-amine (Intermediate 26-2)

[0600] The reactant 26-1 (279.48 mg, 1.92 mmol) was dissolved in N,N-dimethylformamide (10 mL), and sodium hydride (60% effective content, 115.20 mg, 2.88 mmol) was added at 0 °C. The reaction solution was stirred at 0 °C for 2 hours. The intermediate 15-1 (500 mg, 1.92 mmol) was dissolved in N,N-dimethylformamide (5 mL), and the reaction solution was added dropwise. The reaction solution was stirred at 0 °C for 12 hours. After the reaction solution was quenched with water (5 mL), it was extracted three times with ethyl acetate (10 mL*3), and the organic layer was washed with saturated brine. The organic layer was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the title compound (473 mg).

[0601] MS m / z (ESI): 368.7 [M+H] + .

[0602] 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)

[0603] The intermediate 26-2 (36.59 mg, 99.03 μmol) was dissolved in xylene (2 mL), and the intermediate 20-1 (30 mg, 99.03 μmol) and tetrakis(triphenylphosphine)palladium (11.44 mg, 9.90 μmol) were added. The reaction solution was raised to 140 °C, and stirred at 140 °C for 12 hours under nitrogen protection. The reaction solution was concentrated to dryness under reduced pressure, and preparative high performance liquid chromatography was performed (column: Waters Xbridge BEH C18 100*25 mm*5 μm); mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 25%-45%, 12 minutes) to obtain the title compound (2.5 mg).

[0604] MS m / z (ESI): 397.0 [M+H] + .

[0605] 1 H NMR (400 MHz, Methanol-d4) δ = 8.93 (d, J = 8.3 Hz, 1H), 8.27 (s, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.63-7.56 (m, 1H), 7.54-7.50 (m, 1H), 7.41-7.33 (m, 1H), 4.36 (s, 3H)

[0606] 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)

[0607]

[0608] Step 1: Synthesis of 3-bromo-N-(3-methylpyridin-4-yl)-6-(trifluoromethyl)pyridin-2- amine (Intermediate 27-2)

[0609] Intermediate 27-1 (207.61 mg, 1.92 mmol) was dissolved in dry N,N-dimethylformamide (5 mL) at 25 °C, the temperature was lowered to 0 °C, sodium hydride (60% active content, 153.57 mg, 3.84 mmol) was added slowly. After stirring for 30 minutes, Intermediate 15-1 (500 mg, 1.92 mmol) was dissolved in dry N,N-dimethylformamide (2 mL) and added to the reaction system, the reaction was stirred at 25 °C under nitrogen protection for 16 hours. LCMS showed that the target product had been formed. After the reaction was completed, the temperature was lowered to 0 °C, quenched with an aqueous solution (5 mL), then ethyl acetate (50 mL) and water (100 mL) were added to the reaction solution, washed with saturated aqueous sodium chloride solution (100 mL) twice, and the organic phase was combined 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 silica gel column chromatography (ethyl acetate / petroleum ether: 0-70%, 40 mL / min) to give the title compound (300 mg).

[0610] MS m / z (ESI): 331.8 [M+H] + .

[0611] 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)

[0612] 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 solution. The reaction solution was stirred at 140 °C for 16 hours under nitrogen protection. LCMS showed that the target product was generated. After the reaction was completed, ethyl acetate (10 mL) and water (20 mL) were added to the reaction solution, and water (20 mL) was used for extraction twice, and the organic phase was combined 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 high performance liquid chromatography (column: Boston Prime C18 150*30mm*5µm; mobile phase: A: water (0.05% ammonia water + 10 mM ammonium bicarbonate), B: acetonitrile; B%: 25%-55%, 10 minutes) to obtain the title compound (9.2 mg).

[0613] MS m / z (ESI): 360.1 [M+H] + .

[0614] 1 H NMR (400 MHz, 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).

[0615] 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)

[0616]

[0617] Step 1: Synthesis of 3-bromo-N-(4-methylpyridin-3-yl)-6-(trifluoromethyl)pyridin-2- amine (Intermediate 28-2)

[0618] Intermediate 28-1 (207.61 mg, 1.92 mmol) was dissolved in N,N-dimethylformamide (5 mL) at 25 °C, the temperature was lowered to 0 °C, and sodium hydride (60% active content, 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 N,N-dimethylformamide (2 mL) and added to the reaction. The reaction was stirred at 25 °C for 16 h under nitrogen. LCMS showed that the target product had been formed. After the reaction was completed, the temperature was lowered to 0 °C, and the sodium hydride was quenched with an aqueous solution (5 mL). Ethyl acetate (50 mL) and water (100 mL) were added to the reaction, which was washed twice with saturated aqueous sodium chloride solution (100 mL), and the organic phases were combined 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 column chromatography on silica gel (ethyl acetate / petroleum ether: 0-50%, 40 mL / min) to give the title compound (350 mg).

[0619] MS m / z (ESI): 331.8 [M+H] + .

[0620] 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)

[0621] Intermediate 28-2 (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. The reaction was stirred at 140 °C for 16 h under nitrogen. LCMS showed that the target product had been formed. After the reaction was completed, ethyl acetate (10 mL) and water (20 mL) were added to the reaction, which was washed twice with saturated sodium chloride solution (20 mL), and the organic phases were combined 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 high performance liquid chromatography (column: Boston Prime C18 150*30mm*5μm; mobile phase: A: water (0.05% ammonia water + 10 mM ammonium bicarbonate), B: acetonitrile; B%: 25%-55%, 10 min) to give the title compound (7.5 mg).

[0622] 1H NMR (400 MHz, Methanol-d4) d = 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).

[0623] MS m / z (ESI): 360.1 [M+H] + .

[0624] 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)

[0625]

[0626] Step 1 : Synthesis of 3-bromo-N-(3-methylpyridin-2-yl)-6-(trifluoromethyl)pyridin-2- amine (Intermediate 29-2)

[0627] Intermediate 29-1 (207.61 mg, 1.92 mmol) was dissolved in dry N,N-dimethylformamide (5 mL) solution at 25 °C, the temperature was lowered to 0 °C, sodium hydride (60% active content, 153.57 mg, 3.84 mmol) was slowly added into it. After stirring for 30 minutes, intermediate 15-1 (500 mg, 1.92 mmol) was dissolved in dry N,N-dimethylformamide (2 mL) solution, which was then added into the reaction mixture, the reaction was stirred at 25 °C under nitrogen atmosphere for 16 hours. LCMS showed that the target product had been formed. After the reaction was completed, the temperature was lowered to 0 °C, sodium hydride was quenched with water solution (5 mL), then ethyl acetate (50 mL) and water (100 mL) were added into the reaction mixture, it was washed with saturated sodium chloride aqueous solution (100 mL) for 2 times, the organic phase was combined 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 silica gel column chromatography (ethyl acetate / petroleum ether: 0-5%, 40 mL / min) to give the title compound (200 mg).

[0628] MS m / z (ESI): 331.9 [M+H] + .

[0629] 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)

[0630] 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 solution. The reaction solution was stirred at 140 °C for 16 hours under nitrogen protection. LCMS showed that the target product was generated. After the reaction was completed, ethyl acetate (10 mL) and water (20 mL) were added to the reaction solution, and the organic phase was extracted with aqueous solution (20 mL) twice, and then combined 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 high performance liquid chromatography (column: Waters Xbridge BEH C18 100*25mm*5μm; mobile phase: A: water (0.225% formic acid), B: acetonitrile; B%: 37%-47%, 12 min) to obtain the title compound (1.7 mg).

[0631] 1H NMR (400 MHz, 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).

[0632] MS m / z (ESI): 360.1 [M+H] + .

[0633] Example 30: 5-(2-chlorophenyl)-7-(trifluoromethyl)-3,5-dihydro-4H-pyrrolo[2,3- c][1,8]naphthyridin-4-one (Compound 30)

[0634]

[0635] Step 1: Synthesis of 3-bromo-N-(2-chlorophenyl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 30-2)

[0636] The reactant 30-1 (489.83 mg, 3.84 mmol) was dissolved in N,N-dimethylformamide (10 mL), and sodium hydride (60% effective content, 230.38 mg, 5.76 mmol) was added at 0 °C. The reaction solution was stirred at 0 °C for 2 hours. The intermediate 15-1 (1 g, 3.84 mmol) was dissolved in N,N-dimethylformamide (5 mL) and added dropwise to the reaction solution. The reaction solution was stirred at 0 °C for 12 hours. The reaction solution was quenched with water (5 mL) and extracted with ethyl acetate (10 mL*3) three times. The organic layer was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the title compound (500 mg).

[0637] MS m / z (ESI): 350.8 [M+H] + .

[0638] 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)

[0639] The 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)Cl2 (46.83 mg, 64.00 μmol) were added. The reaction solution was stirred at 90 °C under nitrogen protection for 1 hour. The reaction solution was quenched with water (5 mL) and extracted with ethyl acetate (5 mL*3) three times. The organic layer was concentrated to dryness under reduced pressure, and preparative thin layer chromatography (silica, petroleum ether: ethyl acetate = 10:1) was performed to obtain the title compound (100 mg).

[0640] MS m / z (ESI): 399.0 [M+H] + .

[0641] Step 3: Synthesis of 5-(2-chlorophenyl)-7-(trifluoromethyl)-3,5-dihydro-4H-pyrrolo[2,3- c][1,8]naphthyridin-4-one (compound 30)

[0642] 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), Pd(dtbpf)Cl2 (15.53 mg, 23.83 μmol) were added. The reaction was stirred at 100 °C for 2 h under nitrogen protection. The reaction was concentrated to dryness, and purified by preparative high performance liquid chromatography (column: Waters Xbridge BEH C18 100*25mm*5μm); mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 35%-55% in 12 min). The title compound was obtained (13.9 mg).

[0643] MS m / z (ESI): 364.0 [M+H] + .

[0644] 1 H NMR (400 MHz, Methanol-d4) d = 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).

[0645] Example 31, 1 -Methyl-5-(2-methylphenyl)-7-(trifluoromethyl)-1,5-dihydro-4H- imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 31)

[0646]

[0647] Step 1 : Synthesis of 3-bromo-N-(2-methylphenyl)-6-(trifluoromethyl)pyridin-2- amine (Intermediate 31-2)

[0648] Intermediate 31-1 (205.72 mg, 1.92 mmol) was dissolved in N,N-dimethylformamide (5 mL), and sodium hydride (60% active content, 191.97 mg, 4.80 mmol) was added at 0 °C. After stirring at 0 °C for 30 min, a solution of intermediate 15-1 (500 mg, 1.92 mmol) in N,N-dimethylformamide was added, and the reaction was stirred at 20 °C for 16 h. Sodium hydride (76.79 mg, 1.92 mmol, 60% active content) was added again, and the reaction was stirred at 40 °C for 30 min. The reaction was cooled to 0 °C, quenched with 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 by flash silica gel column chromatography (eluent: dichloromethane / methanol, 99 / 1 to 97 / 3). 4 g Silica gel column, 0-10% ethyl acetate / petroleum ether gradient elution @ 20 mL / min) to give the title compound (137 mg).

[0649] MS m / z (ESI): 330.9 [M+H] + .

[0650] Step 2: Synthesis of N-(2-methylphenyl)-6-(trifluoromethyl)-3- (trimethylstannyl)pyridin-2-amine (Intermediate 31-3)

[0651] Intermediate 31-2 (110 mg, 332.20 pmol), hexamethyldistannane (217.67 mg, 664.39 pmol), tetrakis(triphenylphosphine)palladium (38.39 mg, 33.22 pmol) were dissolved in xylene (5 mL) successively, stirred at 140 °C for 5 h under nitrogen protection. The reaction was cooled to 20 °C, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column (eluent: petroleum ether / ethyl acetate = 10 / 1) to give the title compound (137 mg). 12g Silica gel column, 0-10% ethyl acetate / petroleum ether gradient elution @ 30 mL / min) to give the title compound (137 mg).

[0652] MS m / z (ESI): 414.9 [M+H] + .

[0653] 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)

[0654] Intermediate 31-3 (137 mg, 330.09 pmol), Intermediate 15-4 (72.30 mg) and tetrakis(triphenylphosphine)palladium (38.14 mg, 33.01 pmol) were dissolved in xylene (4 mL), stirred at 140 °C for 16 h under nitrogen protection. The reaction 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*25mm*5pm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 30%-60%, 12 min) to give the title compound (5.1 mg).

[0655] MS m / z (ESI): 359.1 [M+H] +

[0656] 1H NMR (400 MHz, Methanol-d4) d = 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).

[0657] Example 32: 5-(2-chloro-4-fluorophenyl)-l-methyl-7-(trifluoromethyl)-l,5- dihydro-4H-imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 32)

[0658]

[0659] Step 1: Synthesis of 3-bromo-N-(2-chloro-4-fluorophenyl)-6- (trifluoromethyl)pyridin-2-amine (Intermediate 32-2)

[0660] The reactant 32-1 (279.45 mg, 1.92 mmol) was dissolved in N,N- dimethylformamide (10 mL), sodium hydride (60% active content, 115.19 mg, 2.88 mmol) was added at 0 °C. The reaction solution was stirred at 0 °C for 2 h. The intermediate 15-1 (500 mg, 1.92 mmol) was dissolved in N,N-dimethylformamide (5 mL) and added dropwise to the reaction solution. The reaction solution was stirred at 0 °C for 12 h. The reaction solution was quenched with water (5 mL) and extracted with ethyl acetate (10 mL*3) three times. The organic layer was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to give the title compound (470 mg).

[0661] MS m / z (ESI): 368.8 [M+H] + .

[0662] Step 2: Synthesis of N-(2-chloro-4-fluorophenyl)-6-(trifluoromethyl)-3- (trimethylstannyl)pyridin-2-amine (Intermediate 32-3)

[0663] The intermediate 32-2 (200 mg, 541.21 pmol) was dissolved in xylene (3 mL), hexamethyldistannane (709.27 mg, 2.16 mmol), and tetrakis(triphenylphosphine)palladium (62.54 mg, 54.12 pmol) were added. The reaction solution was raised to 140 °C and stirred under nitrogen protection for 2 h. The reaction solution was quenched with saturated potassium fluoride solution (5 mL) and extracted with ethyl acetate (5 mL*3) three times. The organic layer was concentrated to dryness under reduced pressure, and preparative thin layer chromatography (silica, dichloromethane:methanol = 10: 1) was performed to give the title compound (190 mg).

[0664] MS m / z (ESI): 453.0 [M+H]+.

[0665] Step 3: Synthesis of 5-(2-chloro-4-fluorophenyl)-l-methyl-7-(trifluoromethyl)- 1,5-dihydro-4H-imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 32)

[0666] Intermediate 32-3 (190 mg, 419.01 μmol) was dissolved in xylene (2 mL), and intermediate 15-4 (91.78 mg), tetrakis(triphenylphosphine)palladium (48.42 mg, 41.90 μmol) were added. The reaction was stirred at 140 °C for 12 h under nitrogen. The reaction was concentrated to dryness under reduced pressure and purified by preparative HPLC (column: Waters Xbridge BEH C18 100*25mm*5μm); mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 30%-50%, 12 min) to give the title compound (4.1 mg).

[0667] MS m / z (ESI): 397.0 [M+H] + .

[0668] 1 H NMR (400 MHz, 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)

[0669] Example 33, 5-(2-methoxyphenyl)-l-methyl-7-(trifluoromethyl)-l,5-dihydro-4H- imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 33)

[0670]

[0671] Step 1: Synthesis of 3-bromo-N-(2-methoxyphenyl)-6-(trifluoromethyl)pyridin-2- amine (Intermediate 33-2)

[0672] Intermediate 33-1 (236.43 mg, 1.92 mmol) was dissolved in dry N,N-dimethylformamide (8 mL) at 25 °C under nitrogen. When the temperature dropped to 0 °C, sodium hydride (60% active content, 153.57 mg, 3.84 mmol) was added to the reaction solution, which was stirred at 0 °C for 30 min. Intermediate 15-1 (500 mg, 1.92 mmol) was added. The reaction solution was stirred at 20 °C for 16 h under nitrogen. LCMS showed that the target product was formed. After the reaction was completed, water (200 mL) was added to the reaction solution, which was extracted with ethyl acetate (100 mL) three times, and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 1:0 to 50:1) to obtain the title compound (185 mg).

[0673] MS m / z (ESI): 346.8 [M+H] + .

[0674] 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)

[0675] Intermediate 33-2 (40.10 mg, 115.53 μmol) was added to dry xylene (1 mL) at 25 °C under nitrogen, and Pd(PPh3)4 (13.35 mg, 11.55 μmol) and intermediate 20-1 (35 mg, 115.53 μmol) were added to the reaction solution, which was reacted at 140 °C under nitrogen for 16 h. After the reaction was completed, the reaction 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*25mm*5μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 24%-44%, 12 min) to obtain the title compound (1.7 mg).

[0676] 1 H NMR (400 MHz, 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).

[0677] MS m / z (ESI): 375.0 [M+H] + .

[0678] Example 34, 5-(2-Isopropylphenyl)-l-methyl-7-(trifluoromethyl)-l,5-dihydro-4H- imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 34)

[0679]

[0680] Step 1: Synthesis of 3-bromo-N-(2-isopropylphenyl)-6-(trifluoromethyl)pyridin-2- amine (Intermediate 34-2)

[0681] Intermediate 34-1 (259.57 mg, 1.92 mmol) was dissolved in N,N- dimethylformamide (7 mL), sodium hydride (60% active content, 230.36 mg, 5.76 mmol) was added at 0 °C, stirred for 30 min at 0 °C, a solution of Intermediate 15-1 (500 mg, 1.92 mmol) in N,N-dimethylformamide (7 mL) was added, the reaction was stirred at 20 °C for 16 h. Cooled to 0 °C, quenched with water (5 mL), extracted with ethyl acetate (30 mL), the organic phase was concentrated to dryness under reduced pressure, the residue was purified by flash silica gel column (elution gradient 0~10% ethyl acetate / petroleum ether @ 40 mL / min) to give the title compound (160 mg). 4g silica gel column, elution gradient 0~10% ethyl acetate / petroleum ether @ 40 mL / min) to give the title compound (160 mg).

[0682] MS m / z (ESI): 358.8 [M+H] +

[0683] Step 2: Synthesis of 5-(2-Isopropylphenyl)-l-methyl-7-(trifluoromethyl)-l,5-dihydro- 4H-imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 34)

[0684] Intermediate 34-2 (160 mg, 356.36 µmol), Intermediate 20-1 (107.96 mg, 356.36 µmol), tetrakis(triphenylphosphine)palladium (41.18 mg, 35.64 µmol) were sequentially dissolved in durene (5 mL), stirred at 140 °C for 5 hours under nitrogen protection. After the reaction was completed, it was cooled 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*25mm*5µm; mobile phase: [water(0.225% formic acid)-acetonitrile; B is acetonitrile, B%: 35%-45%, 12 min), and then purified by preparative high performance liquid chromatography (column: Boston Prime C18 150*30mm*5µm; mobile phase: [A: water(0.05% ammonia water+10mM ammonium bicarbonate), B: acetonitrile]; B%: 40%-70%, 10 min) to give the title compound (5.3 mg).

[0685] MS m / z (ESI): 387.1 [M+H] + ;

[0686] 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).

[0687] Example 35, 5-(2-chloro-3-fluorophenyl)-7-(trifluoromethyl)oxazolo[4,5- c][1,8]naphthyridin-4(5H)-one (Compound 35)

[0688]

[0689] Step 1: Synthesis of 2-((2-chloro-3-fluorophenyl)amino)-6- (trifluoromethyl)pyridine-3-carboxylic acid (Intermediate 35-2)

[0690] 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 at -78 °C. After the dropwise addition was completed, the reaction solution was stirred at -78 °C for 1 hour, and then intermediate 25-1 (768 mg, 5.3 mmol) was added. The reaction solution was slowly warmed to room temperature and stirred for 3 hours. Saturated aqueous ammonium chloride solution (10 mL) and ethyl acetate (10 mL*3) were sequentially added to the reaction solution, 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, filtered, and then concentrated under reduced pressure to remove the solvent. The residue was purified by preparative high-performance liquid chromatography (column: Gemini NXC18 5 μm*10*150 mm; mobile phase: A: water (0.225% formic acid v / v), B: acetonitrile; B%: 30%-50%) to obtain the title compound (460 mg).

[0691] MS m / z (ESI): 335.1 [M+H] + .

[0692] Step 2: Synthesis of ethyl 5-(2-((2-chloro-3-fluorophenyl)amino)-6- (trifluoromethyl)pyridin-3-yl)oxazole-4-carboxylate (Intermediate 35-4)

[0693] Intermediate 35-2 (250 mg, 0.75 mmol) and cesium carbonate (489 mg, 1.50 mmol) were dissolved in N,N-dimethylformamide (4 mL), and diazophosphoryl diphenyl phosphate (DPPA) (412 mg, 1.50 mmol) was added at 0 °C. The reaction solution was stirred at room temperature for 1 hour, and then intermediate 35-3 (85 mg, 0.75 mmol) was added at 0 °C. The reaction solution was stirred at 25 °C for 2 hours. Water (10 mL) and ethyl acetate (10 mL*3) were sequentially added to the reaction solution, and the organic phase was washed with saturated brine (10 mL*2). The washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to remove the solvent. The residue was purified by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 100:0-50:50) to obtain the title compound (169 mg).

[0694] MS m / z (ESI): 429.9 [M+H] + .

[0695] Step 3: Synthesis of 5-(2-chloro-3-fluorophenyl)-7-(trifluoromethyl)oxazolo[4,5- c][1,8]naphthyridin-4(5H)-one (Compound 35)

[0696] 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 was filtered and the residue was purified by preparative high performance liquid chromatography (column: Gemini NX C18 5 pm*10*150 mm; mobile phase: A: water (0.225% formic acid v / v), B: acetonitrile; B%: 30%-50%, 11 min) to give the title compound (29 mg).

[0697] MS m / z (ESI): 383.9 [M+H] + .

[0698] 1 H NMR (400 MHz, DMSO-d6) d 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).

[0699] Example 36: 5-(2-chloro-3-methylphenyl)-l-methyl-7-(trifluoromethyl)-l,5- dihydro-4H-imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 36)

[0700]

[0701] Step 1: Synthesis of 3-bromo-N-(2-chloro-3-methylphenyl)-6- (trifluoromethyl)pyridin-2-amine (Intermediate 36-2)

[0702] 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, 60% active content) was added at 0 °C. The reaction 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, which was stirred at 0 °C for 12 hours. The reaction was completed, water (5 mL) was added to the reaction, which was extracted with ethyl acetate (10 mL*3 times), the organic layer was washed with saturated brine (30 ml), and the organic layer 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: ethyl acetate = 10: 1) to give the title compound (400 mg).

[0703] MS m / z (ESI): 364.9 [M+H] + .

[0704] Step 2: Synthesis of N-(2-chloro-3-methylphenyl)-6-(trifluoromethyl)-3- (trimethylstannyl)pyridin-2-amine (Intermediate 36-3)

[0705] Intermediate 36-2 (400 mg, 1.09 mmol) was dissolved in xylene (4 mL), hexamethyldistannane (716.96 mg, 2.19 mmol), tetrakis(triphenylphosphine)palladium (126.44 mg, 109.42 μmol) was added. The reaction was heated to 140 °C and stirred for 2 h under nitrogen. After the reaction was completed, the reaction was added to saturated potassium fluoride solution (5 mL), extracted with ethyl acetate (5 mL*3 times), the organic phase was combined and 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 give the title compound (320 mg).

[0706] MS m / z (ESI): 451.0 [M+H] + .

[0707] 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)

[0708] Intermediate 36-3 (320 mg, 711.93 μmol) was dissolved in xylene (3 mL), intermediate 15-4 (155.94 mg, 711.93 μmol), tetrakis(triphenylphosphine)palladium (82.27 mg, 71.19 μmol) was added. The reaction was stirred at 140 °C for 12 h under nitrogen. The reaction was concentrated to dryness, and the residue was purified by preparative high performance liquid chromatography (column: Waters Xbridge BEH C18 100*25mm*5μm); mobile phase: [water(0.225% formic acid)-acetonitrile]; B: acetonitrile; B%: 35%-55%, 12 min). The title compound (29.9 mg) was obtained.

[0709] MS m / z (ESI): 393.0 [M+H] + .

[0710] 1H NMR (400 MHz, Methanol-d4) d = 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)

[0711] Example 37, 5-(2,3-dichlorophenyl)-l-methyl-7-(trifluoromethyl)-l,5-dihydro-4H- imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 37)

[0712]

[0713] Step 1: Synthesis of 3-bromo-N-(2,3-dichlorophenyl)-6-(trifluoromethyl)pyridin-2- amine (Intermediate 37-2)

[0714] Intermediate 37-1 (273.72 mg, 1.69 mmol) was dissolved in N,N-dimethylformamide (6 mL). The reaction solution was added with NaH (122.86 mg, 3.07 mmol, 60% effective content) at 0 °C under nitrogen protection, and stirred for 30 minutes. The reaction solution was added with Intermediate 15-1 (400 mg, 1.54 mmol) dissolved in N,N-dimethylformamide (2 mL) at 0 °C, and stirred for 16 hours at 20 °C. After the reaction was completed, the reaction solution was quenched with water (20 ml), extracted with ethyl acetate (10 ml*3 times), and 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 (column: 12 g The mobile phase was 100% petroleum ether @ 40 mL / min to obtain the title compound (500 mg).

[0715] MS m / z (ESI): = 384.8 [M+H] + .

[0716] Step 2: Synthesis of N-(2,3-dichlorophenyl)-6-(trifluoromethyl)-3-(trimethylstannyl)pyridin- 2-amine (Intermediate 37-3)

[0717] 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 solution was stirred for 1 hour at 140 °C under nitrogen protection. After the reaction was completed, the reaction solution was quenched with an aqueous cesium fluoride solution (20 ml), extracted with ethyl acetate (10 ml*3 times), and 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 (column: 20 g 100% petroleum ether @ 40 mL / min to obtain the title compound (283 mg).

[0718] MS m / z (ESI): 470.9 [M+H] + .

[0719] Step 3: Synthesis of 5-(2,3-dichlorophenyl)-l-methyl-7-(trifluoromethyl)-l,5- dihydro-4H-imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 37)

[0720] Intermediate 37-3 (150 mg, 319.21 μmol) and intermediate 15-4 (104.88 mg, 478.82 μmol) were dissolved in xylene (2 mL), Pd(PPh3)4(55.33 mg, 47.88 μmol) was added at 20 °C, and the reaction solution was stirred at 140 °C under nitrogen protection for 16 hours. After the reaction was completed, the reaction solution was diluted with water (20 ml), extracted with ethyl acetate (10 ml*3 times), and 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), followed by further purification by high performance liquid chromatography (column: YMC-Actus Triart C18 250*50 mm*7 μm; mobile phase: [A: water (0.05% ammonia water v / v), B: acetonitrile]; B%: 42%-62%, 11 min) to obtain the title compound (33.2 mg).

[0721] 1 H NMR (400 MHz, DMSO-d6) d = 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).

[0722] MS m / z (ESI): 412.9 [M+H] + .

[0723] Example 38, 5-(2-chloro-3-fluorophenyl)-l,7-dimethyl-l,5-dihydro-4H- imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 38)

[0724]

[0725] Step 1: Synthesis of 3-bromo-N-(2-chloro-3-fluorophenyl)-6-methylpyridin-2- amine (Intermediate 38-2)

[0726] Intermediate 25-1 (2 g, 13.79 mmol) was dissolved in tetrahydrofuran (20 mL), the reaction was cooled to 0 °C, NaH (1.1 g, 27.5 mmol, 60% active) was added, the reaction was stirred at 25 °C for 0.5 h. The reaction was cooled to 0 °C, intermediate 38-1 (2.8 g, 13.79 mmol) was added to the reaction. It was stirred at room temperature for 4 h. Then the reaction was cooled to 0 °C, quenched with ice water (10 mL) slowly, 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, 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 = 10:3) to give the title compound (900 mg).

[0727] MS m / z (ESI): 315.1 [M+H] + .

[0728] 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)

[0729] 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)Cl2 (209 mg, 0.28 mmol) were added, the reaction was stirred at 100 °C under nitrogen protection for 15 h. After the reaction was cooled to room temperature, water (60 mL) and ethyl acetate (80 mL) were added in turn, 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 = 10:1) to give the title compound (200 mg).

[0730] MS m / z (ESI): 363.2 [M+H] + .

[0731] 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)

[0732] 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), to which cesium fluoride (249 mg, 1.65 mmol) and Pd(dtbpf)Cl2(35 mg, 0.05 mmol) were added, and the reaction was stirred at 100 °C under nitrogen protection for 16 hours. After the reaction was cooled to room temperature, water (30 mL) and ethyl acetate (40 mL) were added in turn, the organic phase was washed with water (30 mL*2), and 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, and the residue was subjected to preparative thin layer chromatography (dichloromethane:methanol = 5:1) to obtain the title compound (55 mg).

[0733] MS m / z (ESI): 375.3 [M+H] + .

[0734] 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)

[0735] Intermediate 38-4 (55 mg, 0.15 mmol) was dissolved in acetonitrile (2 mL), to which 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (112 mg, 0.73 mmol) was added. The reaction was stirred at 25 °C for 15 hours. The reaction 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%-45%, 12 min) to obtain the title compound (15 mg).

[0736] MS m / z (ESI): 343.2 [M+H] + .

[0737] 1 H 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).

[0738] Example 39, 7-chloro-5-(2-chloro-3-fluorophenyl)-1-methyl-1,5-dihydro-4H- imidazo[4,5-c]quinolin-4-one (Compound 39)

[0739]

[0740] Step 1: Synthesis of 5-chloro-2-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) aniline (Intermediate 39-2)

[0741] Intermediate 39-1 (5 g, 24.2 mmol) was dissolved in anhydrous 1,4-dioxane (50 mL), to which was added bis(pinacolato)diboron (7.4 g, 29.0 mmol), Pd(dppf)Cl2(1.8 g, 2.4 mmol) and potassium acetate (4.8 g, 48.4 mmol), and the reaction was stirred at 100 °C under nitrogen protection for 12 h. After the reaction was cooled to room temperature, water (100 mL) and ethyl acetate (100 mL) were added in turn, the organic phase was washed with water (50 mL*2), and 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, and the residue was purified by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 100:1) to give the title compound (5 g).

[0742] MS m / z (ESI): 254.0 [M+H] + .

[0743] Step 2: Synthesis of methyl 5-(2-amino-4-chlorophenyl)-l-methyl-lH-imidazole-4- carboxylate (Intermediate 39-3)

[0744] 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), to which was added Pd(dtpf)Cl2(6.4 mg, 9.8 μmol) and K3PO4(62.7 mg, 295.8 μmol), and the reaction was stirred at 100 °C under nitrogen protection for 12 h. After the reaction was cooled to room temperature, water (5 mL) and ethyl acetate (5 mL) were added in turn, the organic phase was washed with water (5 mL*2), and 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, and the residue was purified by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 1:1) to give the title compound (15 mg).

[0745] MS m / z (ESI): 266.0 [M+H] + .

[0746] Step 3: Synthesis of 7-chloro-5-(2-chloro-3-fluorophenyl)-l-methyl-l,5-dihydro-4H- imidazo[4,5-c]quinolin-4-one (Compound 39)

[0747] Intermediate 39-3 (10 mg, 37.6 pmol) and intermediate 39-4 (11 mg, 56.4 pmol) were dissolved in anhydrous 1,4-dioxane (5 mL) to which was added Pd2(dba)3(3.45 mg, 3.7 pmol), Cs2CO3(24 mg, 75 pmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (2.18 mg, 3.76 pmol) and the reaction was stirred at 100 °C under nitrogen for 12 h. When the reaction had cooled to room temperature, it was filtered and concentrated to dryness under reduced pressure and purified by preparative high performance liquid chromatography [YMC-Actus Triart C18 column 5 pm silica, 30 mm diameter, 150 mm length; a mixture of water (containing 0.05% NH4HCO3) and acetonitrile of decreasing polarity as eluent; acetonitrile gradient 40-70% over 15 min] to give the title compound (5.0 mg).

[0748] MS m / z (ESI): 362.0 [M+H] + .

[0749] 1 H NMR (400 MHz, CDC13) 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).

[0750] Example 40, 5-(2-methylpyridin-3-yl)-7-(trifluoromethyl)oxazolo[4,5- c] [ 1,8] naphthyridin-4(5H)-one (Compound 40)

[0751]

[0752] Step 1: Synthesis of 2-((2-methylpyridin)amino)-6-(trifluoromethyl)pyridine-3- carboxylic acid (Intermediate 40-1)

[0753] Intermediate 35-1 (200 mg, 0.89 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL), and a solution of LiHMDS in THF (1 M, 1.8 ml, 1.8 mmol) was added dropwise at -78 °C. After the addition was completed, the reaction was stirred at -78 °C for 1 h, and then 3-amino-2-methylpyridine (115 mg, 1.1 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 3 h. Saturated aqueous ammonium chloride solution (8 mL) and ethyl acetate (8 mL*3) were added to the reaction in sequence, 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, filtered, 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%-50%) to give the title compound (105 mg).

[0754] MS m / z (ESI): 298.0 [M+H] + .

[0755] Step 2: Synthesis of ethyl 5-(2-((2-methylpyridin-3-yl)amino)-6- (trifluoromethyl)pyridin-3-yl)oxazole-4-carboxylate (Intermediate 40-2)

[0756] Intermediate 40-1 (105 mg, 0.35 mmol) and cesium carbonate (228 mg, 0.70 mmol) were dissolved in N,N-dimethylformamide (1 mL), and diphenyl phosphorazide (DPPA) (192 mg, 0.70 mmol) was added at 0 °C. After the addition was completed, the reaction was stirred at room temperature for 1 h, and then Intermediate 35-3 (40 mg, 0.35 μmol) was added at 0 °C. The reaction was stirred at 25 °C for 2 h. Water (5 mL) and ethyl acetate (5 mL*3) were added to the reaction in sequence, and the organic phase was washed with saturated brine (5 mL*2). The washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was purified by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 100:0-50:50) to give the title compound (75 mg).

[0757] MS m / z (ESI): 393.1 [M+H] + .

[0758] Step 3: Synthesis of 5-(2-methylpyridin-3-yl)-7-(trifluoromethyl)oxazolo[4,5- c][1,8]naphthyridin-4(5H)-one (Compound 40)

[0759] 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 was filtered and purified by preparative high performance liquid chromatography (column: Gemini NX C18 5 pm*10*150 mm; mobile phase: A: water (0.225% formic acid v / v), B: acetonitrile; B%: 30%-50%, 11 min) to give the title compound (14 mg).

[0760] MS m / z (ESI): 347.1 [M+H] + .

[0761] 1 H NMR (400 MHz, DMSO-d6) d 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).

[0762] 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)

[0763]

[0764]

[0765] Step 1: Synthesis of 3-bromo-6-(trifluoromethyl)-N-(2- (trifluoromethyl)pyridin-3-yl)pyridin-2-amine (Intermediate 41-2)

[0766] 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) under nitrogen protection, potassium tert-butoxide (323.14 mg, 2.88 mmol) was added to the reaction, which was stirred at 20 °C for 16 hours. After the reaction was completed, water (20 mL) was added to the reaction, extracted with ethyl acetate (20 mL*3 times), and the organic phase was combined and 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 give the title compound (247.9 mg).

[0767] MS m / z (ESI): 387.8 [M+H]+ .

[0768] 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)

[0769] Intermediate 41-2 (127.45 mg, 330.09 μmol) was added to dry xylene (6 mL) under nitrogen protection, and then tetrakis(triphenylphosphine)palladium (38.14 mg, 33.01 μmol) and Intermediate 20-1 (100 mg, 330.09 μmol) were added. The reaction was stirred at 140 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction was filtered and the solvent was removed by concentration under reduced pressure. The residue was purified by preparative high performance liquid chromatography (column: Waters Xbridge BEH C18 100*25mm*5μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 27%-47%, 14 min) to give the title compound (15.3 mg).

[0770] MS m / z (ESI): 414.1 [M+H] + .

[0771] 1 H NMR (400 MHz, 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). Compound 41 (13.6 mg) was prepared by supercritical fluid chromatography (column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: A: carbon dioxide; B: ethanol (0.1% ammonia water); B%: 25%; flow rate: 70 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).

[0772] Compound 41-P1:

[0773] 1H NMR (400 MHz, Methanol-d4) d = 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).

[0774] MS m / z (ESI): 414.0 [M+H] + .

[0775] Compound 41-P2:

[0776] 1 H NMR (400 MHz, Methanol-d4) d = 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).

[0777] MS m / z (ESI): 414.0 [M+H] + .

[0778] 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)

[0779]

[0780] Step 1: Synthesis of 2-cyclopropyl-3-nitropyridine (Intermediate 42-3)

[0781] 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), and cesium carbonate (10.28 g, 31.54 mmol) and Pd(dppf)Cl2(576.90 mg, 788.43 μmol) were added. The reaction was stirred at 90 °C for 16 hours under nitrogen protection. After the reaction was completed, water (40 mL) was added to the reaction, and ethyl acetate (40 mL*3 times) was used for extraction, and the organic phase was combined and 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 purification (silica gel, petroleum ether / ethyl acetate = 3 / 1) to give intermediate 42-3 (2.5 g, 10.00 mmol, 63.62% yield, white solid). 20 g Silica Flash column, gradient 0-12% ethyl acetate / petroleum ether @ 80 mL / min), to give the title compound (2.0 g).

[0782] MS m / z (ESI): 164.8 [M+H] + .

[0783] Step 2: Synthesis of 2-cyclopropylpyridin-3-amine (Intermediate 42-4)

[0784] 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 into the reaction solution. The reaction solution was stirred at 25 °C for 16 hours under nitrogen protection. After the reaction was completed, water (40 mL) was added into the reaction solution, extracted with ethyl acetate (40 mL*3 times), the organic phases were combined and 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 column chromatography (silica gel, petroleum ether / ethyl acetate=10 / 1) to give the title compound (2.00 g). 12 g Silica Flash column, gradient 0-15% ethyl acetate / petroleum ether @ 40 mL / min), to give the title compound (254.7 mg).

[0785] MS m / z (ESI): 134.9 [M+H] + .

[0786] Step 3: Synthesis of 3-bromo-N-(2-cyclopropylpyridin-3-yl)-6- (trifluoromethyl)pyridin-2-amine (Intermediate 42-5)

[0787] Under nitrogen protection, Intermediate 42-4 (154.56 mg, 1.15 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL), NaH (69.11 mg, 1.73 mmol, 60% effective content) was added into the reaction solution when the temperature dropped to 0 °C, and the reaction solution was stirred at 0 °C for 30 minutes. Intermediate 15-1 (300 mg, 1.15 mmol) was further added, and the reaction solution was stirred at 20 °C for 16 hours under nitrogen protection. After the reaction was completed, water (10 mL) was added into the reaction solution, extracted with ethyl acetate (10 mL*3 times), the organic phases were combined and 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 column chromatography (silica gel, petroleum ether / ethyl acetate=10 / 1) to give the title compound (60.9 mg). 12 g Silica Flash column, gradient 0-13% ethyl acetate / petroleum ether @ 40 mL / min), to give the title compound (60.9 mg).

[0788] MS m / z (ESI): 386.1 [M+H] + .

[0789] Step 4: Synthesis of 5-(2-cyclopropylpyridin-3-yl)-l-methyl-7-(trifluoromethyl)- 1,5-dihydro-4H-imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 42)

[0790] Intermediate 42-5 (58.14 mg, 162.33 μmol) was added to anhydrous xylene (2 mL) under nitrogen protection, and then tetrakis(triphenylphosphine)palladium (41.96 mg, 36.31 μmol) and intermediate 20-1 (110.00 mg, 363.10 μmol) were added. The reaction was stirred at 140 °C for 16 h under nitrogen protection. After the reaction was completed, the reaction was filtered and the solvent was removed by concentration under reduced pressure. The residue was purified by preparative high performance liquid chromatography (column: Waters Xbridge BEH C18 100*25mm*5μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 16%-36%, 12 min) to give the title compound (19.1 mg).

[0791] MS m / z (ESI): 386.1 [M+H] + .

[0792] 1 H NMR (400 MHz, 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)

[0793] Compound 42 (17.0 mg) was prepared by supercritical fluid chromatography (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: A: carbon dioxide; B: ethanol (0.1% ammonia water); B%: 30%; flow rate: 70 mL / min) to give Compound 42-P1 (3.3 mg, RT: 4.350 min) and Compound 42-P2 (3.4 mg, RT: 4.073 min).

[0794] Compound 42-P1:

[0795] 1 H NMR (400 MHz, 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 = 1.6, 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).

[0796] MS m / z (ESI): 386.1 [M+H] + .

[0797] Compound 42-P2:

[0798] 1 H NMR (400 MHz, 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 = 1.6, 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).

[0799] MS m / z (ESI): 386.1 [M+H] + .

[0800] Example 43, 5-(3-fluoro-2-methylphenyl)-l-methyl-7-(trifluoromethyl)-l,5- dihydro-4H-imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 43)

[0801]

[0802] Step 1: Synthesis of 3-bromo-N-(3-fluoro-2-methylphenyl)-6- (trifluoromethyl)pyridin-2-amine (Intermediate 43-2)

[0803] Intermediate 15-1 (300 mg, 1.15 mmol) and intermediate 43-1 (143.91 mg, 1.15 mmol) were dissolved in dry N,N-dimethylformamide (5 mL) under nitrogen protection, 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 the reaction was completed, water (20 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL*3 times), and 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).

[0804] MS m / z (ESI): 348.8 [M+H] + .

[0805] 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)

[0806] Intermediate 43-2 (115.24 mg, 330.09 μmol) was added to dry xylene (6 mL) under nitrogen protection, 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. Subsequently, the reaction solution was stirred at 140 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction was filtered and the solvent was removed under reduced pressure. The residue was purified by preparative high performance liquid chromatography (column: Waters Xbridge BEH C18 100*25mm*5μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 25%-45%, 14 minutes), and then by preparative supercritical fluid chromatography (column: DAICEL CHIRALCEL OJ (250mm*30mm, 10μm); mobile phase: [A: carbon dioxide), B: ethanol]; B%: 20%) to obtain compound 43-P1 (1.0 mg, RT: 3.432 min) and compound 43-P2 (1.5 mg, RT: 3.643 min).

[0807] Compound 43-P1:

[0808] MS m / z (ESI): 377.1 [M+H] + .

[0809] 1H NMR (400 MHz, 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).

[0810] Compound 43-P2:

[0811] MS m / z (ESI): 377.1 [M+H] + .

[0812] 1 H NMR (400 MHz, 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).

[0813] 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)

[0814]

[0815] Step 1: Synthesis of methyl 5-bromo-1-(methyl-d3)-1H-imidazole-4-carboxylate (Intermediate 44-2)

[0816] NaH (117.06 mg, 2.93 mmol, 60% active content) was added to a solution of Intermediate 44-1 (300 mg, 1.46 mmol) in tetrahydrofuran (5 mL) at 0 °C, the reaction was stirred for 30 min, deuterated iodomethane (415.41 mg, 2.93 mmol) was added, and the reaction was stirred at 20 °C for 16 h. After the reaction was completed, methanol (10 mL) was added to quench the reaction, and the reaction solution was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: 15-70% ethyl acetate / petroleum ether gradient elution @ 40 mL / min) to give the title compound (270 mg). 12g silica gel column, eluent: 15-70% ethyl acetate / petroleum ether gradient elution @ 40 mL / min) to give the title compound (270 mg).

[0817] MS m / z (ESI): 222.0 [M+H] + .

[0818] 1 H NMR (400 MHz, Chloroform-d) d = 7.46 (s, 1H), 4.03-3.82 (s, 3H).

[0819] Step 2: Synthesis of 5-(2-chloro-3-fluorophenyl)-l-(methyl-d3)-7-(trifluoromethyl)- 1,5-dihydro-4H-imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 44)

[0820] Intermediate 44-2 (80 mg, 360.27 pmol) was dissolved in xylene (8 mL) with intermediate 25-3 (163.37 mg, 360.27 pmol), and tetrakis(triphenylphosphine)palladium (41.63 mg, 36.03 pmol) was added. After stirring at 140 °C for 16 hours under nitrogen protection, the reaction was cooled to 20 °C and concentrated to dryness under reduced pressure. The residue was purified by thin layer chromatography (tetrahydrofuran:dichloromethane = 1:1), followed by preparative high performance liquid chromatography (formic acid condition; column: Waters Xbridge BEH C18 100*25mm*5pm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 30%-50%, 14 min) to give the title compound (41.6 mg).

[0821] MS m / z (ESI): 400.0 [M+H] + .

[0822] 1 H NMR (400 MHz, Methanol-d4) d = 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).

[0823] Example 45, Synthesis of l-methyl-5-(2-methylpyridin-3-yl)-7-(trifluoromethyl)- 1,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one (Compound 45)

[0824]

[0825] Step 1: Synthesis of 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5- (trifluoromethyl)aniline (Intermediate 45-2)

[0826] Intermediate 45-1 (5 g, 20.83 mmol) and bis-pinacolborane (6.35 g, 25.00 mmol) were dissolved in anhydrous dioxane (50 mL), to which potassium acetate (4.09 g, 41.66 mmol) and Pd(dppf)Cl2(1.52 g, 2.08 mmol) were added. The reaction was stirred at 80 °C for 4 hours under nitrogen protection. After the reaction was cooled to room temperature, water (50 mL) and ethyl acetate (50 mL) were added in sequence. The organic phase was washed with water (50 mL*2), and 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, and the residue was separated and purified by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the title compound (5.22 g).

[0827] MS m / z (ESI): 288.0 [M+H] + .

[0828] Step 2: Synthesis of methyl 5-(2-amino-4-(trifluoromethyl)phenyl)-1-methyl-1H- imidazole-4-carboxylate (Intermediate 45-3)

[0829] Intermediate 45-2 (500 mg, 1.74 mmol) and Intermediate 15-4 (318 mg, 1.45 mmol) were dissolved in anhydrous dioxane (5 mL), to which potassium phosphate (616 mg, 2.9 mmol), water (0.5 mL), and Pd(dtbpf)Cl2(95 mg, 0.1 mmol) were added. The reaction was stirred at 100 °C for 4 hours under nitrogen protection. After the reaction was cooled to room temperature, water (5 mL) and ethyl acetate (5 mL) were added in sequence. The organic phase was washed with water (5 mL*2), and 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, and the residue was separated and purified by preparative thin-layer chromatography (dichloromethane:methanol = 40:1) to obtain the title compound (200 mg).

[0830] MS m / z (ESI): 300.0 [M+H] + .

[0831] 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)

[0832] Intermediate 45-3 (60 mg, 0.2 mmol) and intermediate 45-4 (69 mg, 0.4 mmol) were dissolved in dry dioxane (1 mL) to which was added cesium carbonate (196 mg, 0.6 mmol), XantPhos (23 mg, 0.04 mmol) and Pd2(dba)3(11 mg, 0.02 mmol) and the reaction was stirred at 100 °C under nitrogen for 12 h. Once cooled to room temperature, the reaction was filtered and 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; a mixture of water (containing 0.05% NH4HCO3) and acetonitrile of decreasing polarity as eluent; acetonitrile gradient ratio 55-75% over 12 min] to give the title compound (8 mg).

[0833] MS m / z (ESI): 359.0 [M+H] + .

[0834] 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).

[0835] Example 46, 7-chloro-l-methyl-5-(2-methylpyridin-3-yl)-l,5-dihydro-4H- imidazo[4,5-c]quinolin-4-one (Compound 46)

[0836]

[0837] Step 1: Synthesis of 5-chloro-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (Intermediate 46-2)

[0838] The reactant 46-1 (5 g, 24.22 mmol) was dissolved in anhydrous 1,4-dioxane (50 mL), to which 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, and the reaction was stirred at 100°C under nitrogen protection for 12 hours. After the reaction was completed, the reaction was cooled to room temperature, and water (50 mL) and ethyl acetate (100 mL) were added in sequence, the organic phase was washed with water (50 mL*2), and the organic phase was dried over anhydrous sodium sulfate. After filtration, concentration under reduced pressure, and purification of the residue by column chromatography (petroleum ether: ethyl acetate = 100:1), the title compound (5 g) was obtained.

[0839] MS m / z (ESI): 254.0 [M+H] + .

[0840] Step 2: Synthesis of methyl 5-(2-amino-4-chlorophenyl)-1-methyl-1H-imidazole-4-carboxylate (intermediate 46-3)

[0841] 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), to which Pd(dppf)Cl2 (0.1 g, 0.138 mmol), K3PO4 (1.9 g, 8.95 mmol) were added, and the reaction was stirred at 100°C under nitrogen protection for 12 hours. After the reaction was completed, the reaction was cooled to room temperature, and water (50 mL) and ethyl acetate (100 mL) were added in sequence, the organic phase was separated after standing, the organic phase was 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 obtain the title compound (0.8 g).

[0842] MS m / z (ESI): 266.0 [M+H] +

[0843] 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)

[0844] Intermediate 46-3 (150 mg, 0.56 mmol) and 2-methyl-3-bromo-pyridine (144.5 mg, 0.84 mmol) were dissolved in dry toluene (5 mL) to which Pd2(dba)3(51 mg, 56 μmol), Cs2CO3(360 mg, 1.10 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (32.7 mg, 56 μmol) were added. The reaction was stirred at 100 °C under nitrogen for 12 h. After completion of the reaction, the reaction was allowed to cool 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 get the crude product which was further purified by preparative HPLC [YMC-Actus Triart C18 column, 5 μm, silica, 30 mm diameter, 150 mm length; a mixture of water (containing 0.05% NH4HCO3) and acetonitrile of decreasing polarity as eluent; acetonitrile gradient ratio 40-70%, elution time 15 min] to get the title compound (21.4 mg).

[0845] MS m / z (ESI): 325.0 [M+H] + .

[0846] 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).

[0847] Compound 46 (21 mg) was prepared by supercritical fluid chromatography (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm; mobile phase: A: carbon dioxide; B: ethanol (0.1% ammonia water) B%: 40% to get compound 46-P1 (5.2 mg, RT: 1.519 min) and compound 46-P2 (5.8 mg, RT: 2.025 min).

[0848] Compound 46-P1:

[0849] 1H NMR (400 MHz, 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).

[0850] MS m / z (ESI): 325.1 [M+H] + .

[0851] Compound 46-P2:

[0852] 1 H NMR (400 MHz, 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).

[0853] MS m / z (ESI): 325.1 [M+H] + .

[0854] Example 47, 7-Chloro-l-methyl-5-(2-(trifluoromethyl)pyridin-3-yl)-l,5-dihydro-4H- imidazo[4,5-c]quinolin-4-one (Compound 47)

[0855]

[0856] Step 1: Synthesis of 7-Chloro-l-methyl-5-(2-(trifluoromethyl)pyridin-3-yl)-l,5-dihydro- 4H-imidazo[4,5-c]quinolin-4-one (Compound 47)

[0857] Intermediate 46-3 (150 mg, 0.56 mmol) and 2-trifluoromethyl-3-bromo-pyridine (189 mg, 0.84 mmol) were dissolved in dry toluene (5 mL) to which Pd2(dba)3(51 mg, 56 μmol), Cs2CO3(360 mg, 1.10 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (32.7 mg, 56 μmol) were added. The reaction was stirred at 100 °C under nitrogen for 12 h. After completion of the reaction, the reaction was allowed to cool to room temperature, filtered and concentrated to dryness under reduced pressure. The crude was purified by column chromatography (dichloromethane:methanol = 20:1) to give the title compound (37.7 mg) by preparative high performance liquid chromatography [YMC-Actus Triart C18 column, 5 μm, silica, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.05% NH4HCO3) and acetonitrile of decreasing polarity as eluent; acetonitrile gradient ratio 40% - 70%, elution time 15 min].

[0858] MS m / z (ESI): 379.0 [M+H] + .

[0859] 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).

[0860] Compound 47 (35 mg) was prepared by supercritical fluid chromatography (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: A: carbon dioxide; B: isopropanol (0.1% ammonia water); 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).

[0861] Compound 47-P1:

[0862] 1H NMR (400 MHz, 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).

[0863] MS m / z (ESI): 379.0 [M+H] + .

[0864] Compound 47-P2:

[0865] 1 H NMR (400 MHz, 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).

[0866] MS m / z (ESI): 379.0 [M+H] + .

[0867] Example 48, 5-(2-cyclopropylpyridin-3-yl)-l-methyl-7-(trifluoromethyl)-l,5- dihydro-4H-imidazo[4,5-c]quinolin-4-one (Compound 48)

[0868]

[0869] Intermediate 45-3 (250 mg, 0.83 mmol) and 3-bromo-2-cyclopropylpyridine (181 mg, 0.91 mmol) were dissolved in anhydrous toluene solution (3 mL), to which cesium carbonate (541 mg, 1.66 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (96 mg, 0.17 mmol) and Pd2(dba)3(76 mg, 0.08 mmol) were added, and the reaction was stirred at 100 °C under nitrogen protection for 4 h. After the reaction was completed, the reaction 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, 30 mm diameter, 150 mm length; a mixture of water (containing 0.05% NH4HCO3) and acetonitrile with decreasing polarity as eluent; acetonitrile gradient ratio 55%-75%, elution time 12 min] to give the title compound (90 mg).

[0870] MS m / z (ESI): 385.1 [M+H] + .

[0871] 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).

[0872] Compound 48 (90 mg) was prepared by supercritical fluid chromatography (column: DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 μm); mobile phase: A: carbon dioxide; B: ethanol (0.1% ammonia water); B%: 20%; flow rate: 70 mL / min) to give compound 48-P1 (31.3 mg, RT: 3.257 min) and compound 48-P2 (33.2 mg, RT: 3.564 min).

[0873] Compound 48-P1:

[0874] 1H NMR (400 MHz, 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).

[0875] MS m / z (ESI): 385.1 [M+H] + .

[0876] Compound 48-P2:

[0877] 1 H NMR (400 MHz, 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).

[0878] MS m / z (ESI): 385.1 [M+H] + .

[0879] Example 49, 7-chloro-5-(2-cyclopropylpyridin-3-yl)-l-methyl-l,5-dihydro-4H- imidazo[4,5-c]quinolin-4-one (Compound 49)

[0880]

[0881] Intermediate 46-3 (150 mg, 0.56 mmol) and 3-bromo-2-cyclopropylpyridine (144.5 mg, 0.73 mmol) were dissolved in dry toluene (5 mL) to which Pd2(dba)3(51 mg, 56 μmol), Cs2CO3(360 mg, 1.10 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (32.7 mg, 56 μmol) were added. The reaction was stirred at 100 °C under nitrogen for 12 h. When the reaction was cooled to room temperature, the reaction was filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 20:1) to give a crude product, which was purified by preparative high-performance liquid chromatography [YMC-Actus Triart C18 column, 5 μm, silica, 30 mm diameter, 150 mm length; a mixture of water (containing 0.05% NH4HCO3) and acetonitrile with decreasing polarity as eluent; acetonitrile gradient ratio 40-70%, elution time 15 min] to give the title compound (73.3 mg).

[0882] MS m / z (ESI): 351.1 [M+H] + .

[0883] 1 H 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).

[0884] Compound 49 (73 mg) was prepared by supercritical fluid chromatography (column: (S,S) WHELK-O1 (250 mm*30 mm, 5 μm; mobile phase: A: carbon dioxide; B: methanol (0.1% ammonia water), B%: 55%) to give compound 49-P1 (17 mg, RT: 2.385 min) and compound 49-P2 (21.2 mg, RT: 3.855 min).

[0885] Compound 49-P1:

[0886] 1H NMR (400 MHz, 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).

[0887] MS m / z (ESI): 351.1 [M+H] + .

[0888] Compound 49-P2:

[0889] 1 H NMR (400 MHz, 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).

[0890] MS m / z (ESI): 351.1 [M+H] + .

[0891] 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)

[0892]

[0893] Step 1: Synthesis of methyl 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H- imidazole-4-carboxylate (Intermediate 50-3)

[0894] Intermediate 50-1 (5 g) was dissolved in anhydrous N,N-dimethylformamide (70 mL) at 25 °C, potassium carbonate (16.44 g) and intermediate 50-2 (11.38 g) were added, and the reaction was stirred at 25 °C for 16 hours under nitrogen protection. After the reaction was completed, water (200 mL) and ethyl acetate (100 mL) were added to the reaction solution, the organic phase was washed with saturated aqueous sodium chloride solution (200 mL*2), and 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 (0-50% tetrahydrofuran / petroleum ether, 40 mL / min) to obtain the title compound (6.5 g).

[0895] MS m / z (ESI): = 284.9 [M+H] + .

[0896] Step 2: Synthesis of methyl 5-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H- imidazole-4-carboxylate (intermediate 50-4).

[0897] Intermediate 50-3 (6.5 g) was dissolved in acetic acid (130 mL) at 25 °C, N- bromosuccinimide (NBS) (4.07 g) was added, and the reaction was stirred at 60 °C for 16 hours under nitrogen protection. After the reaction was completed, saturated sodium bicarbonate solution was added to the reaction solution to adjust pH = 7, water (100 mL) and ethyl acetate (200 mL) were added in sequence, the organic phase was washed with water (100 mL*2), and the washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate. Filtration and concentration under reduced pressure to dryness. Purification by column chromatography (0-30% tetrahydrofuran / petroleum ether, 60 mL / min) to obtain the title compound (1 g).

[0898] MS m / z (ESI): = 362.9 [M+H] + .

[0899] Step 3: Synthesis of 3-bromo-N-(2-chlorophenyl)-6-(trifluoromethyl)pyridin-2-amine (intermediate 50-5)

[0900] Intermediate 50-1 (2.0 g) was dissolved in N,N-dimethylformamide solution (20 mL), sodium hydride (60%) (0.5 g) was added at 0-5 °C, the reaction solution was stirred at 0 °C for 0.5 h, and intermediate 15-1 (1.0 g) was added to the reaction solution. After the addition was completed, the reaction solution was stirred at room temperature for 12 h. The reaction solution was slowly poured into saturated aqueous ammonium chloride solution (50 mL), extracted with ethyl acetate (60 mL*2), and the combined organic phase was washed with saturated brine (100 mL). The washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was subjected to preparative thin-layer chromatography (silica, petroleum ether: ethyl acetate = 10:1) to obtain the title compound (1.5 g).

[0901] MS m / z (ESI): 351.0 [M+H] + .

[0902] Step 4: Synthesis of N-(2-chlorophenyl)-6-(trifluoromethyl)-3-(trimethylstannyl)pyridin-2-amine (Intermediate 50-6)

[0903] Intermediate 50-5 (500 mg) and hexamethylditin (700 mg) were dissolved in anhydrous xylene solution (5 mL), and Pd(PPh3)4 (164 mg) was added thereto. The reaction solution was stirred at 120 °C under nitrogen protection for 1 h. After the reaction was cooled to room temperature, water (50 mL) and ethyl acetate (50 mL) were sequentially added, the organic phase was washed with water (50 mL*2), and the washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate. The title compound (300 mg) was obtained by preparative thin-layer chromatography (silica, petroleum ether: ethyl acetate = 100:1).

[0904] MS m / z (ESI): 437.0 [M+H] +

[0905] 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).

[0906] Intermediate 50-6 (60 mg) was dissolved in xylene (1 mL) at 25 °C, to which was added catalyst Pd(PPh3)4 (19.08 mg) and intermediate 50-4 (71.91 mg), and the reaction was stirred at 140 °C under nitrogen protection for 16 h. After the reaction was completed, the reaction was cooled to room temperature, and water (10 mL) and ethyl acetate (5 mL) were added in turn, the organic phase was washed with water (10 mL*2), and the washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate. After filtration, it was concentrated to dryness under reduced pressure, and purified by preparative thin-layer chromatography (silica, petroleum ether / tetrahydrofuran = 5 / 1) to give the title compound (60 mg).

[0907] MS m / z (ESI): = 523.0 [M+H] + .

[0908] 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)

[0909] Intermediate 50-7 (50 mg) was dissolved in anhydrous methanol (1 mL) at 20 °C, and cesium fluoride (145.22 mg) was added to the reaction, which was stirred at 20 °C under nitrogen protection for 15 h. After the reaction was completed, it was concentrated to dryness under reduced pressure. Water (10 mL) and ethyl acetate (5 mL) were added in turn, the organic phase was washed with water (10 mL*2), and the washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate. After filtration, it was concentrated to dryness under reduced pressure, and purified by high performance liquid chromatography (acidic conditions, column: Waters Xbridge BEH C18 100*25mm*5um; mobile phase: A: water (0.225% formic acid), B: acetonitrile; B%: 24%-44%, 12 min) to give the title compound (8.1 mg).

[0910] 1 H NMR (400 MHz, DMSO-d6) d = 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).

[0911] MS m / z (ESI): = 409.0 [M+H] + .

[0912] Example 51, 5-(2-chlorophenyl)-7-(trifluoromethyl)oxazolo[5,4-c][l,8]naphthyridin- 4(5H)-one (Compound 51)

[0913]

[0914] Step 1: Synthesis of ethyl 4-(2-((2-chlorophenyl)amino)-6- (trifluoromethyl)pyridin-3-yl)oxazole-5-carboxylate (Intermediate 51-2)

[0915] Intermediate 50-6 (500 mg) and Intermediate 51-1 (700 mg) were dissolved in anhydrous xylene solution (5 mL), to which Pd(PPh3)4(53.05 mg) was added, and the reaction was stirred at 140 °C under nitrogen protection for 4 hours. After the reaction was cooled to room temperature, water (50 mL) and ethyl acetate (50 mL) were added in turn, the organic phase was washed with water (50 mL*2), and the washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate. The title compound (100 mg) was obtained by preparative thin layer chromatography (silica, petroleum ether: ethyl acetate = 3: 1).

[0916] MS m / z (ESI): 412.0 [M+H] + .

[0917] Step 2: Synthesis of 5-(2-chlorophenyl)-7-(trifluoromethyl)oxazolo[5,4-c][l,8]naphthyridin- 4(5H)-one (Compound 51)

[0918] Intermediate 51-2 (100 mg) was dissolved in anhydrous acetonitrile solution (2 mL), to which K3PO4(257 mg) was added, and the reaction was stirred at 25 °C under nitrogen protection for 2 hours. After the reaction was cooled to room temperature, the reaction was filtered, concentrated to dryness under reduced pressure, and the title compound (20.0 mg) was obtained by high-pressure preparation purification [YMC-Actus Triart C18 column 5 μm silica, 30 mm diameter, 150 mm length; a mixture of water (containing 0.05% NH4HCO3) and acetonitrile with decreasing polarity as eluent; acetonitrile gradient ratio 50%-80%, elution time 15 minutes].

[0919] MS m / z (ESI): 366.0 [M+H] + .

[0920] 1 H NMR (400 MHz, 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).

[0921] 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)

[0922]

[0923] Step 1: Synthesis of 3-((3-bromo-6-(trifluoromethyl)pyridin-2-yl)amino)benzonitrile (Intermediate 52-2)

[0924] The reactant 52-1 (113.40 mg) was dissolved in N,N-dimethylformamide (10 mL), and the reactant 15-1 (250 mg) was added. The reaction solution was stirred at 60 °C for 12 h. After the reaction was completed, water (5 mL) was added to the reaction solution, which was extracted with ethyl acetate (10 mL*3 times) and washed with saturated brine (10 mL*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).

[0925] MS m / z (ESI): = 341.9 [M+H] + .

[0926] 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)

[0927] The intermediate 52-2 (190 mg) was dissolved in xylene (3 mL), and the intermediate 20-1 (168.25 mg) and tetrakis(triphenylphosphine)palladium (64.18 mg) were added. The reaction solution was raised to 140 °C and stirred at 140 °C for 12 h under nitrogen protection. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (column: Waters Xbridge BEH C18 100*25mm*5um); mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 26%-46%, 12 min) to obtain the title compound (6.1 mg).

[0928] MS m / z (ESI): = 370.0 [M+H] + .

[0929] 1H NMR (400 MHz, 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)

[0930] 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)

[0931]

[0932] 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)

[0933] Compound 50 (100 mg) was dissolved in anhydrous dichloromethane (4 mL) at 25 °C, triethylamine (49.51 mg) was added into the reaction solution, the temperature of the reaction system was reduced to 0 °C, methylsulfonyl chloride (56.05 mg) was dissolved in anhydrous dichloromethane (1 mL) and slowly added into the reaction solution, the reaction solution was stirred at 25 °C for 3 hours under nitrogen protection. After the reaction was completed, the organic phase was concentrated to dryness under reduced pressure to obtain the title compound (108 mg).

[0934] MS m / z (ESI): = 487.0 [M+H] + .

[0935] 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)

[0936] Intermediate 53-1 (36 mg) was dissolved in anhydrous dioxane (1 mL) at 20 °C, dimethylamine aqueous solution (416.71 mg) was added into the reaction solution. The reaction solution 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 condition, column: Waters Xbridge BEH C18 100*25mm*5um; mobile phase: A: water (0.225% formic acid), B: acetonitrile; B%: 12%-32%, 12 minutes) to obtain the title compound (8.8 mg).

[0937] 1H NMR (400 MHz, 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).

[0938] MS m / z (ESI): = 436.0 [M+H] + .

[0939] 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)

[0940]

[0941] Intermediate 53-1 (36 mg) was dissolved in anhydrous dioxane (1 mL) at 20 °C, and methylamine aqueous solution (114.82 mg) was added to the reaction. The reaction 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*25mm*5um; mobile phase: A: water (0.225% formic acid), B: acetonitrile; B%: 7%-27%, 12 min) to give the title compound (5.3 mg).

[0942] 1 H NMR (400 MHz, 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).

[0943] MS m / z (ESI): = 436.0 [M+H] + .

[0944] 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)

[0945]

[0946] Intermediate 53-1 (36 mg) was dissolved in anhydrous dioxane (1 mL) at 20 °C, and an ammonia solution (392.64 mg) was added to the reaction solution. The reaction solution 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*25mm*5um; mobile phase: A: water (0.225% formic acid), B: acetonitrile; B%: 17%-37%, 12 min) to obtain the title compound (5.3 mg).

[0947] 1H NMR (400 MHz, METHANOL-d4) d = 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).

[0948] MS m / z (ESI): = 408.0 [M+H] + .

[0949] Example 56, 5-(2-chlorophenyl)-1,7-dimethyl-1,5-dihydro-4H-imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 56)

[0950]

[0951] Step 1: Synthesis of 3-bromo-N-(2-chlorophenyl)-6-methylpyridin-2-amine (Intermediate 56-3)

[0952] The reactant 56-2 (3.7 g) was dissolved in tetrahydrofuran (30 mL), and sodium hydride (1.9 g) was added to the reaction solution at 0°C, and stirred at room temperature for 30 min. The reaction solution was cooled to 0°C, and the reactant 56-1 (5 g) was added. The reaction solution was stirred at 25°C for 6 hours under nitrogen protection. After the reaction was completed, the reaction was cooled to 0°C, and water (100 mL) and ethyl acetate (300 mL) were sequentially added. The organic phase was washed with water (60 mL*2), and the washed organic phase was dried with 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 column chromatography (petroleum ether: ethyl acetate = 100:1) to obtain the title compound (6 g).

[0953] MS m / z (ESI): 297.2 [M+H] + .

[0954] 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)

[0955] The intermediate 56-3 (3 g) and bis(pinacolato)diboron (5.1 g) were dissolved in 1,4-dioxane (30 mL), and potassium acetate (2.9 g) and Pd(dppf)Cl2 (738 mg) were added thereto. The reaction solution was stirred at 100°C for 15 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, and water (200 mL) and ethyl acetate (90 mL) were sequentially added. The organic phase was washed with water (30 mL*2), and the washed organic phase was dried with 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 5μm*10*150mm; mobile phase: A: 0.05% TFA v / v, B: acetonitrile; B%: 40%-45%, 15 min) to obtain the title compound (800 mg).

[0956] MS m / z (ESI): 345.2 [M+H] + .

[0957] Step 3: Synthesis of methyl 5-(2-((2-chlorophenyl)amino)-6-methylpyridin-3-yl)-1-methyl-1H-imidazole-4-carboxylate (intermediate 56-5)

[0958] Intermediate 56-4 (200 mg) and intermediate 15-4 (195 mg) were dissolved in dioxane (2 mL) and water (0.4 mL), to which cesium fluoride (267 mg) and Pd(PPh3)2Cl2(39 mg) were added, and the reaction was stirred at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction was cooled to room temperature, and water (30 mL) and ethyl acetate (40 mL) were added in sequence. The organic phase was washed with saturated brine (30 mL*2), and the washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate, filtered, and 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 (70 mg).

[0959] MS m / z (ESI): 357.2 [M+H] + .

[0960] 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)

[0961] 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 thereto, and the reaction was stirred at 25 °C for 16 hours under nitrogen protection. After the reaction was completed, water (30 mL) and ethyl acetate (40 mL) were added in sequence to the reaction, 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, concentrated under reduced pressure, and dried. The residue was purified by preparative high-performance liquid chromatography [YMC-Actus Triart C18 column 5 μm silica, 30 mm diameter, 150 mm length; a mixture of water (containing 0.05% NH4HCO3) and acetonitrile with decreasing polarity as an eluent; acetonitrile gradient ratio 40%-75%, elution time 13 minutes] to obtain the title compound (4 mg).

[0962] MS m / z (ESI): 325.2 [M+H] + .

[0963] 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).

[0964] 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)

[0965]

[0966] Step 1 : Synthesis of 3-bromo-6-(trifluoromethyl)-N-[2- (trifluoromethyl)phenyl]pyridin-2-amine (Intermediate 57-2)

[0967] Intermediate 15-1 (200 mg) and reactant 57-1 (123.73 mg) were dissolved in anhydrous N,N-dimethylformamide (4 mL), to which sodium tert-butoxide (184.50 mg) was added, and the reaction was stirred at 25 °C for 16 h. After the reaction was completed, water (20 mL) was added to the reaction solution, which was extracted with ethyl acetate (10 mL*3 times), and 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: ethyl acetate = 10:1) to obtain the title compound (61.6 mg).

[0968] MS m / z (ESI): 384.9 [M+H] + .

[0969] 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)

[0970] Intermediate 57-2 (60 mg) and intermediate 20-1 (47.2 mg) were dissolved in xylene (1 mL), to which tetrakis(triphenylphosphine)palladium (18.0 mg) was added, and the reaction was stirred at 140 °C under nitrogen protection for 16 h. After the reaction was completed, water (10 mL) was added to the reaction solution, which was extracted with ethyl acetate (5 mL*3 times), and 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 high-performance liquid chromatography (column: Waters Xbridge BEH C18 100*25mm*5um; mobile phase: A: water (0.225% formic acid v / v), B: acetonitrile; B%: 23%-53%, 12 min). Further separation by supercritical fluid chromatography (column: DAICEL CHIRALCEL OD-H (250mm*30mm, 5um); mobile phase: [A: carbon dioxide; B: 0.1% ammonia water / ethanol]; B%: 35%) obtained Compound 57-P1 (1.9 mg, RT: 3.805 min) and Compound 57-P2 (1.9 mg, RT: 4.112 min).

[0971] Compound 57-P1:

[0972] MS m / z (ESI): 413.0 [M+H] + .

[0973] 1 H NMR (400 MHz, Methanol-d4) d 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).

[0974] Compound 57-P2:

[0975] MS m / z (ESI): 413.0 [M+H] + .

[0976] 1 H NMR (400 MHz, Methanol-d4) d 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).

[0977] 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)

[0978]

[0979] Step 1: Synthesis of 2-chloro-4-(difluoromethoxy)aniline (Intermediate 58-2)

[0980] The reaction 58-1 (1 g) was dissolved in anhydrous acetonitrile (10 mL) solution at 25 °C, N-chlorosuccinimide (839.13 mg) was added thereto, and the reaction was stirred at 80 °C under nitrogen protection for 16 hours. After the reaction was completed, ethyl acetate (20 mL) and water (40 mL) were added to the reaction solution, washed with saturated sodium chloride aqueous solution (40 mL*2 times), and the combined organic phase was dried with 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).

[0981] MS m / z (ESI): = 193.8 [M+H] + .

[0982] Step 2: Synthesis of 3-bromo-N-(2-chloro-4-(difluoromethoxy)phenyl)-6- (trifluoromethyl)pyridin-2-amine (Intermediate 58-3)

[0983] Intermediate 58-2 (730 mg) was dissolved in anhydrous N,N-dimethylformamide (9 mL) solution at 25 °C, the temperature was reduced to 0 °C, sodium hydride (301.66 mg) was slowly added, after stirring for 30 min, intermediate 15-1 (982.14 mg) was dissolved in anhydrous N,N-dimethylformamide (2 mL) solution, then added to the reaction system, the reaction solution was stirred at 25 °C for 16 h under nitrogen protection. After the reaction was completed, the temperature was reduced to 0 °C, water (5 mL) was added, then ethyl acetate (20 mL) and water (40 mL) were added to the reaction solution, washed with saturated sodium chloride aqueous solution (40 mL*2 times), the organic phases were combined and 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).

[0984] MS m / z (ESI): = 417 [M+H] + .

[0985] Step 3: Synthesis of N-(2-chloro-4-(difluoromethoxy)phenyl)-6-(trifluoromethyl)-3- (trimethylstannyl)pyridin-2-amine (Intermediate 58-4).

[0986] Intermediate 58-3 (300 mg) was dissolved in anhydrous xylene (3 mL) solution at 20 °C, Pd(PPh3)4 (83.02 mg) and hexamethyldistannane (470.78 mg) were added to the reaction solution. The reaction solution was stirred at 140 °C for 16 h under nitrogen protection. After the reaction was completed, saturated cesium fluoride solution (10 mL) was added to quench the reaction, then ethyl acetate (10 mL) and water (20 mL) were added, extracted with ethyl acetate (20 mL*2 times), the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure, the residue was purified by thin layer chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (80 mg).

[0987] MS m / z (ESI): = 503.0 [M+H] + .

[0988] 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).

[0989] 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 pmol) were added to the reaction. The reaction was stirred at 140 °C for 16 h under nitrogen protection. After the reaction was completed, ethyl acetate (10 mL) and water (20 mL) were added to the reaction, and the organic phase was extracted with ethyl acetate (20 mL*2 times), and 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 (acidic conditions, column: Waters Xbridge BEH C18 100*25mm*5pm; mobile phase: A: water (0.225% formic acid), B: acetonitrile; B%: 32%-52%, 12 min). Further purification was performed by supercritical fluid chromatography (basic conditions, column: Phenomenex-Cellulose-2 (250mm*30mm, 10pm); mobile phase: [0.1% ammonia water], B: ethanol; B%: 40%-40%), to give compound 58-P1 (1.5 mg, RT: 2.495 min) and compound 58-P2 (1.9 mg, RT: 3.176 min).

[0990] Compound 58-P1

[0991] 1 H NMR (400 MHz, METHANOL-d4) d = 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).

[0992] MS m / z (ESI): = 445.0 [M+H] + .

[0993] Compound 58-P2

[0994] 1 H NMR (400 MHz, METHANOL-d4) d = 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).

[0995] MS m / z (ESI): = 445.0 [M+H] + .

[0996] Example 59, 5-(4-methoxyphenyl)-l-methyl-7-(trifluoromethyl)-l,5-dihydro-4H- imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 59)

[0997]

[0998] Step 1: Synthesis of 3-bromo-N-(4-methoxyphenyl)-6-(trifluoromethyl)pyridin-2- amine (Intermediate 59-2).

[0999] Intermediate 59-1 (23.64 mg) was dissolved in dry N,N-dimethylformamide (0.5 mL) solution at 25 °C, the temperature was lowered to 0 °C, sodium hydride (15.36 mg) was slowly added, after stirring for 30 minutes, intermediate 15-1 (500 mg) was dissolved in dry N,N-dimethylformamide (0.5 mL) solution, and then added to the reaction system, the reaction solution was stirred at 25 °C under nitrogen protection for 16 hours. After the reaction was completed, the temperature was lowered to 0 °C, sodium hydride was quenched with water solution (1 mL), then ethyl acetate (10 mL) and water (20 mL) were added to the reaction solution, extracted twice with saturated aqueous sodium chloride solution (20 mL), the organic phase was combined and dried over anhydrous sodium sulfate. After filtration, the organic layer was concentrated to dryness under reduced pressure, and the residue was purified by silica gel preparative thin-layer chromatography (petroleum ether / tetrahydrofuran = 10 / 1) to obtain the title compound (40 mg).

[1000] MS m / z (ESI): = 346.8 [M+H] + .

[1001] Step 2: Synthesis of 5-(4-methoxyphenyl)-l-methyl-7-(trifluoromethyl)-l,5-dihydro-4H- imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 59).

[1002] Intermediate 59-2 (40 mg) was dissolved in anhydrous xylene (1 mL) at 20 °C, Pd(PPh3)4 (13.32 mg) and intermediate 20-1 (34.91 mg) were added to the reaction solution. The reaction was stirred at 140 °C for 16 hours under nitrogen protection. After the reaction was completed, ethyl acetate (10 mL) and water (20 mL) were added to the reaction solution, extracted with ethyl acetate (20 mL*2 times), and the organic phases were combined and 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 high performance liquid chromatography (acidic conditions, column: Waters Xbridge BEH C18 100*25mm*5um; mobile phase: A: water (0.225% formic acid), B: acetonitrile; B%: 21%-41%, 12 min) to give the title compound (2.2 mg).

[1003] 1H NMR (400 MHz, METHANOL-d4) d = 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).

[1004] MS m / z (ESI): = 375.0 [M+H] + .

[1005] Example 60, 1 -Methyl-5-(1 -methyl-1 H-pyrazol-5-yl)-7-(trifluoromethyl)-1,5-dihydro- 4H-imidazo[4,5-c][1,8]naphthyridin-4(5H)-one (Compound 60)

[1006]

[1007] Step 1 : Synthesis of 3-bromo-N-(1 -methyl-1 H-pyrazol-5-yl)-6- (trifluoromethyl)pyridin-2-amine (Intermediate 60-2)

[1008] Intermediate 60-1 (18.65 mg) was dissolved in anhydrous N,N- dimethylformamide (1 mL) at 25 °C, and sodium hydride (23.04 mg) was added to the reaction solution when the temperature was reduced to 0 °C. The reaction solution was stirred at 0 °C for 30 minutes under nitrogen protection, and intermediate 15-1 (50 mg) was added to the reaction solution. The reaction was stirred at 20 °C for 16 hours under nitrogen protection. After the reaction was completed, the temperature was reduced to 0 °C and water (20 mL) was added, extracted with ethyl acetate (10 mL*2 times), and the organic phases were combined and 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 give the title compound (45 mg).

[1009] MS m / z (ESI): = 320.8 [M+H] + .

[1010] Step 2: Synthesis of N-(l-methyl-lH-pyrazol-5-yl)-6-(trifluoromethyl)-3- (trimethylstannyl)pyridin-2-amine (Intermediate 60-3)

[1011] 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. The reaction was stirred at 140 °C for 16 h under nitrogen. After the reaction was completed, saturated aqueous cesium fluoride solution (10 mL) was added to the reaction, and extraction was performed with ethyl acetate (10 mL x 2 times), and the organic phase was combined and 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).

[1012] MS m / z (ESI): = 407.1 [M+H] + .

[1013] Step 3: Synthesis of l-methyl-5-(l-methyl-lH-pyrazol-5-yl)-7-(trifluoromethyl)- 1,5-dihydro-4H-imidazo[4,5-c][l,8]naphthyridin-4(5H)-one (Compound 60)

[1014] 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, and the reaction was stirred at 140 °C for 16 h under nitrogen. After the reaction was completed, the reaction was filtered, and the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 100*25mm*5um; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 17%-27%, 12 min) to obtain the title compound (1.1 mg).

[1015] 1H NMR (400 MHz, METHANOL-d4) d = 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).

[1016] MS m / z (ESI): 349.1 [M+H] + .

[1017] Example 61, 5-(2-chlorophenyl)-1-ethyl-7-(trifluoromethyl)-1,5-dihydro-4H- imidazo[4,5-c][1,8]naphthyridin-4-one (Compound 61)

[1018]

[1019] Step 1: Synthesis of methyl 5-bromo-1-ethyl-1H-imidazole-4-carboxylate (Intermediate 61-2)

[1020] Potassium carbonate (606.75 mg) was added to a solution of Intermediate 61-1 (300 mg) in N,N-dimethylformamide (4 mL) at 20 °C, the reaction was stirred for 0.5 h, iodoethane (273.89 mg) was added, the reaction was stirred at 50 °C for 16 h. After the reaction was completed, the filtrate was obtained by filtration, concentrated to dryness under reduced pressure, the residue was slurried with tetrahydrofuran (10 mL), the filtrate was obtained by filtration again, concentrated to dryness under reduced pressure. The residue was purified by thin layer chromatography (tetrahydrofuran: petroleum ether = 2:1) to give the title compound (130 mg).

[1021] MS m / z (ESI): 233.0 [M+H] +

[1022] 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)

[1023] Intermediate 61-2 (56 mg) and Intermediate 50-6 (104.63 mg) were dissolved in durene (5 mL) and added with tetrakis(triphenylphosphine)palladium (27.77 mg), the reaction was stirred at 140 °C for 16 h under nitrogen atmosphere. Then the reaction was cooled to 20 °C, potassium tert-butoxide (40.44 mg) was added, the reaction was stirred at 90 °C for 16 h. After the reaction was completed, the reaction was filtered, the filtrate was concentrated to dryness under reduced pressure, the residue was purified by thin layer chromatography (tetrahydrofuran: petroleum ether = 3:1), then purified by high performance liquid chromatography (formic acid condition; column: Waters Xbridge BEH C18 100*25mm*5um; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 28%-48%, 12 min) to give the title compound (1.6 mg).

[1024] MS m / z (ESI): 393.0 [M+H] + .

[1025] 1 HNMR (400 MHz, 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).

[1026] Example 62, 5-(2,4-dichlorophenyl)-l-methyl-7-(trifluoromethyl)-l,5-dihydro-4H- imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 62)

[1027]

[1028] Step 1: Synthesis of 3-bromo-N-(2,4-dichlorophenyl)-6-(trifluoromethyl)pyridin-2- amine (Intermediate 62-2)

[1029] The reactant 62-1 (273.72 mg) was dissolved in N,N-dimethylformamide (6 mL). The reaction solution was added with sodium hydride (122.86 mg) at 0 °C under nitrogen protection, and stirred for 30 minutes. The reaction solution was added with a solution of intermediate 15-1 (400 mg) in N,N-dimethylformamide (2 mL) at 0 °C, and stirred at 20 °C for 16 hours. After the reaction was completed, the reaction solution was quenched with water (20 mL), extracted with ethyl acetate (10 mL*3 times), and 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 (Silica Flash column, gradient 0% ethyl acetate / petroleum ether @ 40 mL / min) to give the title compound (500 mg). 12g Silica Flash column, gradient 0% ethyl acetate / petroleum ether @ 40 mL / min) to give the title compound (500 mg).

[1030] MS m / z (ESI): 384.8 [M+H] + .

[1031] Step 2: Synthesis of N-(2,4-dichlorophenyl)-6-(trifluoromethyl)-3-(trimethylstannyl)pyridin- 2-amine (Intermediate 62-3)

[1032] Intermediate 62-2 (300 mg) was dissolved in xylene (3 mL), Pd(PPh3)4 (89.81 mg) and hexamethyldistannane (1.02 g) were added at 20 °C. The reaction was stirred at 140 °C under nitrogen atmosphere for 1 h. After the reaction was completed, the reaction was quenched with saturated aqueous cesium fluoride solution (20 mL), extracted with ethyl acetate (20 mL*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) to give the title compound (190 mg). 20 g Silica Flash column, petroleum ether @ 40 mL / min) to give the title compound (190 mg).

[1033] MS m / z (ESI): 470.9 [M+H] + .

[1034] 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)

[1035] Intermediate 62-3 (150 mg) and intermediate 15-4 (104.88 mg) were dissolved in xylene (2 mL), Pd(PPh3)4 (55.33 mg) was added at 20 °C. The reaction was stirred at 140 °C under nitrogen atmosphere for 16 h. After the reaction was completed, the reaction was diluted with water (20 mL), extracted with ethyl acetate (20 mL*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 preparative thin layer chromatography (petroleum ether: tetrahydrofuran = 10: 1). Further purification by high performance liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5um; mobile phase: [A: water (0.05% ammonia water v / v), B: acetonitrile]; B%: 45%-65%, 11 min) to give the title compound (10.2 mg).

[1036] 1 H NMR (400 MHz, DMSO-d6) d = 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).

[1037] MS m / z (ESI): 412.9 [M+H] + .

[1038] Example 63, 5-(3-fluorophenyl)-l-methyl-7-(trifluoromethyl)-l,5-dihydro-4H- imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 63)

[1039]

[1040] Step 1: Synthesis of 3-bromo-N-(3-fluorophenyl)-6-(trifluoromethyl)pyridin-2- amine (Intermediate 63-2)

[1041] The reactant 63-1 (128.00 mg) was dissolved in N,N-dimethylformamide (3 mL). The reaction solution was added with sodium hydride (69.11 mg) at 0 °C under nitrogen protection, and stirred for 30 minutes. The reaction solution was added with Intermediate 15-1 (300 mg) at 0 °C, and stirred for 16 hours at 20 °C. After the reaction was completed, the reaction solution was quenched with water (10 mL), extracted with ethyl acetate (20 mL*3 times), and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 10: 1) to give the title compound (117 mg). 20 g Silica Flash column, petroleum ether @ 60 mL / min).

[1042] MS m / z (ESI): 334.8 [M+H] + .

[1043] Step 2: Synthesis of 5-(3-fluorophenyl)-l-methyl-7-(trifluoromethyl)-l,5-dihydro-4H- imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 63)

[1044] The 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 reaction was stirred at 140 °C under nitrogen protection for 16 hours. The reaction solution 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: YMC-Actus Triart C18 150*30mm*5um; mobile phase: [A: water (0.225% formic acid v / v), B: acetonitrile]; B%: 38%-58%, 11 minutes) to give the title compound (8.7 mg).

[1045] 1H NMR (400 MHz, DMSO-d6) d = 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).

[1046] MS m / z (ESI): 363.1 [M+H] + .

[1047] 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)

[1048]

[1049] Step 1 : Synthesis of 3-bromo-N-(pyridin-3-yl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 64-2)

[1050] 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 was stirred at 25 °C for 16 h. After the reaction was completed, water (200 mL) was added to the reaction, and extraction was performed with ethyl acetate (100 mL x 3), and the organic phase was combined and 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: ethyl acetate = 1 :0 to 10:1 ) to give the title compound (380.7 mg).

[1051] MS m / z (ESI): = 317.9 [M+H] + .

[1052] Step 2: Synthesis of N-(pyridin-3-yl)-6-(trifluoromethyl)-3-(trimethylstannyl)pyridin-2- amine (Intermediate 64-3)

[1053] Intermediate 64-2 (380 mg) was dissolved in xylene (4 mL), hexamethyldistannane (782.79 mg), tetrakis(triphenylphosphine)palladium (138.05 mg) was added. The reaction was stirred at 140 °C for 4 h under nitrogen protection. After the reaction was completed, the reaction solution was added to saturated potassium fluoride solution (5 mL), extracted with ethyl acetate (5 mL*3 times), and the organic phase was concentrated to dryness under reduced pressure. The residue was purified by preparative thin layer chromatography (petroleum ether: ethyl acetate = 3:1) to give the title compound (50 mg).

[1054] MS m / z (ESI): = 403.9 [M+H] + .

[1055] 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)

[1056] Intermediate 64-3 (50 mg) was dissolved in xylene (2 mL), intermediate 15-4 (27.24 mg), tetrakis(triphenylphosphine)palladium (14.37 mg) was added. The reaction was stirred at 140 °C for 12 h under nitrogen protection. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (column: Waters Xbridge BEH C18 100*25mm*5um); mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 9%-29%, 12 min) to give the title compound (16.6 mg).

[1057] MS m / z (ESI): = 346.0 [M+H] + .

[1058] 1 H NMR (400 MHz, METHANOL-d4) d = 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).

[1059] 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)

[1060]

[1061] Step 1: Synthesis of 5-bromo-2-(trifluoromethyl)pyrimidin-4(3H)-one (Intermediate 65-2)

[1062] Intermediate 65-1 (5 g) was dissolved in N,N-dimethylformamide (50 mL), then N-bromosuccinimide (6.5 g) was added into the reaction solution. The reaction solution was stirred at 50 °C for 18 h. After the reaction solution was cooled to room temperature, water (60 mL) and ethyl acetate (80 mL) were added into the reaction solution successively, the organic phase was washed with water (30 mL*2), and the washed 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 subjected to preparative thin-layer chromatography (petroleum ether: ethyl acetate = 10:1) to give the title compound (5 g).

[1063] MS m / z (ESI): 243.2 [M+H] +

[1064] Step 2: Synthesis of 5-bromo-N-(2-chloro-3-fluorophenyl)-2- (trifluoromethyl)pyrimidin-4-amine (Intermediate 65-4)

[1065] Intermediate 65-2 (500 mg) and 2,6-dimethylpyridine (330 mg) were dissolved in anhydrous tetrahydrofuran (5 mL), and triflic anhydride (697 mg) was added dropwise into the reaction solution at -78 °C. The reaction solution was stirred at 0 °C for 2 h, and then Intermediate 65-3 (896 mg) was added into the reaction solution. The reaction solution was stirred at 70 °C for 3 h. H2O (20 mL) and ethyl acetate (20 mL*3) were added into the reaction solution successively, the organic phase was washed with saturated brine (30 mL*2), and the washed organic phase was dried over anhydrous sodium sulfate. The title compound (270 mg) was obtained by preparative thin-layer chromatography (silica, petroleum ether: ethyl acetate = 100:0-50:50).

[1066] MS m / z (ESI): 370.2 [M+H] +

[1067] Step 3: Synthesis of (4-((2-chloro-3-fluorophenyl)amino)-2- (trifluoromethyl)pyrimidin-5-yl)boronic acid (Intermediate 65-5)

[1068] Intermediate 65-4 (300 mg) and bis-pinacolborane (278 mg) were dissolved in 1,4-dioxane (3 mL), to which potassium acetate (211 mg) and Pd(dppf)Cl2(46 mg) were added, and the reaction liquid was stirred at 100°C for 15 hours under nitrogen protection. After the reaction liquid was cooled to room temperature, water (40 mL) and ethyl acetate (80 mL) were added in sequence, the organic phase was washed with water (30 mL*2), and 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, and the residue was subjected to preparative thin layer chromatography (dichloromethane:methanol = 10:1) to obtain the title compound (200 mg).

[1069] MS m / z (ESI): 336.1 [M+H] +

[1070] 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)

[1071] Intermediate 65-5 (200 mg) and intermediate 15-4 (195 mg) were dissolved in dioxane (2 mL) and water (0.4 mL), to which cesium fluoride (267 mg) and Pd(dtbpf)Cl2(39 mg) were added, and the reaction liquid was stirred at 100°C for 16 hours under nitrogen protection. After the reaction was cooled to room temperature, water (30 mL) and ethyl acetate (40 mL) were added in sequence, the organic phase was washed with saturated brine (30 mL*2), and 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 5μm*10*150mm; mobile phase: A: 0.05% TFA v / v, B: acetonitrile; B%: 40%-45%, 12 min) to obtain the title compound (13 mg).

[1072] MS m / z (ESI): 398.1 [M+H] + .

[1073] 1 H 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).

[1074] Example 66, 5-(2-chloro-3-fluorophenyl)-1-methyl-7-(trifluoromethyl)-1,5-dihydro-4H- imidazo[4,5-c]quinolin-4-one (Compound 66)

[1075]

[1076] Intermediate 45-3 (50 mg) and intermediate 66-1 (70 mg) were dissolved in anhydrous dioxane (1 mL), cesium carbonate (163 mg), XantPhos (19 mg) and Pd2(dba)3(10 mg) were added. The reaction was stirred at 100 °C under nitrogen for 12 h. When the reaction was cooled to room temperature, the reaction was 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, 30 mm diameter, 150 mm length; a mixture of water (containing 0.05% NH4HCO3) and acetonitrile of decreasing polarity as eluent; acetonitrile gradient ratio 55-75%, elution time 12 min] to give the title compound (2 mg).

[1077] MS m / z (ESI): 396.0 [M+H] + .

[1078] 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).

[1079] Example 67, 5-(2-ethylpyridin-3-yl)-l-methyl-7-(trifluoromethyl)-l,5-dihydro-4H- imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 67)

[1080]

[1081] Step 1: Synthesis of 3-nitro-2-vinyl-pyridine (Intermediate 67-3)

[1082] Intermediate 67-1 (2.5 g) was added to dioxane (50 mL) and water (16 mL) under nitrogen, to the reaction was added intermediate 67-2 (4.22 g), PdCl2(dppf) (10.62 mg) and cesium carbonate (10.28 g). The reaction was stirred at 90 °C under nitrogen for 16 h. After the reaction was completed, water (40 mL) was added to the reaction, extracted with ethyl acetate (40 mL*3 times), the organic phase was combined and 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 purification (Sephadex LH-20, methanol as eluent). 20 g Silica Flash column, gradient 0-12% ethyl acetate / petroleum ether @ 80 mL / min) to give the title compound (1.98 g).

[1083] MS m / z (ESI): 150.9 [M+H] + .

[1084] Step 2: Synthesis of 2-ethylpyridin-3-amine (Intermediate 67-4)

[1085] Intermediate 67-3 (140.49 mg) was dissolved in anhydrous methanol (50 mL) under nitrogen protection, wet palladium carbon (300 mg) was added to the reaction solution, the reaction solution was stirred at 45 °C for 16 hours under hydrogen atmosphere. After the reaction was completed, filtration was carried out, and the filtrate was concentrated under reduced pressure to remove the solvent to give the title compound (1.22 g).

[1086] MS m / z (ESI): 123.2 [M+H] + .

[1087] Step 3: Synthesis of 3-bromo-N-(2-ethylpyridin-3-yl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 67-5)

[1088] Intermediate 67-4 (140.49 mg) was dissolved in anhydrous N,N-dimethylformamide (3 mL) under nitrogen protection, and sodium hydride (69.00 mg) was added to the reaction solution when the temperature dropped to 0 °C. The reaction solution was stirred at 0 °C for 30 minutes. Intermediate 15-1 (300 mg) was dissolved in anhydrous N,N-dimethylformamide (2 mL) and added to the reaction solution. The reaction solution was stirred at 25 °C for 16 hours under nitrogen protection. After the reaction was completed, water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL*3 times), and 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 silica gel column chromatography (eluent: ethyl acetate / petroleum ether=0-10%, 40 mL / min) to give the title compound (31.8 mg). 12g Silica Flash column, gradient 0-13% ethyl acetate / petroleum ether @ 40 mL / min) to give the title compound (31.8 mg).

[1089] MS m / z (ESI): 345.9 [M+H] + .

[1090] 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)

[1091] Intermediate 67-5 (31.8 mg) was added to dry xylene (1 mL) under nitrogen protection, and then tetrakis(triphenylphosphine)palladium (10.62 mg) and intermediate 20-1 (27.83 mg) were added. Subsequently, the reaction was stirred at 140 °C for 16 h under nitrogen protection. After the reaction was completed, water (10 mL) was added to the reaction, and extraction was performed with ethyl acetate (10 mL*3 times), and the organic phase was combined 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 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%: 11%-41%, 12 min) to obtain the title compound (7 mg). The solvent was removed by freeze-drying, 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% ammonia water)]; B%: 25%-25%) to obtain compound 67-P1 (2.03 mg, RT: 4.35 min) and compound 67-P2 (2.02 mg, RT: 5.01 min).

[1092] Compound 67-P1

[1093] MS m / z (ESI): 374.1 [M+H] + .

[1094] 1 H NMR (400 MHz, METHANOL-d4) d 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).

[1095] Compound 67-P2

[1096] MS m / z (ESI): 374.1 [M+H] + .

[1097] 1H NMR (400 MHz, METHANOL-d4) d 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).

[1098] Example 68, 5-(2-methoxypyridin-3-yl)-l-methyl-7-(trifluoromethyl)-l,5-dihydro-4H- imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 68)

[1099]

[1100] Step 1: Synthesis of 3-bromo-N-(2-methoxypyridin-3-yl)-6-(trifluoromethyl)pyridin-2- amine (Intermediate 68-2)

[1101] Under nitrogen protection, intermediate 68-1 (238.33 mg) was dissolved in anhydrous N,N-dimethylformamide (5 mL), and sodium hydride (115.19 mg) was added when the temperature dropped to 0 °C. The reaction 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. The reaction was stirred at 25 °C for 16 h under nitrogen protection. After the reaction was completed, water (10 mL) was added to the reaction, and ethyl acetate was used for extraction (10 mL*3 times), and the organic phase was combined and 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 silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1: 1) to give the title compound (231.4 mg). 12g Silica Flash column chromatography, gradient 0-5% ethyl acetate / petroleum ether @ 40 mL / min) to give the title compound (231.4 mg).

[1102] MS m / z (ESI): 347.9 [M+H] + .

[1103] Step 2: Synthesis of 5-(2-methoxypyridin-3-yl)-l-methyl-7-(trifluoromethyl)-l,5-dihydro- 4H-imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 68)

[1104] Intermediate 68-2 (231.4 mg) was added to dry xylene (7 mL) under nitrogen protection, and then tetrakis(triphenylphosphine)palladium (76.81 mg) and intermediate 20-1 (201.37 mg) were added. The reaction was stirred at 140 °C for 16 h under nitrogen protection. After the reaction was completed, the reaction was filtered and the solvent was removed by concentration under reduced pressure. The residue was purified by thin layer chromatography (petroleum ether: ethyl acetate = 10:1) to give a crude product (20 mg). The crude product was added to dry xylene (7 mL), and then potassium tert-butoxide (30 mg) was added. The reaction was stirred at 100 °C for 2 h. After the reaction was completed, the reaction was filtered and the solvent was removed by concentration under reduced pressure. The residue was purified by preparative high performance liquid chromatography (column: Waters Xbridge BEH C18 100*25mm*5um; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 23%-43%, 12 min) to give the title compound (6.3 mg).

[1105] MS m / z (ESI): 376.1 [M+H] + .

[1106] 1 H NMR (400 MHz, METHANOL-d4) d 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).

[1107] 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)

[1108]

[1109] Step 1: Synthesis of 3-bromo-N-(5-(difluoromethoxy)pyridin-2-yl)-6- (trifluoromethyl)pyridin-2-amine (Intermediate 69-2)

[1110] The intermediate 69-2 (100 mg) and the intermediate 20-1 (119.50 mg) were dissolved in xylene (5 mL), Pd(PPh3)4 (30.08 mg) was added at 20 °C, and the reaction was stirred at 140 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (dichloromethane:methanol = 10:1). Further purification by high performance liquid chromatography (column: Phenomenex CI 8 150*30 mm*5 μm; mobile phase: [A: water (ammonia water + ammonium bicarbonate), B: acetonitrile]; B%: 35%-55%, 2 minutes) gave the title compound (46.3 mg). 12g Silica Flash column, gradient 0-5% ethyl acetate / petroleum ether @ 40 mL / min) to give the title compound (400 mg).

[1111] MS m / z (ESI): 383.8 [M+H] + .

[1112] 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)

[1113] The intermediate 69-2 (100 mg) and the intermediate 20-1 (119.50 mg) were dissolved in xylene (5 mL), Pd(PPh3)4 (30.08 mg) was added at 20 °C, and the reaction was stirred at 140 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (dichloromethane:methanol = 10:1). Further purification by high performance liquid chromatography (column: Phenomenex CI 8 150*30 mm*5 μm; mobile phase: [A: water (ammonia water + ammonium bicarbonate), B: acetonitrile]; B%: 35%-55%, 2 minutes) gave the title compound (46.3 mg).

[1114] 1 H NMR (400 MHz, DMSO-d6) d = 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).

[1115] MS m / z (ESI): 412.1 [M+H] + .

[1116] Example 70, 5-(3-fluoro-2-methoxyphenyl)-l-methyl-7-(trifluoromethyl)-l,5- dihydro-4H-imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 70)

[1117]

[1118] Step 1: Synthesis of 3-bromo-N-(3-fluoro-2-methoxyphenyl)-6- (trifluoromethyl)pyridin-2-amine (Intermediate 70-2)

[1119] Under nitrogen protection, intermediate 70-1 (270.97 mg) was dissolved in anhydrous N,N-dimethylformamide (5 mL), and sodium hydride (115.19 mg, 60% active content) was added to the reaction solution when the temperature dropped to 0 °C. The reaction solution 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 solution. The reaction solution was stirred at 25 °C for 16 h under nitrogen protection. After the reaction was completed, water (10 mL) was added to the reaction solution, and extraction was performed with ethyl acetate (10 mL*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 flash silica gel column chromatography (eluent: petroleum ether / ethyl acetate=10 / 1, silica flash column, gradient 0-5% ethyl acetate / petroleum ether @ 40 mL / min) to give the title compound (231.4 mg). 12g Silica Flash column, gradient 0-5% ethyl acetate / petroleum ether @ 40 mL / min) to give the title compound (231.4 mg).

[1120] MS m / z (ESI): 365.0 [M+H] + .

[1121] Step 2: Synthesis of 5-(3-fluoro-2-methoxyphenyl)-l-methyl-7-(trifluoromethyl)- 1,5-dihydro-4H-imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 70)

[1122] Intermediate 70-2 (100 mg) was added to dry xylene (7 mL) under nitrogen protection, and then tetrakis(triphenylphosphine)palladium (41.96 mg) and intermediate 20-1 (110.00 mg) were added. The reaction was stirred at 140 °C for 16 h under nitrogen protection. After completion of the reaction, the reaction was filtered and the solvent was removed by concentration under reduced pressure. The residue was purified by preparative high performance liquid chromatography (column: Waters Xbridge BEH C18 100*25mm*5um; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 24%-44%, 12 min) and then by preparative supercritical fluid chromatography (column: DAICEL CHIRALCEL OD-H (250mm*30mm, 5um); mobile phase: [A: supercritical carbon dioxide, B: ethanol (0.1% ammonia water)]; B%: 40%-40%) to give compound 70-P1 (3.5 mg, RT: 5.883 min) and compound 70-P2 (3.8 mg, RT: 6.298 min).

[1123] Compound 70-P1

[1124] MS m / z (ESI): 393.1 [M+H] + .

[1125] 1 H NMR (400 MHz, METHANOL-d4) d 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).

[1126] Compound 70-P2

[1127] MS m / z (ESI): 393.1 [M+H] + .

[1128] 1 H NMR (400 MHz, METHANOL-d4) d 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).

[1129] 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)

[1130]

[1131] Step 1: Synthesis of 3-bromo-N-[4-(difluoromethoxy)-3-fluorophenyl]-6- (trifluoromethyl)pyridin-2-amine (Intermediate 71-2)

[1132] 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 solution. The reaction solution was stirred at 25 °C for 16 hours. After the reaction was completed, water (20 mL) was added to the reaction solution, which was extracted with ethyl acetate (10 mL*3 times), and 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 silica gel column chromatography (Silica Flash column, gradient 0-10% ethyl acetate / petroleum ether @ 40 mL / min) to give the title compound (218.9 mg). 12g Silica Flash column, gradient 0-10% ethyl acetate / petroleum ether @ 40 mL / min) to give the title compound (218.9 mg).

[1133] MS m / z (ESI): 401.0 [M+H] + .

[1134] 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)

[1135] Intermediate 71-2 (100 mg) was added to anhydrous xylene (4 mL) under nitrogen protection, and then tetrakis(triphenylphosphine)palladium (28.81 mg) and Intermediate 20-1 (75.53 mg) were added to the reaction solution. Subsequently, the reaction solution was stirred at 140 °C for 16 hours under nitrogen protection. After the reaction was completed, 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*25mm*5um; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 31%-51%, 14 min) to give the title compound (25.8 mg).

[1136] MS m / z (ESI): 429.1 [M+H] + .

[1137] 1 H NMR (400 MHz, 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).

[1138] Example 72, l-(methyl-d3)-5-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-l,5- dihydro-4H-imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 72)

[1139]

[1140] Step 1: Synthesis of N-(2-methylpyridin-3-yl)-6-(trifluoromethyl)-3- (trimethylstannyl)pyridin-2-amine

[1141] Intermediate 20-3 (300 mg) was dissolved in xylene (8 mL), hexamethyldistannane (591.88 mg), tetrakis(triphenylphosphine)palladium (104.38 mg) was added. The reaction was heated to 140 °C for 1 h under nitrogen protection. The reaction was cooled to 20 °C, quenched with potassium fluoride solution (20 mL), extracted with ethyl acetate (10 mL), the organic phase was concentrated to dryness under reduced pressure, the residue was purified by silica gel column (eluent: 10-35% ethyl acetate / petroleum ether gradient @ 30 mL / min) to give the title compound (130 mg) 12g silica gel column, eluent: 10-35% ethyl acetate / petroleum ether gradient @ 30 mL / min) to give the title compound (130 mg)

[1142] MS m / z (ESI): 417.9 [M+H] + .

[1143] Step 2: Synthesis of l-(methyl-d3)-5-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-l,5- dihydro-4H-imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 72)

[1144] Intermediate 72-1 (130 mg) and intermediate 44-2 (69.39 mg) were dissolved in xylene (5 mL), and tetrakis(triphenylphosphine)palladium (36.11 mg) was added. The reaction was stirred at 140 °C for 16 h under nitrogen protection. After the reaction was completed, the reaction was concentrated to dryness under reduced pressure, and the residue was purified by thin layer chromatography (tetrahydrofuran:dichloromethane = 1:1). The residue was further purified by preparative high performance liquid chromatography (formic acid condition; column: Waters Xbridge BEH C18 100*25mm*5um; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 4%-34%, 12 min) to give the title compound (22.3 mg).

[1145] MS m / z (ESI): 363.0 [M+H] + .

[1146] 1 H NMR (400 MHz, METHANOL-d4) d = 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).

[1147] 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)

[1148]

[1149]

[1150] Step 1: Synthesis of 3-amino-2-chlorobenzonitrile (Intermediate 73-2)

[1151] Intermediate 73-1 (500 mg) was dissolved in anhydrous ethanol (9 mL) and water (3 mL) at 25 °C, and iron powder (458.84 mg) and ammonium chloride (732.50 mg) were added. The reaction was stirred at 70 °C for 16 h under nitrogen protection. After the reaction was completed, the temperature was reduced to 25 °C and water (50 mL) was added. The organic phase was extracted with ethyl acetate (50 mL*2 times), and the combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent to give the title compound (375 mg).

[1152] MS m / z (ESI): = 153.1 [M+H] + .

[1153] Step 2: Synthesis of 3-((3-bromo-6-(trifluoromethyl)pyridin-2-yl)amino)-2- chlorobenzonitrile (Intermediate 73-3)

[1154] Intermediate 73-2 (256.03 mg) was dissolved in N,N-dimethylformamide (5 mL) at 25 °C, and sodium hydride (117.96 mg, 60% active content) was added to the reaction at 0 °C. The reaction was stirred at 0 °C for 0.5 h under nitrogen protection, and then Intermediate 15-1 (150 mg) was added to the reaction. After the reaction was completed, water (200 mL) was added to the reaction, and extraction was performed with ethyl acetate (100 mL*2 times). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent to obtain the title compound (120 mg).

[1155] MS m / z (ESI): = 375.7 [M+H] + .

[1156] 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)

[1157] 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. The reaction was reacted at 140 °C for 16 h under nitrogen protection. After the reaction was completed, the reaction was filtered, and the solvent was removed under reduced pressure. The residue was purified by preparative high performance liquid chromatography (column: Waters Xbridge BEH C18 100*25mm*5um; mobile phase: [water (0.225%) formic acid-acetonitrile]; B%: 25%-45%, 12 min) to obtain the title compound (65 mg).

[1158] Compound 73 was further purified by preparative supercritical fluid chromatography (column: DAICEL CHIRALCEL OJ (250mm*30mm, 10um); mobile phase: A: carbon dioxide B: ethanol (0.1% ammonia water)) to obtain Compound 73-P1 (13.3 mg, RT: 3.105 min) and Compound 73-P2 (11 mg, RT: 3.557 min).

[1159] Compound 73-P1

[1160] MS m / z (ESI): = 404.0 [M+H] + .

[1161] Compound 73-P11 H NMR (400 MHz, 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).

[1162] MS m / z (ESI): = 404.0 [M+H] + .

[1163] Compound 73-P2

[1164] 1 H NMR (400 MHz, 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).

[1165] 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)

[1166]

[1167] Step 1: Synthesis of 4-(chloromethyl)-1-methyl-1H-pyrazole (Intermediate 74-2)

[1168] The reactant 74-1 (2 g) was dissolved in dichloromethane (23 mL), and thionyl chloride (3.18 g) was added at 0 °C. The reaction solution was stirred at 25 °C under nitrogen protection for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product of the title compound (3.02 g).

[1169] 1 H NMR (400 MHz, DMSO-d6) δ = 7.79 (s, 1H), 7.48 (s, 1H), 4.68 (s, 2H), 3.81 (s, 3H)

[1170] Step 2: Synthesis of methyl 5-bromo-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H- imidazole-4-carboxylate (Intermediate 74-4)

[1171] Intermediate 74-2 (300 mg) and intermediate 74-3 (471.01 mg) were dissolved in acetonitrile (10 mL), sodium iodide (344.39 mg) and potassium carbonate (952.60 mg) were added at 25 °C, and the reaction solution was stirred at 80 °C for 24 h. After the reaction was completed, the reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 mL*3 times), and the organic phase was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol = 10:1) to give the title compound (201 mg).

[1172] 1 H NMR (400 MHz, 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).

[1173] MS m / z (ESI): = 299.0 [M+H] + .

[1174] 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)

[1175] 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 under nitrogen protection at 25 °C. The reaction was stirred at 140 °C under nitrogen protection for 16 h. After the reaction was completed, the reaction solution 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*30mm*5um; mobile phase: [A: water (ammonia + ammonium bicarbonate), B: acetonitrile]; B%: 25%-45%, 2 min) to give the title compound (29.4 mg).

[1176] 1 H NMR (400 MHz, 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).

[1177] MS m / z (ESI): 440.2 [M+H] + .

[1178] 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)

[1179]

[1180] Step 1: Synthesis of 5-Bromo-N-(2-methylpyridin-3-yl)-2- (trifluoromethyl)pyrimidin-4-amine (Intermediate 75-2)

[1181] 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 reaction was stirred at 0 °C for 2 h, and then Intermediate 75-1 (667 mg) was added. The reaction was stirred at 70 °C for 3 h. H2O (20 mL) and ethyl acetate (20 mL*3) were added to the reaction successively, 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 the title compound (230 mg) was obtained by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 100:0-50:50).

[1182] MS m / z (ESI): 333.2 [M+H] + .

[1183] Step 2: Synthesis of (4-((2-methylpyridin-3-yl)amino)-2- (trifluoromethyl)pyrimidin-5-yl)boronic acid (Intermediate 75-3)

[1184] 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)Cl2(42 mg) were added. The reaction was stirred at 100 °C under nitrogen protection for 15 h. After the reaction was cooled to room temperature, water (40 mL) and ethyl acetate (80 mL) were added successively, and 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, and the title compound (160 mg) was obtained by preparative thin-layer chromatography (dichloromethane:methanol = 10:1).

[1185] MS m / z (ESI): 299.1 [M+H] + .

[1186] Step 3: Synthesis of l-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)

[1187] Intermediate 75-3 (160 mg) and intermediate 15-4 (175 mg) were dissolved in dioxane (2 mL) and water (0.4 mL), to which cesium fluoride (156 mg) and Pd(dtbpf)Cl2 (39 mg) were added, and the reaction was stirred at 100 °C for 16 hours under nitrogen protection. After the reaction was cooled to room temperature, water (30 mL) and ethyl acetate (40 mL) were added in turn, the organic phase was washed with saturated brine (30 mL*2), and 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: mobile phase A: 0.05% TFA v / v, B: acetonitrile; B%: 40%-45%, 12 min) to give the title compound (15 mg).

[1188] MS m / z (ESI): 361.1 [M+H] + .

[1189] 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).

[1190] Example 76, l-methyl-5-(pyrimidin-5-yl)-7-(trifluoromethyl)-l,5-dihydro-4H- imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 76)

[1191]

[1192] Step 1: Synthesis of 2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6- (trifluoromethyl)pyridine (Intermediate 76-3)

[1193] Intermediate 76-1 (100 g) was dissolved in THF (1000 mL), and intermediate 76-2 (124 g) was added to the reaction solution. The reaction solution was stirred at -78 °C for 10 min under nitrogen protection, and lithium diisopropylamine (318 mL) was added portionwise. The reaction solution was stirred at 25 °C for 4 h. The reaction solution was lowered to 0 °C, and hydrochloric acid aqueous solution was added to adjust the pH of the reaction solution to 4. Then, extraction was performed with ethyl acetate (1500 mL*2), and the combined organic phase was washed with brine (300 mL*2). The washed organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Distillation was performed under reduced pressure (90 °C) to obtain the title compound (130 g).

[1194] MS m / z (ESI): 292.1 [M+H] + .

[1195] Step 2: Synthesis of methyl 5-(2-fluoro-6-(trifluoromethyl)pyridin-3-yl)-1-methyl-1H- imidazole-4-carboxylate (Intermediate 76-4)

[1196] Intermediate 15-4 (29.0 g) and intermediate 76-3 (58 g) were dissolved in 1,4- dioxane (250 mL) and water (25 mL), and cesium fluoride (60.25 g), Ruphos (6.2 g), and Ruphos Pd G3 (11.10 g) were added. The reaction solution was stirred at 100 °C for 4 h under nitrogen protection. After the reaction solution was cooled to room temperature, 290 mL of 6M K2CO3 aqueous solution was added, and stirring was performed at 25 °C for 0.5 h. Extraction was performed with ethyl acetate (300 mL*2), and the combined organic phase was washed with brine (300 mL*2). The washed organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification was performed by preparative thin-layer chromatography (silica, dichloromethane:methanol = 20:1) to obtain the title compound (22.3 g).

[1197] MS m / z (ESI): 304.1 [M+H] + .

[1198] 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)

[1199] 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 completed, the mixture was stirred at 25 °C for 1 hour. After the reaction was completed, saturated aqueous ammonium chloride solution (8 mL) and ethyl acetate (8 mL*3) were added to the reaction solution in sequence. The organic phase was washed with water (8 mL*2), and 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 high performance liquid chromatography (column: Gemini NX C18 5 μm*10*150 mm; mobile phase: water (0.225% formic acid v / v), B: acetonitrile; B%: 30%-50%) to obtain the title compound (6 mg).

[1200] MS m / z (ESI): 347.0 [M+H] + .

[1201] 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).

[1202] 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)

[1203]

[1204] Step 1: Synthesis of methyl 1-methyl-5-(2-(pyrazin-2-ylamino)-6- (trifluoromethyl)pyridin-3-yl)-1H-imidazole-4-carboxylate (Intermediate 77-1)

[1205] Intermediate 76-4 (100 mg) and 2-aminopyrazine (31 mg) were dissolved in anhydrous tetrahydrofuran (2 mL), and lithium bis(trimethylsilyl)amide (1 mL) was added dropwise at 0 °C. After the addition was completed, the mixture was stirred at 25 °C for 1 hour. After the reaction was completed, saturated aqueous ammonium chloride solution (8 mL) and ethyl acetate (8 mL*3) were added to the reaction solution in sequence. The organic phase was washed with water (8 mL*2), and 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 flash chromatography (Silica Flash column, gradient 0-5% methanol / dichloromethane, 80 mL / min) to obtain the title compound (60.0 mg). 20g Silica Flash column, gradient 0-5% methanol / dichloromethane, 80 mL / min) to obtain the title compound (60.0 mg).

[1206] MS m / z (ESI): 379.0 [M+H] +

[1207] 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)

[1208] 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 h. After the reaction was completed, saturated aqueous ammonium chloride solution (8 mL) and ethyl acetate (8 mL*3) were added successively, 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, 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*25mm*5um; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 33%-50%, 12 min) to give the title compound (23.5 mg).

[1209] MS m / z (ESI): 347.0 [M+H] + .

[1210] 1 H NMR (400 MHz, DMSO-d6) d 8.93-8.81 (m, 4H) 8.38 (s, 1H), 7.88 (d, J = 8.2 Hz, 1H), 4.30 (s, 3H).

[1211] 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)

[1212]

[1213] Intermediate 76-4 (50 mg) and intermediate 78-1 (22 mg, 0.17 mmol) were dissolved in tetrahydrofuran (1 mL) and the reaction was stirred at 0 °C for 10 min under nitrogen protection. Lithium bis(trimethylsilyl)amide (0.34 mL) was added to the reaction. The reaction was stirred at 24 °C for 2 h. The reaction was quenched by adding 5 mL H2O at 0 °C. Water (15 mL) and ethyl acetate (30 mL) were added successively. The organic phase was washed with saturated brine (30 mL*2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product 50 mg. The crude product was purified by preparative high performance liquid chromatography (column: Gemini NX C18 5 pm*10*150 mm; mobile phase: A: 0.05% TFA v / v, B: acetonitrile; B%: 40%-45%, 12 min) to give the title compound (5 mg).

[1214] MS m / z (ESI): 381.2 [M+H] + .

[1215] 1 H NMR (400 MHz, DMSO-d6) d 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).

[1216] 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)

[1217]

[1218] 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)

[1219] Intermediate 76-4 (80 mg) and intermediate 79-1 (29 g) were dissolved in tetrahydrofuran (2 mL) and a solution of lithium bis(trimethylsilyl)amide (1 mol / L in THF, 0.4 mL) was added dropwise at 0 °C. The reaction was stirred at 0 °C for 3 h. The reaction was concentrated under reduced pressure to remove the solvent and the title compound (31 mg) was purified by preparative high performance liquid chromatography (column: Gemini NX C18 5 pm*10*150 mm; mobile phase: A: water (0.225% formic acid v / v), B: acetonitrile; B%: 40%-60%, 12 min).

[1220] MS m / z (ESI): 361.1 [M+H] + .

[1221] 1 H 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).

[1222] Example 80: 5-(2-chloro-3-ethynylphenyl)-l-methyl-7-(trifluoromethyl)-l,5- dihydro-4H-imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 80)

[1223]

[1224] Step 1: synthesis of 2-chloro-3-((triisopropylsilyl)ethynyl)aniline (Intermediate 80-3)

[1225] 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 to the reaction solution in sequence, 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 the solvent was removed by reduced pressure concentration. The residue was subjected to preparative thin layer chromatography (silica, petroleum ether: ethyl acetate = 4: 1) to give the title compound (174 mg).

[1226] MS m / z (ESI): 308.1 [M+H] + .

[1227] Step 2: synthesis of 5-(2-chloro-3-((triisopropylsilyl)ethynyl)phenyl)-l-methyl-7- (trifluoromethyl)-l,5-dihydro-4H-imidazo[4,5-c][l,8]naphthyridin-4-one (Intermediate 80-4)

[1228] Intermediate 80-3 (125 mg) and intermediate 76-4 (152 mg) were dissolved in anhydrous tetrahydrofuran (4 mL), and a solution of lithium bis(trimethylsilyl)amide in THF (1 mol / L, 0.8 mL) was added dropwise at 0 °C. The reaction solution was stirred at 0 °C for 2 h. The reaction solution was concentrated by reduced pressure to remove the solvent, and the residue was subjected to preparative thin layer chromatography (silica, dichloromethane:methanol = 20: 1) to give the title compound (165 mg).

[1229] MS m / z (ESI): 558.9 [M+H] + .

[1230] Step 3: Synthesis of 5-(2-chloro-3-ethynylphenyl)-l-methyl-7- (trifluoromethyl)-l,5-dihydro-4H-imidazo[4,5-c][l,8]naphthyridin-4-one (Compound 80)

[1231] 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 solution was washed with water (15 mL) and extracted with ethyl acetate (10 mL*2). The organic phase was dried over an appropriate amount of anhydrous sodium sulfate, the solvent was removed by concentration under reduced pressure, and the title compound (32 mg) was obtained by purification 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%-50%, 11 min).

[1232] MS m / z (ESI): 403.0 [M+H] + .

[1233] 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).

[1234] Compound 80 (46.5 mg) was prepared by supercritical fluid chromatography separation (column: DAICEL CHIRALPAK AD-H (250 mm*30 mm, 5 um); mobile phase: A: carbon dioxide; B: ethanol (0.1% ammonia water); B%: 45%; flow rate: 70 ml / min), to obtain compound 80-P1 (6.4 mg, RT: 1.499 min) and compound 80-P2 (9.1 mg, RT: 1.893 min).

[1235] Compound 80-P1:

[1236] 1H NMR (400 MHz, METHANOL-d4) d = 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).

[1237] MS m / z (ESI): 403.1 [M+H] + .

[1238] Compound 80-P2:

[1239] 1 H NMR (400 MHz, METHANOL-d4) d = 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).

[1240] MS m / z (ESI): 403.0 [M+H] + .

[1241] Example 81, 5-(2-cyclopropylpyridin-3-yl)-7-(trifluoromethyl)oxazolo[4,5- c] [ 1,8] naphthyridin-4(5H)-one (Compound 81 )

[1242]

[1243] Step 1: Synthesis of 2-((2-cyclopropylpyridin-3-yl)amino)-6- (trifluoromethyl)pyridine-3-carbox...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: （I） in, L is selected from chemical bonds or O; R 1 selected from halogen or optionally substituted with R 1a C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclyl; X1 is selected from N or CH; X2 is CH; Ring A is selected from a 5-6 membered heteroaryl group, which is optionally substituted with R 2 substituents; X and Y are ring atoms of ring A. X and Y are each independently selected from C atoms or N atoms. When at least one of X and Y is selected from N atoms, X and Y are connected by a single bond. When both X and Y are selected from C atoms, X and Y are connected by a single bond or a double bond. R 2 selected from halogen, =0, OH, CN or optionally substituted with R 2a NH2, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclyl, C1-C 10 alkoxy, C3-C 10 cycloalkyloxy, 3-10 membered heterocyclyloxy; Ring Q is selected from C6-C 10 Aryl or 5-10 heteroaryl, the C6-C 10 Aryl or 5-10 heteroaryl groups are selectively coated with R. 3 replace; R 3 selected from halogen, =0, OH, CN, NO2or optionally R 3a substituted SH, NH2, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclyl, C1-C 10 alkoxy, C3-C 10 cycloalkyloxy, 3-10 membered heterocyclyloxy; Each R 1a R 2a R 3a Independently selected from deuterium, F, Cl, Br, I, OH, CN, =O, or arbitrarily selected by R b The following groups may be substituted: NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic, 5-6 membered heteroaryl, C1-C6 alkoxy, C3-C6 cycloalkyloxy, 4-7 membered heterocyclic oxy; and Each R b Independently selected from F, Cl, Br, I, OH, CN, =O, NH2, SH, C1-C6 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic groups; and The premise is that the compounds shown in formula (I) do not include the following compounds: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 2. The compound of formula (I) according to claim 1, wherein R 1 is selected from halogen or the following group optionally substituted by R 1a C1-C3 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl; and / or each R 1a is independently selected from F, Cl, Br, I, OH, CN, =0 or the following group optionally substituted by R b NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, C1-C6 alkoxy; or a pharmaceutically acceptable salt thereof.

3. The compound of formula (I) according to claim 2, wherein R 1 is selected from halogen or optionally R 1a substituted C1-C3 alkyl, 4-7 membered heterocyclyl; and / or each R 1a is independently selected from F, CI, Br and I.

4. The compound of formula (I) according to claim 3, wherein R 1 is selected from halogen or the following groups optionally substituted with R 1a methyl, ethyl, oxetanyl; and / or each R 1a is independently selected from F, CI, Br and I; or a pharmaceutically acceptable salt thereof.

5. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Cl, CH3, CF3, OCH2CH3 or .

6. The compound of formula (I) according to claim 5, or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Cl, CH3, CF3, and OCH2CH3.

7. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Cl, CH3, CF3, OCH2CH3 or .

8. The compound of formula (I) according to claim 7, or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Cl, CH3, CF3, and OCH2CH3.

9. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, 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.

10. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, 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.

11. The compound of formula (I) according to claim 5, or a pharmaceutically acceptable salt thereof, 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.

12. The compound of formula (I) according to claim 7, or a pharmaceutically acceptable salt thereof, 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.

13. The compound of Formula (I) according to any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from 5-6 membered heteroaryl, said 5-6 membered heteroaryl containing at least one heteroatom or heteroatom group selected from N, O, S, S(O)2 among its ring atoms, said 5-6 membered heteroaryl being optionally substituted with R 2 substituents.

14. The compound of formula (I) according to claim 13, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from optionally R 2 The following groups are substituted: pyrrole, pyrazol, imidazole, oxazol, isoxazol, and triazolyl.

15. The compound of formula (I) according to claim 14, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from optionally R 2 The following groups are substituted: , , , or .

16. The compound of formula (I) according to any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from OH, =O, or optionally R 2a The following groups are substituted: NH2, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, wherein R 2a It is selected from deuterium, F, Cl, Br, I, C1-C3 alkyl, NH2 optionally substituted with C1-C3 alkyl, or 5-6 heteroaryl optionally substituted with C1-C3 alkyl.

17. The compound of formula (I) according to any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from OH, =O, methyl, ethyl, CD3, CH2CH2N(CH3)2, CH2CH2OH, CH2CH2NH(CH3), CH2CH2NH2, OCH3, NHCH3, CHF2, CF3, cyclopropyl or .

18. The compound of formula (I) according to claim 13, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from OH, =O, or optionally R 2a The following groups are substituted: NH2, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, wherein R 2a It is selected from deuterium, F, Cl, Br, I, C1-C3 alkyl, NH2 optionally substituted with C1-C3 alkyl, or 5-6 heteroaryl optionally substituted with C1-C3 alkyl.

19. The compound of formula (I) according to claim 13, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from OH, =O, methyl, ethyl, CD3, CH2CH2N(CH3)2, CH2CH2OH, CH2CH2NH(CH3), CH2CH2NH2, OCH3, NHCH3, CHF2, CF3, cyclopropyl or .

20. The compound of formula (I) according to any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

21. The compound of formula (I) according to any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein ring Q is selected from phenyl, pyridyl, pyrazolyl, pyrimidinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrazolyl, pyrimidinyl, or pyrazinyl group is optionally replaced by R. 3 replace.

22. The compound of formula (I) according to claim 13, or a pharmaceutically acceptable salt thereof, wherein ring Q is selected from phenyl, pyridyl, pyrazolyl, pyrimidinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrazolyl, pyrimidinyl, or pyrazinyl group is optionally replaced by R. 3 replace.

23. The compound of formula (I) according to claim 16, or a pharmaceutically acceptable salt thereof, wherein ring Q is selected from phenyl, pyridyl, pyrazolyl, pyrimidinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrazolyl, pyrimidinyl, or pyrazinyl group is optionally replaced by R. 3 replace.

24. The compound of formula (I) according to claim 18, or a pharmaceutically acceptable salt thereof, wherein ring Q is selected from phenyl, pyridyl, pyrazolyl, pyrimidinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrazolyl, pyrimidinyl, or pyrazinyl group is optionally replaced by R. 3 replace.

25. The compound of formula (I) according to claim 20, or a pharmaceutically acceptable salt thereof, wherein ring Q is selected from phenyl, pyridyl, pyrazolyl, pyrimidinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrazolyl, pyrimidinyl, or pyrazinyl group is optionally replaced by R. 3 replace.

26. The compound of formula (I) according to any one of claims 1-12, 18 and 22-25, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from halogens, =O, OH, CN, or optionally R 3a The following groups are substituted: SH, C2-C3 ynyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyloxy; and R 3a Selected from halogens, CN, or C1-C3 alkyl groups.

27. The compound of formula (I) according to any one of claims 1-12, 18 and 22-25, or a pharmaceutically acceptable salt thereof, wherein R 3 It is selected from halogen, CN, C3-C6 cycloalkyl, C2-C3 alkynyl, C1-C6 alkyl optionally substituted with halogen, or C1-C6 alkoxy optionally substituted with halogen.

28. The compound of formula (I) according to any one of claims 1-12, 18 and 22-25, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from F, Cl, Br, CN, SH, isopropyl, cyclopropyl, methyl, ethyl, trifluoromethyl, ethynyl, OCHF2, methoxy or methylthio.

29. The compound of formula (I) according to claim 13, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from halogens, =O, OH, CN, or optionally R 3a The following groups are substituted: SH, C2-C3 ynyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyloxy; and R 3a Selected from halogens, CN, or C1-C3 alkyl groups.

30. The compound of formula (I) according to claim 13, or a pharmaceutically acceptable salt thereof, wherein R 3 It is selected from halogens, CN, C3-C6 cycloalkyl, C2-C3 alkynyl, C1-C6 alkyl optionally substituted with halogen, or C1-C6 alkoxy optionally substituted with halogen.

31. The compound of formula (I) according to claim 13, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from F, Cl, Br, CN, SH, isopropyl, cyclopropyl, methyl, ethyl, trifluoromethyl, ethynyl, OCHF2, methoxy or methylthio.

32. The compound of formula (I) according to claim 16, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from halogens, =O, OH, CN, or optionally R 3a The following groups are substituted: SH, C2-C3 ynyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyloxy; and R 3a Selected from halogens, CN, or C1-C3 alkyl groups.

33. The compound of formula (I) according to claim 16, or a pharmaceutically acceptable salt thereof, wherein R 3 It is selected from halogens, CN, C3-C6 cycloalkyl, C2-C3 alkynyl, C1-C6 alkyl optionally substituted with halogen, or C1-C6 alkoxy optionally substituted with halogen.

34. The compound of formula (I) according to claim 16, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from F, Cl, Br, CN, SH, isopropyl, cyclopropyl, methyl, ethyl, trifluoromethyl, ethynyl, OCHF2, methoxy or methylthio.

35. The compound of formula (I) according to claim 20, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from halogens, =O, OH, CN, or optionally R 3a The following groups are substituted: SH, C2-C3 ynyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyloxy; and R 3a Selected from halogens, CN, or C1-C3 alkyl groups.

36. The compound of formula (I) according to claim 20, or a pharmaceutically acceptable salt thereof, wherein R 3 It is selected from halogens, CN, C3-C6 cycloalkyl, C2-C3 alkynyl, C1-C6 alkyl optionally substituted with halogen, or C1-C6 alkoxy optionally substituted with halogen.

37. The compound of formula (I) according to claim 20, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from F, Cl, Br, CN, SH, isopropyl, cyclopropyl, methyl, ethyl, trifluoromethyl, ethynyl, OCHF2, methoxy or methylthio.

38. The compound of formula (I) according to claim 21, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from halogens, =O, OH, CN, or optionally R 3a The following groups are substituted: SH, C2-C3 ynyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyloxy; and R 3a Selected from halogens, CN, or C1-C3 alkyl groups.

39. The compound of formula (I) according to claim 21, or a pharmaceutically acceptable salt thereof, wherein R 3 It is selected from halogens, CN, C3-C6 cycloalkyl, C2-C3 alkynyl, C1-C6 alkyl optionally substituted with halogen, or C1-C6 alkoxy optionally substituted with halogen.

40. The compound of formula (I) according to claim 21, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from F, Cl, Br, CN, SH, isopropyl, cyclopropyl, methyl, ethyl, trifluoromethyl, ethynyl, OCHF2, methoxy or methylthio.

41. The compound of formula (I) according to any one of claims 1-12 and 18, or a pharmaceutically acceptable salt thereof, wherein ring Q is selected from phenyl, pyridyl, pyrazolyl, pyrimidinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrazolyl, pyrimidinyl, or pyrazinyl group is optionally replaced by R. 3 Replace; each R 3 It is independently selected from halogen, CN, C3-C6 cycloalkyl, C2-C3 alkynyl, C1-C6 alkyl optionally substituted with halogen, or C1-C6 alkoxy optionally substituted with halogen.

42. The compound of formula (I) according to any one of claims 1-12 and 18, or a pharmaceutically acceptable salt thereof, wherein ring Q is selected from phenyl, pyridyl, pyrazolyl, pyrimidinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrazolyl, pyrimidinyl, or pyrazinyl group is optionally replaced by R. 3 Replace; each R 3 It is independently selected from F, Cl, Br, CN, isopropyl, cyclopropyl, methyl, ethyl, trifluoromethyl, ethynyl, OCHF2 or methoxy.

43. The compound of formula (I) according to any one of claims 1-12 and 18, or a pharmaceutically acceptable salt thereof, wherein ring Q is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

44. The compound of formula (I) according to claim 13, or a pharmaceutically acceptable salt thereof, wherein ring Q is selected from phenyl, pyridyl, pyrazolyl, pyrimidinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrazolyl, pyrimidinyl, or pyrazinyl group is optionally replaced by R. 3 Replace; each R 3 It is independently selected from halogen, CN, C3-C6 cycloalkyl, C2-C3 alkynyl, C1-C6 alkyl optionally substituted with halogen, or C1-C6 alkoxy optionally substituted with halogen.

45. The compound of formula (I) according to claim 13, or a pharmaceutically acceptable salt thereof, wherein ring Q is selected from phenyl, pyridyl, pyrazolyl, pyrimidinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrazolyl, pyrimidinyl, or pyrazinyl group is optionally replaced by R. 3 Replace; each R 3 It is independently selected from F, Cl, Br, CN, isopropyl, cyclopropyl, methyl, ethyl, trifluoromethyl, ethynyl, OCHF2 or methoxy.

46. ​​The compound of formula (I) according to claim 13, or a pharmaceutically acceptable salt thereof, wherein ring Q is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

47. The compound of formula (I) according to claim 16, or a pharmaceutically acceptable salt thereof, wherein ring Q is selected from phenyl, pyridyl, pyrazolyl, pyrimidinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrazolyl, pyrimidinyl, or pyrazinyl group is optionally replaced by R. 3 Replace; each R 3 It is independently selected from halogen, CN, C3-C6 cycloalkyl, C2-C3 alkynyl, C1-C6 alkyl optionally substituted with halogen, or C1-C6 alkoxy optionally substituted with halogen.

48. The compound of formula (I) according to claim 16, or a pharmaceutically acceptable salt thereof, wherein ring Q is selected from phenyl, pyridyl, pyrazolyl, pyrimidinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrazolyl, pyrimidinyl, or pyrazinyl group is optionally replaced by R. 3 Replace; each R 3 It is independently selected from F, Cl, Br, CN, isopropyl, cyclopropyl, methyl, ethyl, trifluoromethyl, ethynyl, OCHF2 or methoxy.

49. The compound of formula (I) according to claim 16, or a pharmaceutically acceptable salt thereof, wherein ring Q is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

50. The compound of formula (I) according to claim 20, or a pharmaceutically acceptable salt thereof, wherein ring Q is selected from phenyl, pyridyl, pyrazolyl, pyrimidinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrazolyl, pyrimidinyl, or pyrazinyl group is optionally replaced by R. 3 Replace; each R 3 It is independently selected from halogen, CN, C3-C6 cycloalkyl, C2-C3 alkynyl, C1-C6 alkyl optionally substituted with halogen, or C1-C6 alkoxy optionally substituted with halogen.

51. The compound of formula (I) according to claim 20, or a pharmaceutically acceptable salt thereof, wherein ring Q is selected from phenyl, pyridyl, pyrazolyl, pyrimidinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrazolyl, pyrimidinyl, or pyrazinyl group is optionally replaced by R. 3 Replace; each R 3 It is independently selected from F, Cl, Br, CN, isopropyl, cyclopropyl, methyl, ethyl, trifluoromethyl, ethynyl, OCHF2 or methoxy.

52. The compound of formula (I) according to claim 20, or a pharmaceutically acceptable salt thereof, wherein ring Q is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

53. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is the compound of formula (Ia) or a pharmaceutically acceptable salt thereof: (Ia) in, Ring A, Ring Q, X1, X2, L, R 1 As defined in claim 1.

54. A compound selected from one of the following structures or a pharmaceutically acceptable salt thereof: or .

55. A pharmaceutical composition comprising the compound of any one of claims 1 to 54 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

56. Use of the compound of any one of claims 1 to 54 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 55, in the preparation of a medicament for the prevention or treatment of tumors with reduced or absent MTAP activity.

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