Quinolinone compound and naphthyridinone compound and application thereof

Abstract

The invention belongs to the technical field of biological medicine, and particularly relates to a quinolinone compound and a naphthyridinone compound as shown in a formula (I) and application thereof, and the quinolinone compound and the naphthyridinone compound can be used as molecular glue capable of selectively inducing PDE3A and SLFN12 compound formation and tumor cell apoptosis and can be used for cancer treatment. # imgabs0 #

Description

Quinolinone compounds and naphthyridinone compounds and uses thereof Technical Field

[0001] The present application relates to the field of biomedicine technology, and specifically to a molecular glue that can selectively induce the formation of a type 3A phosphodiesterase (PDE3A) and SLFN12 complex and apoptosis of tumor cells, a preparation method thereof, and its application in tumor treatment. Background Art

[0002] Phosphodiesterase (PDE) is a superfamily enzyme system that can mediate the hydrolysis of intracellular second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) (Chen J, Liu N, Huang YP, et al. Nature Comm 2021; 12: 6204), regulating the intracellular concentrations of cAMP and cGMP. Since the second messenger signaling pathways mediated by cAMP and cGMP are involved in regulating various cell functions, PDE can affect intracellular signal cascades, conduction and regulation of different physiological processes by regulating the activity of cAMP and cGMP, such as cell proliferation and apoptosis, inflammatory response, contraction of cardiomyocytes and smooth muscle cells, endothelial cell permeability, immune response, etc. (Fertig BA and Baillie GS. J Cardiovasc Dev Dis 2018; 5: 8; Nourian YH, Salimian J, Ahmadi A, et al. Biochem Biophys Rep 2023; 34: 101438). According to their hydrolysis specificity for cAMP or cGMP, PDE can be divided into 11 families, among which PDE4, 7, and 8 are cAMP-specific, PDE5, 6, and 9 are cGMP-specific, and PDE1, 2, 3, 10, and 11 can hydrolyze cAMP and cGMP at the same time (Ahmad F, Murata T, Simizu K, et al. Oral Dis 2015; 21: e25-e50; Barone I, Giordano C, Bonofiglio D, et al. Oncotarget 2017; 8: 99179-99202).

[0003] The PDE3 enzyme has two isoforms, PDE3A and PDE3B (Begum N, Shen WX, Manganiello V. Curr Opin Pharmacol 2011;11:725-9), located on chromosomes 11 and 12, respectively. PDE3A is primarily distributed in the heart, vascular smooth muscle, platelets, and oocytes, effectively regulating myocardial and smooth muscle contraction, platelet aggregation, and oocyte maturation. Although several PDE3 inhibitors have been used to treat cardiovascular diseases, studies have shown that long-term inhibition of PDE3A activity can cause toxic side effects such as palpitations and sudden death in cardiac patients, reduced platelet production, and impaired oocyte maturation (Ai YW, He HB, Chen PH, et al. Nature Comm 2020;11:3236). Furthermore, current PDE3A inhibitors primarily target the enzyme's catalytic region, the cAMP / cGMP binding site. Due to the high homology of the catalytic regions within the PDE family, PDE3A inhibitors vary in selectivity and exhibit significant toxic side effects. For example, the traditional inhibitor anagrelide can inhibit both PDE3A and PDE2, causing adverse reactions such as headache, palpitations, diarrhea, and vomiting (Birgegard G, Brorkholm M, Kutti J, et al. Haematologica 2004; 89:520-7). Milrinone can cause adverse symptoms such as arrhythmia, angina pectoris, and hypotension. Therefore, improving the safety of PDE3A inhibitors is a top priority in the development of PDE3A drugs.

[0004] Recent studies have shown that multiple chemically distinct compounds, such as anagrelide, DNMDP, and nailfine, can induce the formation of a PDE3A and SLFN12 complex through molecular glue. This complex stabilizes the intracellular SLFN12 protein level (under normal conditions, SLFN12 is degraded through the ubiquitination pathway, and the intracellular level is very low). The PDE3A-SLFN12 complex can bind to downstream ribosomal RNA (rRNA) (Li DR, Chen J, Ai YW, et al. Mol Cell 2019; 75: 1103-1116), blocking the binding of SRP (signal recognition particle) to the ribosome. Since the ribosome needs the assistance of SRP to transport to the endoplasmic reticulum membrane for further synthesis of membrane secretory proteins, the binding of PDE3A-SLFN12 to rRNA can lead to a decrease in the protein levels of the anti-apoptotic proteins Bcl-2 and Mcl-1, making them unable to inhibit the activity of Bax and Bak. Bax and Bak oligomerization further promotes increased mitochondrial membrane permeability, cytochrome release, and induction of tumor cell apoptosis (Li DR, Chen J, Ai YW, et al. Mol Cell 2019;75:1103-1116). It was also found that nauclefine does not inhibit the hydrolysis of cAMP by PDE3A (Ai YW, He HB, Chen PH, et al. Nature Comm 2020;11:3236). It mainly induces tumor cell apoptosis through the PDE3A-SLFN12 complex, thus avoiding the risk of toxic side effects caused by PDE3A enzyme inhibition.

[0005] Based on the PDE3A-SLFN12-dependent apoptosis mechanism, this application aims to develop molecular glue compounds that can efficiently mediate the interaction between PDE3A and SLFN12, thereby promoting tumor cell apoptosis. While having high pharmacological and pharmacodynamic activity, the molecular glue of this application is expected to reduce the risks associated with inhibiting PDE enzyme activity and has high therapeutic potential in tumors expressing PDE3A and SLFN12.

[0006] Summary of the Invention

[0007] To solve the above technical problems, on the one hand, the present application provides a compound represented by the following formula (I), a pharmaceutically acceptable salt thereof, a deuterated substance thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof:

[0008] in,

[0009] Z is selected from CR1 or N;

[0010] W is selected from C=O, CR2R7, NR3 or O;

[0011] R1 is selected from H, halogen, hydroxy, cyano, alkynyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C6 cycloalkyl;

[0012] R2 and R7 are each independently selected from H, a deuterium atom, a C1-C3 alkyl group or a C1-C3 haloalkyl group; or, R2 and R7 together with the connected carbon atom form a C3-C6 cycloalkyl group;

[0013] R3 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl;

[0014] n is selected from any integer between 0 and 6, such as 0, 1, 2, 3, 4, 5, 6;

[0015] R a Each independently selected from H, halogen, cyano, alkynyl, optionally substituted C1-C6 alkoxy, C1-C6 haloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C9 cycloalkyl, optionally substituted C4-C9 cycloalkenyl or optionally substituted 3-10 membered heterocyclyl; the optional substitution means that the mentioned group is unsubstituted or replaced by one or more independently selected from deuterium, halogen, cyano, amino, C1-C6 alkyl (including deuterated C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, hydroxyl, C1-C6 alkoxy (including deuterated C1-C6 alkoxy), C1-C6 haloalkoxy, C6-C 10 substituted by aryl, 5-10 membered heteroaryl, or C1-C6 hydroxyalkyl;

[0016] Ring A is selected from C6-C 10 Aryl, 5-10 membered heteroaryl, C4-C 10 carbocyclic group or 4-10 membered heterocyclic group.

[0017] In some embodiments, R a Each independently selected from H, halogen, cyano, alkynyl, optionally substituted C1-C6 alkoxy, C1-C6 haloalkyl, optionally substituted C6-C 10aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C9 cycloalkyl, optionally substituted C4-C9 cycloalkenyl or optionally substituted 3-10 membered heterocyclyl; the optional substitution means that the mentioned group is unsubstituted or replaced by one or more independently selected from deuterium, halogen, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, hydroxyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, C6-C 10 The alkyl group may be substituted by a substituent selected from the group consisting of aryl, 5-10 membered heteroaryl, and C1-C6 hydroxyalkyl.

[0018] The present application provides a compound represented by the following formula (I), a pharmaceutically acceptable salt thereof, a deuterated substance thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof:

[0019] in,

[0020] Z is selected from CR1 or N;

[0021] W is selected from C=O, CR2R7, NR3 or O;

[0022] R1 is selected from H, halogen, hydroxy, cyano, alkynyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C6 cycloalkyl;

[0023] R2 and R7 are each independently selected from H, a deuterium atom, a C1-C3 alkyl group or a C1-C3 haloalkyl group; or, R2 and R7 together with the connected carbon atom form a C3-C6 cycloalkyl group;

[0024] R3 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl;

[0025] n is selected from any integer between 0 and 6, such as 0, 1, 2, 3, 4, 5, 6;

[0026] R a Each independently selected from H, halogen, cyano, alkynyl, optionally substituted C1-C6 alkoxy, C1-C6 haloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C9 cycloalkyl, optionally substituted C4-C9 cycloalkenyl, or optionally substituted 3-10 membered heterocyclyl;

[0027] Ring A is selected from C6-C 10 Aryl, 5-10 membered heteroaryl, C4-C 10 carbocyclic group or 4-10 membered heterocyclic group.

[0028] In some preferred embodiments, Z is selected from CH; W is selected from C═O, CH 2 , NR 3 or O; and R 3 is selected from H or CH 3 .

[0029] In some preferred embodiments, Z is selected from N; W is selected from C=O, CH2 or NH.

[0030] In some more preferred embodiments, Z is selected from CH; W is selected from NH.

[0031] In some embodiments, Z is selected from CR1 or N, and R1 is selected from H, halogen, hydroxyl, or C1-C3 alkyl. In some embodiments, Z is selected from CH or N.

[0032] In some embodiments, W is selected from C=O, CR2R7, NR3 or O, R2 and R7 are each independently selected from H, a deuterium atom or C1-C3 alkyl, and R3 is selected from H, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments, W is selected from C=O, CH2, NR3 or O, and R3 is selected from H or C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl or C1-C2 alkyl). In some embodiments, W is selected from CH2 or NH.

[0033] In some preferred embodiments, R a Each independently selected from H, halogen, cyano, optionally substituted C1-C3 alkoxy, C1-C3 haloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C3-C6 cycloalkyl or optionally substituted 3- to 10-membered heterocyclyl.

[0034] In some more preferred embodiments, the R a Each is independently selected from H, F, Cl, Br, CN, OCH3, OCD3, OCHF2, OCF3, CF3, CHF2, CH2F, an optionally substituted phenyl ring or an optionally substituted 5-6 membered heteroaryl; the optionally substituted phenyl ring and the optionally substituted 5-6 membered heteroaryl refer to being unsubstituted or optionally substituted by one or more substituents selected from F, Cl, Br, CN, CHF2, CF3, CH2F, CH3, CD3, OCH3, OCHF2, OCF3, OCD3 or NH2.

[0035] In some embodiments, n is selected from any integer between 1-5 (eg, 1, 2, 3, 4, 5), R a Each independently selected from halogen, optionally substituted C1-C6 alkoxy, C1-C6 haloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C3-C6 cycloalkyl or optionally substituted 3- to 10-membered heterocyclyl.

[0036] In some embodiments, n is 1, R a Each independently selected from optionally substituted C6-C 10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl or optionally substituted 3-10 membered heterocyclyl; or, n is any integer between 2 and 5 (e.g., 2, 3, 4, 5), R a Each independently selected from halogen, optionally substituted C1-C6 alkoxy, C1-C6 haloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl or optionally substituted 3-10 membered heterocyclyl. Preferably, n is 1, R a Each independently selected from optionally substituted C6-C 10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C6 cycloalkyl or optionally substituted 6-10 membered heterocyclyl; or, n is any integer between 2 and 5 (e.g., 2, 3, 4, 5), R a Each independently selected from halogen, optionally substituted C1-C6 alkoxy, C1-C6 haloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl or optionally substituted 3-10 membered heterocyclyl, and R a are not halogen at the same time. Or preferably, n is 1, R a Each independently selected from optionally substituted C6-C 10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C6 cycloalkyl or optionally substituted 6-10 membered heterocyclyl; or, n is any integer between 2 and 5 (e.g., 2, 3, 4, 5), wherein one R a Selected from optionally substituted C6-C 10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl or optionally substituted 3-10 membered heterocyclyl, the rest of R a selected from halogen, optionally substituted C1-C6 alkoxy, C1-C6 haloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C3-C6 cycloalkyl or optionally substituted 3- to 10-membered heterocyclyl.

[0037] In some embodiments, n is selected from any integer between 1 and 3 (eg, 1, 2, 3), and R a Each independently selected from halogen, optionally substituted C1-C6 alkoxy, C1-C6 haloalkyl, optionally substituted C6-C 10In some embodiments, n is 1, R a Each independently selected from optionally substituted C6-C 10 aryl, optionally substituted 5-10 membered heteroaryl or optionally substituted 6-10 membered heterocyclyl; or, n is 2 or 3, R a Each independently selected from halogen, optionally substituted C1-C6 alkoxy, C1-C6 haloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5-10 membered heteroaryl or optionally substituted 3-10 membered heterocyclyl, and R a are not halogen at the same time. Or preferably, n is 1, R a Each independently selected from optionally substituted C6-C 10 aryl, optionally substituted 5-10 membered heteroaryl or optionally substituted 6-10 membered heterocyclyl; or, n is 2 or 3, one of R a Selected from optionally substituted C6-C 10 aryl, optionally substituted 5-10 membered heteroaryl or optionally substituted 3-10 membered heterocyclic group, the rest of R a selected from halogen, optionally substituted C1-C6 alkoxy, C1-C6 haloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 3- to 10-membered heterocyclyl.

[0038] In some embodiments, n is selected from any integer between 1 and 3 (eg, 1, 2, 3), and R a Each independently selected from halogen, optionally substituted C1-C6 alkoxy, C1-C6 haloalkyl, optionally substituted C6-C 10 In some embodiments, n is 1, R a Each independently selected from optionally substituted C6-C 10 aryl, optionally substituted 5-8 membered heteroaryl or optionally substituted 6-9 membered heterocyclyl; or, n is 2 or 3, R a Each independently selected from halogen, optionally substituted C1-C6 alkoxy, C1-C6 haloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5-8 membered heteroaryl or optionally substituted 4-9 membered heterocyclyl, and R a are not halogen at the same time. Or preferably, n is 1, R a Each independently selected from optionally substituted C6-C 10 aryl, optionally substituted 5-8 membered heteroaryl or optionally substituted 6-9 membered heterocyclyl; or, n is 2 or 3, one of R aSelected from optionally substituted C6-C 10 aryl, optionally substituted 5-8 membered heteroaryl or optionally substituted 4-9 membered heterocyclic group, the rest of R a selected from halogen, optionally substituted C1-C6 alkoxy, C1-C6 haloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 8-membered heteroaryl, or optionally substituted 4- to 9-membered heterocyclyl.

[0039] In some embodiments, n is 1 or 2, R a Each is independently selected from halogen, optionally substituted C1-C6 alkoxy, C1-C6 haloalkyl, optionally substituted C6 aryl, optionally substituted 5-6 membered heteroaryl or optionally substituted 6-8 membered heterocyclyl. Preferably, when n is 2, at least one R a Not a halogen, or two R a different.

[0040] In some embodiments, the optionally substituted C1-C6 alkoxy, aryl, heteroaryl or heterocyclyl is unsubstituted or replaced by one or more independently selected from deuterium, halogen, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, hydroxyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, C6-C 10 In some embodiments, the optionally substituted C1-C6 alkoxy, aryl, heteroaryl or heterocyclyl is unsubstituted or replaced by one or more independently selected from halogen, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, hydroxyl, C6-C 10 The alkyl group may be substituted by a substituent selected from the group consisting of aryl, 5-10 membered heteroaryl, and C1-C6 hydroxyalkyl.

[0041] In some embodiments, the optionally substituted C1-C6 alkoxy is unsubstituted or substituted with halogen (e.g., F, Cl, Br), and the optionally substituted aryl, heteroaryl or heterocyclyl is unsubstituted or substituted with one or more (e.g., 1-3, 1-2) substituents independently selected from halogen, cyano, amino, C1-C6 alkyl (including deuterated alkyl, such as deuterated methyl), C1-C6 haloalkyl, C1-C6 alkoxy (including deuterated alkoxy, such as deuterated methoxy), C1-C6 haloalkoxy, and C1-C6 alkylamino. In some embodiments, the optionally substituted C1-C6 alkoxy is unsubstituted or substituted with halogen (e.g., F, Cl, Br), and the optionally substituted aryl, heteroaryl or heterocyclyl is unsubstituted or substituted with one or more (e.g., 1-3, 1-2) substituents independently selected from halogen, cyano, amino, C1-C6 alkyl (including deuterated alkyl, such as deuterated methyl), C1-C6 haloalkyl, C1-C6 alkoxy (including deuterated alkoxy, such as deuterated methoxy), and C1-C6 haloalkoxy.

[0042] In some embodiments, n is 1 or 2, R a Each is independently selected from F, Cl, Br, optionally substituted C1-C5 alkoxy, C1-C5 haloalkyl, optionally substituted C6 aryl, optionally substituted 5-6 membered heteroaryl or optionally substituted 6-8 membered heterocyclyl, the optionally substituted C1-C6 alkoxy is unsubstituted or substituted by F, Cl, Br, the optionally substituted aryl, heteroaryl or heterocyclyl is unsubstituted or substituted by one or more (e.g., 1-3, 1-2) substituents independently selected from F, Cl, Br, cyano, amino, C1-C6 alkyl (including deuterated alkyl, such as deuterated methyl), C1-C6 haloalkyl, C1-C6 alkoxy (including deuterated alkoxy, such as deuterated methoxy), C1-C6 haloalkoxy, C1-C6 alkylamino. In some embodiments, n is 1 or 2, R a Each is independently selected from F, Cl, Br, optionally substituted C1-C5 alkoxy, C1-C5 haloalkyl, optionally substituted C6 aryl, optionally substituted 5-6 membered heteroaryl or optionally substituted 6-8 membered heterocyclyl, the optionally substituted C1-C6 alkoxy is unsubstituted or substituted by F, Cl, or Br, and the optionally substituted aryl, heteroaryl or heterocyclyl is unsubstituted or substituted by one or more (e.g., 1-3, 1-2) substituents independently selected from F, Cl, Br, cyano, amino, C1-C6 alkyl (including deuterated alkyl, such as deuterated methyl), C1-C6 haloalkyl, C1-C6 alkoxy (including deuterated alkoxy, such as deuterated methoxy) or C1-C6 haloalkoxy.

[0043] In some embodiments, n is 1 or 2, Ra selected from F, Cl, Br, optionally substituted C6 aryl, optionally substituted 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S (e.g., N atom), the optionally substituted aryl or heteroaryl is unsubstituted or substituted by one or more (e.g., 1-3, 1-2) substituents independently selected from F, Cl, Br, cyano, amino, C1-C6 alkyl (including deuterated alkyl, such as deuterated methyl), C1-C6 haloalkyl, C1-C6 alkoxy (including deuterated alkoxy, such as deuterated methoxy).

[0044] In some embodiments, n is 2, R a is F, Cl, Br, or an optionally substituted C6 aryl group, wherein the optionally substituted aryl group is unsubstituted or substituted by one or more (e.g., 1-3, 1-2, or 1) C1-C6 alkyl groups (including deuterated alkyl groups, such as deuterated methyl groups).

[0045] In some preferred embodiments, ring A is selected from a benzene ring, a naphthalene ring, a C4-C6 carbocyclic group, and a 5-6 membered heterocyclic group.

[0046] In some more preferred embodiments, the ring A is selected from wherein k is selected from 1 or 2.

[0047] In some more preferred embodiments, the ring A is selected from wherein k is selected from 1 or 2.

[0048] In some more preferred embodiments, the ring A is selected from

[0049] In some embodiments, Ring A is selected from C6-C 10 aryl, 6-10 membered heteroaryl, C5-C8 carbocyclyl or 5-8 membered heterocyclyl.

[0050] In some embodiments, ring A is selected from C6 aryl, 6-8 membered heteroaryl containing 1-3 (e.g., 1-2) heteroatoms selected from N, O, or S, C5-C7 carbocyclyl, or 5-7 membered heterocyclyl containing 1-3 (e.g., 1-2) heteroatoms selected from N, O, or S.

[0051] In some embodiments, Ring A is selected from C6 aryl, a 6-membered heterocyclyl containing 1-2 heteroatoms selected from N, O, or S (e.g., containing 1 N atom), or a 6-membered heterocyclyl containing 1-2 heteroatoms selected from N, O, or S (e.g., containing 1 N atom). In some embodiments, Ring A is C6 aryl.

[0052] In some embodiments, in the compound of formula (I), its pharmaceutically acceptable salt, its deuterated substance, its stereoisomer, its tautomer or its mixture,

[0053] Z is selected from CR1 or N, R1 is selected from H, halogen, hydroxy or C1-C3 alkyl;

[0054] W is selected from C=O, CR2R7, NR3 or O, R2 and R7 are each independently selected from H, a deuterium atom or a C1-C3 alkyl group, and R3 is selected from H, a C1-C6 alkyl group or a C1-C6 haloalkyl group;

[0055] n is selected from any integer between 1 and 5 (e.g., 1, 2, 3, 4, 5), R a Each independently selected from halogen, optionally substituted C1-C6 alkoxy, C1-C6 haloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl or optionally substituted 3-10 membered heterocyclyl, the optionally substituted C1-C6 alkoxy, aryl, heteroaryl or heterocyclyl being unsubstituted or substituted by one or more independently selected from deuterium, halogen, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, hydroxyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, C6-C 10 aryl, 5-10 membered heteroaryl, C1-C6 hydroxyalkyl; preferably, n is selected from any integer between 1-3 (e.g., 1, 2, 3), R a Each independently selected from halogen, optionally substituted C1-C6 alkoxy, C1-C6 haloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5-10 membered heteroaryl or optionally substituted 3-10 membered heterocyclyl, the optionally substituted C1-C6 alkoxy is unsubstituted or substituted by halogen (e.g., F, Cl, Br), the optionally substituted aryl, heteroaryl or heterocyclyl is unsubstituted or substituted by one or more (e.g., 1-3, 1-2) substituents independently selected from halogen, cyano, amino, C1-C6 alkyl (including deuterated alkyl, such as deuterated methyl), C1-C6 haloalkyl, C1-C6 alkoxy (including deuterated alkoxy, such as deuterated methoxy), C1-C6 haloalkoxy, C1-C6 alkylamino; preferably, n is 1, R a Selected from optionally substituted C6-C 10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl or optionally substituted 6-10 membered heterocyclyl, or n is any integer between 2 and 5, wherein one R a Selected from optionally substituted C6-C 10aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl or optionally substituted 3-10 membered heterocyclyl;

[0056] Ring A is selected from C6-C 10 aryl, 6-10 membered heteroaryl, C5-C8 carbocyclyl or 5-8 membered heterocyclyl.

[0057] In some embodiments, in the compound of formula (I), its pharmaceutically acceptable salt, its deuterated substance, its stereoisomer, its tautomer or its mixture,

[0058] Z is selected from CH or N;

[0059] W is selected from C=O, CH2, NR3 or O, R3 is selected from H or C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl or C1-C2 alkyl);

[0060] n is 1 or 2, R a R is each independently selected from F, Cl, Br, optionally substituted C1-C5 alkoxy, C1-C5 haloalkyl, optionally substituted C6 aryl, optionally substituted 5-6 membered heteroaryl or optionally substituted 6-8 membered heterocyclyl, the optionally substituted C1-C6 alkoxy is unsubstituted or substituted by F, Cl, or Br, the optionally substituted aryl, heteroaryl or heterocyclyl is unsubstituted or substituted by one or more (e.g., 1-3, 1-2) substituents independently selected from F, Cl, Br, cyano, amino, C1-C6 alkyl (including deuterated alkyl, such as deuterated methyl), C1-C6 haloalkyl, C1-C6 alkoxy (including deuterated alkoxy, such as deuterated methoxy), C1-C6 haloalkoxy, and C1-C6 alkylamino; preferably, when n is 2, at least one R a Not halogen;

[0061] Ring A is selected from C6 aryl, a 6-8 membered heteroaryl containing 1-3 (e.g. 1-2) heteroatoms selected from N, O or S, a C5-C7 carbocyclyl, or a 5-7 membered heterocyclyl containing 1-3 (e.g. 1-2) heteroatoms selected from N, O or S; preferably, ring A is selected from C6 aryl, a 6-membered heteroaryl containing 1-3 (e.g. 1-2) heteroatoms selected from N, O or S, a C6 carbocyclyl, or a 6-membered heterocyclyl containing 1-3 (e.g. 1-2) heteroatoms selected from N, O or S.

[0062] In some embodiments, for the compound of formula (I), its pharmaceutically acceptable salt, its deuterated substance, its stereoisomer, its tautomer or a mixture thereof, the compound of formula (I) has a structure represented by formula (II) or formula (II') or formula (II"):

[0063] in,

[0064] p is selected from 0, 1, 2, 3 or 4;

[0065] R1 is selected from H, halogen, hydroxy, cyano, alkynyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C6 cycloalkyl;

[0066] R3 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl;

[0067] R4 and R5 are each independently selected from H, halogen, cyano, alkynyl, optionally substituted C1-C3 alkoxy, C1-C3 haloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl, optionally substituted C4-C6 cycloalkenyl or optionally substituted 3-10 membered heterocyclyl; the optional substitution means that the mentioned group is unsubstituted or replaced by one or more independently selected from deuterium, halogen, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, hydroxyl, C1-C6 alkoxy, C1-C6 haloalkoxy, 6-10 membered aryl (i.e., C6-C6 10 aryl), 5-10 membered heteroaryl, C1-C6 hydroxyalkyl;

[0068] represents a single bond or a double bond (preferably a single bond).

[0069] In some alternative embodiments, in the above-mentioned compounds of formula (II) or formula (II') or formula (II"), when p is not 0, one R4 and one R5 and the atoms to which they are attached are connected together to form an optionally substituted 4-12 membered heterocyclic group, an optionally substituted C3-C 12 Cycloalkyl or optionally substituted 5-12 membered heteroaryl, for example optionally substituted furanyl, optionally substituted tetrahydrofuranyl, optionally substituted azetidinyl, optionally substituted pyrrolyl, optionally substituted pyrrolidinyl, optionally substituted pyrazolyl.

[0070] In some preferred embodiments, in the compounds of the general formula (II), (II') or (II"), p is selected from 0, 1, 2 or 3; each R4 is independently selected from H, halogen, cyano, C1-C3 haloalkyl or optionally substituted C1-C3 alkoxy; R5 is selected from optionally substituted C6-C 10Aryl, optionally substituted 5-10 membered heteroaryl, cyano, optionally substituted C3-C6 cycloalkyl, optionally substituted 3-10 membered heterocyclyl; the optional substitution means that the mentioned group is unsubstituted or substituted by one or more substituents independently selected from deuterium, halogen, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, hydroxy, C1-C6 alkoxy, C1-C6 haloalkoxy, 6-10 membered aryl, 5-10 membered heteroaryl, C1-C6 hydroxyalkyl.

[0071] In some more preferred embodiments, in the compounds of the above general formula (II) or (II′) or (II″), p is selected from 0, 1, 2 or 3;

[0072] Each R4 is independently selected from H, halogen, cyano, C1-C3 haloalkyl or optionally substituted C1-C3 alkoxy; preferably, the optionally substituted C1-C3 alkoxy is selected from methoxy, ethoxy, -OCH2F, -OCHF2, -OCF3 or -OCH2CF3;

[0073] R5 is selected from optionally substituted C6-C 10 Aryl, optionally substituted 5-10 membered heteroaryl, cyano, optionally substituted C3-C6 cycloalkyl, optionally substituted 3-10 membered heterocyclyl; the optional substitution means that the mentioned group is unsubstituted or substituted by one or more substituents independently selected from deuterium, halogen, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, hydroxy, C1-C6 alkoxy, C1-C6 haloalkoxy, 6-10 membered aryl, 5-10 membered heteroaryl, C1-C6 hydroxyalkyl.

[0074] In some more preferred embodiments, in the compounds of the general formula (II) or (II') or (II") above, R5 is selected from an optionally substituted phenyl ring or an optionally substituted 5-6 membered heteroaryl; the optionally substituted phenyl ring and the optionally substituted 5-6 membered heteroaryl are unsubstituted or optionally substituted with one or more substituents selected from F, Cl, Br, CN, CHF2, CF3, CH2F, CH3, CD3, OCH3, OCHF2, OCF3, OCD3 or NH2.

[0075] In some preferred embodiments, in the above-mentioned compounds of formula (II), (II') or (II"), R5 is not

[0076] In some preferred embodiments, in the above compounds of formula (II) or (II') or (II"), R5 is preferably selected from cyano, wherein m is selected from 0, 1, 2 or 3; R6 is independently selected from H, C1-C3 alkyl, C1-C3 haloalkyl, halogen or cyano, amino or optionally substituted C1-C3 alkoxy; the optionally substituted C1-C3 alkoxy is selected from -OCH3, -OCD3, -OCHD2, -OCH2D, ethoxy, -OCH2F, -OCHF2, -OCF3 or -OCH2CF3; more preferably, R5 is preferably selected from

[0077] In some preferred embodiments, in the above-mentioned compounds of formula (II), (II') or (II"), when R5 is selected from When R4 is not H.

[0078] In some embodiments, the present application further provides a compound represented by the following formula (III), a pharmaceutically acceptable salt thereof, a deuterated substance thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof:

[0079] wherein q is selected from 0 or 1; X1, X2, and X3 are each independently selected from C or N; Z, W, n, R a As defined in any of the above.

[0080] Any of the above implementation plans can be optionally combined to form a new technical solution.

[0081] In some embodiments, the present application further provides a compound represented by the following formula (IV), a pharmaceutically acceptable salt thereof, a deuterated substance thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof:

[0082] Wherein, X is selected from C or N, Z, W, R a As defined above, Represents a single bond or a double bond, connected to R a The --- indicates that the key may or may not exist.

[0083] In some preferred embodiments, X is selected from C, CH or N (eg, X is C or CH);

[0084] R a are each independently selected from halogen (such as F, Cl, Br), substituted or unsubstituted C1-C6 alkoxy, C1-C6 haloalkyl, substituted or unsubstituted C6-C 10aryl (e.g., substituted or unsubstituted C6 aryl), substituted or unsubstituted 5-8 membered heteroaryl (e.g., substituted or unsubstituted 5-6 membered heteroaryl), substituted or unsubstituted 5-10 membered heterocyclyl (e.g., substituted or unsubstituted 6-8 membered heterocyclyl), the C1-C6 alkoxy may be substituted by halogen (e.g., F, Cl, Br), the aryl, heteroaryl or heterocyclyl may be substituted by one or more (e.g., 1-3, 1-2) independently selected from deuterium, halogen, (e.g., F, Cl or Br), cyano, amino, C1-C6 alkyl (including deuterated alkyl, such as deuterated methyl), C1-C6 haloalkyl, C1-C6 alkoxy (including deuterated alkoxy, such as deuterated methoxy), C1-C6 haloalkoxy, C1-C6 alkylamino substituents, and the heteroaryl or the heterocyclic group contains 1-3 (e.g., 1-2, or 1) heteroatoms selected from N, O or S; preferably, R a is selected from F, Cl, Br, substituted or unsubstituted C1-C3 alkoxy, C1-C3 haloalkyl, substituted or unsubstituted C6 aryl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 6-8 membered heterocyclyl, the C1-C6 alkoxy may be substituted by F, Cl, Br, the aryl, heteroaryl or heterocyclyl may be substituted by 1-3 (e.g. 1-2) independently selected from F, Cl, Br, cyano, amino, C1-C6 alkyl (including deuterated alkyl, such as deuterated methyl), C1-C6 haloalkyl (such as C1 -C6 fluoroalkyl, C1-C6 chloroalkyl, C1-C6 bromoalkyl), C1-C6 alkoxy (including deuterated alkoxy, such as deuterated methoxy), C1-C6 haloalkoxy (such as C1-C6 fluoroalkoxy, C1-C6 chloroalkoxy, C1-C6 bromoalkoxy), C1-C6 alkylamino substituents, and the heteroaryl or the heterocyclic group contains 1-3 (such as 1-2) heteroatoms selected from N, O or S (for example, contains 1-2 heteroatoms selected from N or O; or preferably, R a is selected from substituted or unsubstituted C6 aryl, substituted or unsubstituted 5-6 membered heteroaryl, the aryl or heteroaryl may be substituted by 1-3 (e.g. 1-2) substituents independently selected from F, Cl, Br, C1-C6 alkyl (including deuterated alkyl, such as deuterated methyl), C1-C6 haloalkyl (e.g. C1-C6 fluoroalkyl, C1-C6 chloroalkyl, C1-C6 bromoalkyl), and the heteroaryl or heterocyclic group contains 1-3 (e.g. 1-2) heteroatoms selected from N, O or S (e.g. 1-2 heteroatoms selected from N or O); preferably, when there are two or more R a When at least one of the R a Not halogen;

[0085] Z is selected from CH or N, W is selected from C═O, CH 2 , NR 3 or O, and R 3 is selected from H or C 1 -C 6 alkyl (e.g., C 1 -C 5 alkyl, C 1 -C 4 alkyl, C 1 -C 3 alkyl or C 1 -C 2 alkyl); for example, Z is CH and W is NH;

[0086] Represents a single bond or a double bond; connects R a The --- indicates that the bond may be present or absent (preferably absent).

[0087] In some preferred embodiments, the present application further provides a compound represented by the following formula (IV-1), a pharmaceutically acceptable salt thereof, a deuterated substance thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof:

[0088] Among them, X, Z, W, R a 、 and --- as defined above.

[0089] In some preferred embodiments, the present application further provides a compound represented by the following formula (IV-2), a pharmaceutically acceptable salt thereof, a deuterated substance thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof:

[0090] Among them, Z, W and As defined above, m is selected from 0, 1, 2 or 3, R6 is independently selected from C1-C3 alkyl, C1-C3 haloalkyl, halogen (e.g., fluorine, chlorine, bromine), amino or C1-C3 alkoxy; the optionally substituted C1-C3 alkoxy is selected from -OCH3, -OCD3, -OCHD2, -OCH2D, ethoxy, -OCH2F, -OCHF2, -OCF3 or -OCH2CF3; preferably, m is 2, R6 may be the same or different and are each independently selected from C1-C3 alkyl, C1-C3 haloalkyl (such as C1-C3 fluoroalkyl, C1-C3 chloroalkyl, C1-C3 bromoalkyl) or halogen (such as fluorine, chlorine, bromine); More preferably, m is 2, R6 are different and are each independently selected from C1-C3 haloalkyl (such as C1-C3 fluoroalkyl, C1-C3 chloroalkyl, C1-C3 bromoalkyl), fluorine, chlorine, bromine. Wherein, as generally understood in the art, the structural unit Indicates that R6 can optionally replace any position on the pyrazole ring. For example, the structural unit can be wait.

[0091] In some embodiments, for any of the above compounds, pharmaceutically acceptable salts, deuterated substances, stereoisomers, tautomers, or mixtures thereof, the compound is selected from but not limited to:

[0092] Another aspect of the present application is to provide the use of any of the above-mentioned compounds, their pharmaceutically acceptable salts, their deuterated substances, their stereoisomers, their tautomers, or mixtures thereof in the preparation of a drug for regulating the interaction between PDE3A and SLFN12. Alternatively, the present application provides any of the above-mentioned compounds, their pharmaceutically acceptable salts, their deuterated substances, their stereoisomers, their tautomers, or mixtures thereof for use as a drug for regulating the interaction between PDE3A and SLFN12. Alternatively, the present application provides a method for regulating the interaction between PDE3A and SLFN12, comprising administering to a subject in need thereof any of the above-mentioned compounds, their pharmaceutically acceptable salts, their deuterated substances, their stereoisomers, their tautomers, or mixtures thereof. Preferably, the drug is capable of enhancing and / or promoting the interaction between PDE3A and SLFN12.

[0093] In some embodiments, the compound of any one of the above, its pharmaceutically acceptable salt, its deuterated substance, its stereoisomer, tautomer or a mixture thereof is used to prepare a drug for treating and / or preventing a disease, wherein the disease is a hyperproliferative disease. Alternatively, the present application provides a compound of any one of the above, its pharmaceutically acceptable salt, its deuterated substance, its stereoisomer, tautomer or a mixture thereof for treating and / or preventing a disease, wherein the disease is a hyperproliferative disease. Alternatively, the present application provides a method for treating and / or preventing a disease, comprising administering to a subject in need thereof a compound of any one of the above, its pharmaceutically acceptable salt, its deuterated substance, its stereoisomer, tautomer or a mixture thereof, wherein the disease is a hyperproliferative disease.

[0094] In some preferred embodiments, the hyperproliferative disease is a cancer disease.

[0095] In some preferred embodiments, the cancer disease is brain cancer, breast cancer, cervical cancer, AML, lung cancer, skin cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer and sarcoma.

[0096] The molecular glue developed in this application, which exhibits no significant inhibition of PDE3A enzymatic activity and effectively induces apoptosis in tumor cells, can maintain high pharmacological and efficacy while simultaneously reducing toxic side effects, thus having significant implications for the development of PDE3A anti-cancer drugs. Furthermore, the compound of this invention exhibits strong inhibitory activity in melanoma cells, excellent in vivo efficacy data in animals, and favorable pharmacokinetics. DETAILED DESCRIPTION

[0097] The following is a clear and complete description of the technical solutions in the embodiments of this application. Obviously, the embodiments described are only part of the embodiments of this application, not all of them. Based on the embodiments of this application, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of this application.

[0098] The structures of the compounds were determined by mass spectrometry (MS) or nuclear magnetic resonance (NMR) 1 H NMR). 1 H NMR) shifts (δ) are given in parts per million (ppm); nuclear magnetic resonance ( 1 H NMR) was measured using a Bruker AVANCE-400 nuclear magnetic spectrometer. The solvent was deuterated dimethyl sulfoxide (DMSO), the internal standard was tetramethylsilane (TMS), and the chemical shift was 10 -6 The unit is (ppm). Mass spectrometry (MS) was performed using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Therm, model: Finnigan LCQ advantage MAX).

[0099] Thin layer silica gel uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0100] Definitions and General Terms

[0101] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this application belongs. As used herein, the following terms have the meanings ascribed to them below unless otherwise indicated.

[0102] The term "substituted" herein refers to the replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom with a selection from the indicated group, provided that the normal valence of the designated atom in the current situation is not exceeded and the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form stable compounds. It should be understood that other atoms, such as hydrogen atoms or substituents as described herein, may be present as needed to satisfy the valence of the atoms.

[0103] The term "independently" or "separately" means that when more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.

[0104] Whenever a group is described as "optionally", "optionally substituted", or "substituted or unsubstituted", the group may be unsubstituted or substituted with one or more indicated substituents, i.e., "optionally substituted" means "substituted or unsubstituted". If no substituents are specified, it means that the group may be optionally substituted with one or more groups selected from, but not limited to, deuterium, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halogen, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, cyano, nitro, amino, and aminohydroxyl; preferably, the "optionally substituted" refers to being independently selected from deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, F, Cl, Br, hydroxyl, C1-C6 alkoxy, cyano, amino, C6-C6 10 The optionally substituted substituents include aryl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl, C1-C6 hydroxyalkyl, and the optional substituents also include isotopic forms in which any hydrogen atom in the group is replaced by deuterium. Specific examples include but are not limited to methyl, CD3, ethyl, propyl, CF3, CHF2, CH2F, cyclopropyl, F, Cl, cyano, methoxy, ethoxy, OCHF2, OCF3, OCD3, amino, phenyl, naphthyl, pyridyl, pyrazinyl, etc.

[0105] The term "C m -C n " means that the number of carbon atoms is at least m and at most n, including the two endpoints m and n; m and n are integers not equal to 0, where m<n.

[0106] The term "alkyl" appearing alone or in combination in this application refers to a straight or branched saturated hydrocarbon group consisting solely of carbon atoms and hydrogen atoms (including deuterium atoms), including, but not limited to, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, and C1 alkyl (including deuterated C1-C6 alkyl, deuterated C1-C5 alkyl, deuterated C1-C4 alkyl, deuterated C1-C3 alkyl, deuterated C1-C2 alkyl, and deuterated C1 alkyl). As non-limiting examples of alkyl, the following straight or branched saturated hydrocarbon groups can be cited: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and its other seven isomers, n-hexyl and its other sixteen isomers. For example, "C1-C6 alkyl" includes methyl, C1-C3, ethyl, propyl, butyl, pentyl, hexyl and all isomers thereof. The C1-C6 alkyl may be substituted with an optional substituent.

[0107] The term "haloalkyl" in this application refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen substituent, such as F or Cl. For example, "C1- Non-limiting examples of "C6 haloalkyl" include, but are not limited to, -CF3, -CHF2, -CHCF2, -CH2CH2F, -CH2CF3.

[0108] The term "alkoxy" appearing alone or in combination herein refers to an "-O-alkyl" group, including deuterated alkoxy. Alkoxy herein includes, but is not limited to, C1-C6 alkoxy, C1-C5 alkoxy, C1-C4 alkoxy, C1-C3 alkoxy, C1-C2 alkoxy, and C1 alkoxy (including deuterated C1-C6 alkoxy, deuterated C1-C5 alkoxy, deuterated C1-C4 alkoxy, deuterated C1-C3 alkoxy, deuterated C1-C2 alkoxy, and deuterated C1 alkoxy). For example, the term "C1-C3 alkoxy" refers to a saturated, straight-chain or branched hydrocarbon moiety having at least 1 and up to 3 carbon atoms, bound by an oxygen linker atom. Specific exemplary embodiments include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, and tert-butoxy (including deuterated methoxy, deuterated ethoxy, deuterated n-propoxy, deuterated isopropoxy, deuterated n-butoxy, deuterated sec-butoxy, and deuterated tert-butoxy), etc. The "alkoxy" may be substituted with an optional substituent, for example, non-limiting examples of substitutions with F or Cl include -OCF3, -OCF2, etc.

[0109] The term "carbocyclyl" occurring alone or in combination in the present application refers to a monocyclic or bicyclic or tricyclic hydrocarbon ring in which all ring members are carbon atoms, any of which can be saturated (i.e., cycloalkyl) or partially unsaturated (non-aromatic, for example, cycloalkenyl, cycloalkadienyl etc.). The limiting examples of this type of carbocyclyl include but are not limited to cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cyclooctyl, cyclooctenyl, cyclooctadienyl etc. As shown above, condensed rings and bridged rings are also included in the definition of carbocycle. When using the term "carbocyclyl", it includes "cycloalkyl", "cycloalkenyl" and "partially unsaturated cycloalkyl (non-aromatic)".

[0110] The term "cycloalkyl" as used herein, alone or in combination, refers to a saturated monocyclic or polycyclic (such as spirocyclic, fused or bridged) hydrocarbon ring. For example, the term "C3-C6 cycloalkyl" refers to a saturated monocyclic or polycyclic ring having 3 to 6 ring carbon atoms, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, which may be optionally substituted with one or more (such as 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl, etc.

[0111] The term "cycloalkenyl" appearing alone or in combination in this application refers to a monocyclic or polycyclic ring having one or more carbon-carbon double bonds (non-aromatic) formed entirely of carbon atoms. For example, the term "C4-C9 cycloalkenyl" refers to a cycloalkenyl group having 4 to 9 (e.g., 5, 6, 7 or 8) carbon atoms. Specific non-limiting examples include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, etc.

[0112] The term "heterocyclyl" as used herein, alone or in combination, refers to a monocyclic, bicyclic or tricyclic group consisting of carbon atoms and one or more heteroatoms, wherein the cyclic group may be saturated, partially unsaturated (non-aromatic) or fully unsaturated (aromatic), wherein at least one ring has at least one heteroatom (O, S or N), and the heteroatom-containing ring preferably has 1, 2 or 3 heteroatoms selected from O, S and N. For example, a "4-9 membered heterocyclyl" refers to a 4-9 membered ring consisting of carbon atoms and heteroatoms. Specific non-limiting examples of the “heterocyclyl” include, but are not limited to, aziridine, oxirane, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, pyrroline, oxazolidine, piperazine, dioxolane, dioxane, morpholine, tetrahydropyran, 1,2-dihydroazetadiene, 1,2-dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2,3,6-tetrahydropyridine, etc. When the term “heterocyclyl” is used, it includes “heteroaryl”.

[0113] The term "heteroaryl" as used herein, alone or in combination, refers to a monocyclic or fused polycyclic monovalent group having aromatic properties, wherein at least one (e.g., 1, 2, 3, or 4) ring atoms are heteroatoms selected from N, O, and S, and the remaining ring atoms are C. Non-limiting examples include, but are not limited to For example, non-limiting examples of 5- to 10-membered heteroaryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, pyrazinyl, pyridazinyl, pyridinyl, or pyrimidinyl, and the like.

[0114] As used herein, the term "aryl" alone or in combination refers to an aromatic hydrocarbon radical having multiple carbon atoms. Aryl groups are typically monocyclic, bicyclic, or tricyclic aromatic radicals having multiple carbon atoms. Additionally, the term "aryl" as used herein refers to an aromatic substituent that can be a single aromatic ring or multiple aromatic rings fused together, non-limiting examples of which include phenyl, naphthyl, or tetrahydronaphthyl.

[0115] The term "alkynyl" in this application refers to a straight or branched monovalent hydrocarbon group having one or more carbon-carbon triple bonds, for example, having 2 to 8 carbon atoms, such as C2-C6 alkynyl, C2-C5 alkynyl, specific non-limiting examples include but are not limited to ethynyl, propargyl, 1-propynyl, 1-butynyl, pentynyl, hexynyl, etc.

[0116] The term "halogen" herein refers to F, Cl, Br or I. The term "hydroxy" herein refers to an -OH group.

[0117] The term "amino" in this application refers to a -NH2 group, which may be substituted or unsubstituted. When expressed as a substituted amino group, it is -N(R") n , wherein R" is an independently optional suitable substituent (such as any substituent defined above).

[0118] The term "cyano" as used herein refers to a -CN group. The term "nitro" as used herein refers to a -NO2 group.

[0119] The alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, cycloalkenyl, heterocyclic and carbocyclic groups described herein may be optionally substituted with one or more suitable substituents.

[0120] The term "alkylamino" herein refers to a group in which the hydrogen atom in an amino group is substituted by an alkyl group (eg, a C1-C6 alkyl group, a C1-C3 alkyl group, a methyl group, an ethyl group, etc.).

[0121] Unless otherwise indicated, "hetero" and "heteroatom" herein refer to atoms other than carbon or hydrogen, including, but not limited to, O, S, and N. In this document, heteroaryl and heterocyclic groups may contain one or more (e.g., 1-3, 1-2) heteroatoms.

[0122] The term "nitrogen protection" in this application means connecting the reaction bottle to a 1 L nitrogen balloon.

[0123] Unless otherwise specified in the present application, the solution mentioned in the reaction of the present application is an aqueous solution.

[0124] The term "room temperature" in this application refers to a temperature between 10°C and 25°C.

[0125] When referring to a compound in this application, all isomeric forms of the structure are included, such as stereoisomers (including enantiomers and diastereomers), geometric isomers (or conformational isomers), and tautomeric forms. The term "stereoisomer" (or "optical isomer") refers to a stable isomer that has a perpendicular asymmetry plane due to at least one chiral factor (including a chiral center, chiral axis, chiral plane, etc.), thereby being able to rotate plane-polarized light; the term "tautomer" (or "tautomeric form") refers to structural isomers with different energies that can be interconverted through a low energy barrier. For example, proton tautomers (or prototransfer tautomers) include (but are not limited to) interconversions via proton migration, such as keto-enol isomerization, imine-enamine isomerization, and amide-iminoalcohol isomerization; the term "cis-trans isomer" refers to stereoisomers formed by the different positions of atoms (or groups) on either side of a double bond or ring system relative to a reference plane; in cis isomers, the atoms (or groups) are on the same side of the double bond or ring system, while in trans isomers, the atoms (or groups) are on opposite sides of the double bond or ring system.

[0126] In addition, the compounds of the present invention may also contain unnatural proportions of atomic isotopic forms at one or more atoms constituting these compounds, i.e., hydrogen isotopic forms of D or T, or isotopes of any atoms, such as all isotopic forms of C and N. Specifically, radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C) Radiolabeled compounds. All isotopic variations of the compounds of the optional structures of the present application, whether or not radioactive, are encompassed within the scope of protection of the present application. In particular, the present application includes deuterated forms of hydrogen at any position in the compounds of the following general formula, including hydrogen on substituent groups:

[0127] The words "comprise," "include," and "contain" and their equivalents are to be understood as open, non-exclusive, meaning "including but not limited to," meaning that in addition to the listed elements, components, and steps, other unspecified elements, components, and steps may also be encompassed. Unless otherwise indicated, all numbers used herein to represent amounts of ingredients, measurements, or reaction conditions are to be understood as being modified in all cases by the term "about." When associated with a percentage, the term "about" can mean, for example, ±1%, preferably ±0.5%, and more preferably ±0.1%. Unless the context clearly indicates otherwise, singular terms herein encompass plural referents, and vice versa. Similarly, unless the context clearly indicates otherwise, the word "or" herein is intended to include "and."

[0128] Intermediate 1a: Synthesis of 7-bromo-8-chloro-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0129] 1) Synthesis of 5-(6-amino-3-bromo-2-chlorobenzylidene)imidazoline-2,4-dione

[0130] To a solution of 6-amino-3-bromo-2-chlorobenzaldehyde (2 g, 8.53 mmol, synthesized according to the method provided in WO2019167000A1) in ethanol (20 mL) was added sodium methoxide (932 mg, 17.24 mmol). After stirring for half an hour, diethyl (2,5-dioxoimidazolin-4-yl)phosphonate (2.03 g, 8.62 mmol, CAS: 95378-36-2) was added and stirring continued for 4 hours. The reaction was not further treated and the crude product was used directly in the next step. LC-MS: m / z [M+H] + =316 / 318.

[0131] 2) Synthesis of 7-bromo-8-chloro-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0132] Acetic acid (5 mL) was added directly to the reaction mixture from the previous step and stirred at 25°C for 2 hours. A yellow solid precipitated. The reaction mixture was filtered and the filter cake was washed three times with ethanol (10 mL). The filter cake was collected and concentrated under reduced pressure to obtain the title compound as a yellow solid (2.4 g crude product). LC-MS: m / z [M+H] + =298 / 300.

[0133] 3) Synthesis of 7-bromo-8-chloro-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0134] To a solution of 7-bromo-8-chloro-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (2.4 g, 8 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (1.29 g, 32 mmol, 60% w / w in mineral oil). The mixture was stirred at 0°C for 1 hour, followed by the addition of 2-(trimethylsilyl)ethoxymethyl chloride (3.36 g, 20.1 mmol) and stirring at 25°C for 2 hours. The reaction mixture was quenched by pouring into water (100 mL) and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 100:1 to 10:1) to afford the title compound as a yellow solid (200 mg, 4% yield over three steps). LC-MS: m / z [M+H] + =558 / 560.

[0135] Intermediate 1 Synthesis of 7-bromo-8-chloro-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0136] 7-Bromo-8-chloro-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (200 mg, 0.62 mmol, intermediate 1a) was dissolved in trifluoroacetic acid (3 mL) and stirred at 100°C under microwave heating for 1 hour. Dichloroethane (10 ml x 2) was added to the reaction solution and concentrated. The reaction solution was purified by reverse phase chromatography (5% to 95% acetonitrile and water) to give the title compound as a yellow solid (60 mg, yield 56%). 1 H NMR (400MHz, DMSO-d6) δ7.81 (d, J = 8Hz, 1H), 7.75-7.71 (m, 2H); LC-MS: m / z [M+H] + =298 / 300.

[0137] Synthesis of Intermediate 2-(1-(4-methoxybenzyl)-2,5-dioxopyrrolidin-3-yl)phosphonic acid diethyl ester

[0138] 1) Synthesis of 1-(4-methoxybenzyl)-1H-pyrrole-2,5-dione

[0139] Dissolve furan-2,5-dione (5.0 g, 51.02 mmol) and p-methoxybenzylamine (7.7 g, 56.12 mmol) in acetic acid (50 mL). The reaction mixture was heated to 110°C overnight. The reaction mixture was cooled to room temperature and concentrated. Saturated sodium bicarbonate solution (100 mL) and ethyl acetate (100 mL) were added to the residue. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated. Purification by column chromatography (petroleum ether / ethyl acetate = 3:1) afforded the title compound as a white solid (3.0 g, 27% yield). LC-MS: m / z [M+H] + =218.

[0140] 2. Synthesis of diethyl (1-(4-methoxybenzyl)-2,5-dioxopyrrolidin-3-yl)phosphonate

[0141] Dissolve 1-(4-methoxybenzyl)-1H-pyrrole-2,5-dione (1 g, 4.58 mmol) in acetic acid (10 mL). Slowly add triethyl phosphite (1.14 g, 6.87 mmol). Heat the reaction mixture to 100°C and stir for 1 hour. Cool the reaction mixture to room temperature, concentrate most of the acetic acid, and pour the residue into saturated sodium bicarbonate solution (50 mL). Extract with ethyl acetate (50 mL x 2). Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain the title compound as a white oil (1.2 g crude product). LC-MS: m / z [M+H] + =356.

[0142] Synthesis of Intermediate 3 7-bromo-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0143] 1) Synthesis of 6-bromo-3-nitroquinolin-2(1H)-one

[0144] To a 250 mL single-necked flask, add 2-amino-5-bromobenzaldehyde (10.00 g, 50 mmol, CAS: 29124-57-0) and anhydrous ethanol (120 mL). Ethyl 2-nitroacetate (13.3 g, 100 mmol, CAS: 626-35-7) and piperidine (2.13 g, 25 mmol) were then added. The reaction mixture was heated to 80°C and refluxed with stirring overnight. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed twice with isopropyl ether (20 mL) and dried to afford the title compound as a yellow solid (10.00 g, 74% yield). LC-MS: m / z [M+H] + =269 / 271.

[0145] 2) Synthesis of 6-bromo-2-chloro-3-nitro-1,2-dihydroquinoline

[0146] Dissolve 6-bromo-3-nitroquinolin-2(1H)-one (10.00 g, 37.2 mmol) in phosphorus oxychloride (120 mL), and allow the mixture to react overnight at 110°C. Cool the reaction mixture to room temperature, then slowly add ice water (300 mL) to quench the reaction. Filter the resulting suspension, wash the filter cake twice with water (20 mL), and dry to yield the title compound as a gray solid (9.7 g, 90% yield). LC-MS: m / z [M+H] + =289 / 291.

[0147] 3) Synthesis of 6-bromo-3-nitroquinolin-2-amine

[0148] To a 200 mL sealed flask, add 6-bromo-2-chloro-3-nitro-1,2-dihydroquinoline (9.7 g, 33.5 mmol) and 2M methanolic ammonia solution (110 mL). The mixture was reacted at 120°C overnight. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed twice with cyclohexane (20 mL) and dried to afford the title compound as a red solid (7.8 g, 87% yield). LC-MS: m / z [M+H] + =268 / 270.

[0149] 4) Synthesis of 6-bromoquinoline-2,3-diamine

[0150] Dissolve 6-bromo-3-nitroquinolin-2-amine (7.8 g, 29.1 mol) in methanol (120 mL) and add Raney nickel catalyst (0.78 g, CAS: 7440-02-0). Replace the mixture with hydrogen three times. Stir the reaction mixture overnight at room temperature under a hydrogen atmosphere. Filter the mixture through Celite and concentrate the filtrate to obtain the title compound as a red solid (6.8 g, 98% yield). LC-MS: m / z [M+H] + =238 / 240.

[0151] 5) Synthesis of 7-bromo-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0152] Dissolve 6-bromoquinoline-2,3-diamine (6.8 g, 28.6 mmol) in acetonitrile (2 L) and add N,N'-succinimidyl carbonate (7.4 g, 28.9 mmol). Stir the reaction mixture overnight at room temperature. Concentrate the reaction mixture to remove most of the solvent, then dilute with water (200 mL). Stir the mixture at room temperature for half an hour. The solid is collected by filtration and dried to obtain the title compound as an off-white solid (5 g, 66% yield). LC-MS: m / z [M+H] +=264 / 266.

[0153] With reference to the table below, the following intermediate 25 was prepared by following the preparation method of intermediate 3, except that the raw materials described in the "Raw Materials" column were used instead of the corresponding raw materials.

[0154] Intermediate 4 Synthesis of 7-bromo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0155] To a solution of 7-bromo-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (500 mg, 1.9 mmol, Intermediate 3) in N,N-dimethylformamide (10 mL) was added sodium hydride (91 mg, 3.8 mmol, 60% w / w in mineral oil). The mixture was stirred at 0°C for 1 hour, followed by the addition of 2-(trimethylsilyl)ethoxymethyl chloride (790 mg, 4.7 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched by pouring into water (20 mL) and extracted twice with ethyl acetate (20 mL). The organic phases were combined, washed twice with water (30 mL) and twice with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to afford the title compound as a white solid (337 mg, 34% yield). LC-MS: m / z [M+H] + =524 / 526.

[0156] With reference to the table below, the following intermediate 28 was prepared by following the preparation method of intermediate 4, except that the raw materials described in the "Raw Materials" column were used instead of the corresponding raw materials.

[0157] Intermediate 5 Synthesis of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0158] 7-Bromo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (100 mg, 0.19 mmol, intermediate 4), pinacol diboron (97 mg, 0.38 mmol, CAS: 73183-34-3), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (14 mg, 0.019 mmol, CAS: 72287-26-4) and potassium acetate (56 mg, 0.57 mmol) were dissolved in 1,4-dioxane (3 mL), and the atmosphere was replaced with nitrogen three times. The reaction solution was heated and stirred at 85°C under a nitrogen atmosphere overnight. The reaction mixture was cooled to room temperature and diluted with water (20 mL). The mixture was extracted twice with ethyl acetate (20 mL). The organic phases were combined and washed twice with water (20 mL) and saturated brine (20 mL). The organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound as a white solid (150 mg, yield 138%). LC-MS: m / z [M+H] + =572.

[0159] Referring to the table below, the following Intermediates 9 and 26 were prepared by following the preparation method of Intermediate 5, except that the raw materials described in the "Raw Materials" column were used instead of the corresponding raw materials.

[0160] Intermediate 6 Synthesis of a mixture of 3-chloro-1-(difluoromethyl)-4-iodo-1H-pyrazole and 5-chloro-1-(difluoromethyl)-4-iodo-1H-pyrazole

[0161] 1) Synthesis of 3-chloro-4-iodo-1H-pyrazole

[0162] N-iodosuccinimide (5.49 g, 24.39 mmol, CAS: 516-12-1) was added to a solution of 3-chloro-1H-pyrazole (2.5 g, 24.39 mmol, CAS: 14339-33-4) in acetic acid (20 mL). The mixture was stirred at 25°C for 16 hours. The reaction mixture was filtered, the filter cake collected, and concentrated under reduced pressure. Purification by column chromatography (petroleum ether / ethyl acetate = 1:1) afforded the title compound as a pale yellow solid (1.28 g, 23% yield). LC-MS: m / z [M+H] + =229.

[0163] 2) Synthesis of a mixture of 3-chloro-1-(difluoromethyl)-4-iodo-1H-pyrazole and 5-chloro-1-(difluoromethyl)-4-iodo-1H-pyrazole

[0164] 3-Chloro-4-iodo-1H-pyrazole (1.22 g, 5.34 mmol) was added to a mixture of potassium hydroxide (4 g, 71.29 mmol) in acetonitrile (20 mL) and water (20 mL). Diethyl bromofluoromethylphosphonate (2.85 g, 10.68 mmol, CAS: 65094-22-6) was then added to the reaction mixture. The reaction mixture was stirred at 60°C for 5 hours. The reaction mixture was cooled to room temperature and extracted three times with ethyl acetate (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 2:1) to afford a colorless oily mixture (1 g, 67% yield, a mixture of 3-chloro-1-(difluoromethyl)-4-iodo-1H-pyrazole and 5-chloro-1-(difluoromethyl)-4-iodo-1H-pyrazole). The mixture was used directly in the next step without further purification. LC-MS: m / z [M+H] + =279.

[0165] Referring to the table below, the following Intermediates 12 and 14 were prepared by following the preparation method of Intermediate 6, except that the raw materials described in the "Raw Materials" column were used instead of the corresponding raw materials.

[0166] Intermediate 7 Synthesis of a mixture of 3-bromo-4-chloro-1-(difluoromethyl)-1H-pyrazole and 5-bromo-4-chloro-1-(difluoromethyl)-1H-pyrazole

[0167] 5-Bromo-4-chloro-1H-pyrazole (250 mg, 1.38 mmol, CAS: 27258-12-4) was added to a mixture of potassium hydroxide (200 mg, 3.56 mmol) in acetonitrile (1 mL) and water (1 mL). Diethyl bromofluoromethylphosphonate (736 mg, 2.76 mmol, CAS: 65094-22-6) was then added to the reaction mixture. The reaction mixture was stirred at 60°C for 5 hours. The reaction mixture was cooled to room temperature and extracted three times with dichloromethane (2 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to afford a colorless oily mixture (84 mg, 26% yield, a mixture of 3-bromo-4-chloro-1-(difluoromethyl)-1H-pyrazole and 5-bromo-4-chloro-1-(difluoromethyl)-1H-pyrazole). The mixture was used directly in the next reaction without further purification.

[0168] Intermediate 8N 2 ,N 3 ,N 3 Synthesis of tris(4-methoxybenzyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2,3-diamine

[0169] 1) Synthesis of tert-butyl 3-nitro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0170] To a solution of 1-methyl-3,5-dinitro-1,2-dihydropyridin-2-one (4.7 g, 23.60 mmol, CAS: 14150-94-8) and N-tert-butyloxycarbonyl-4-piperidone (4.70 g, 23.60 mmol) in methanol (90 mL) was added a 7M methanolic ammonia solution (37.09 mL, 259.64 mmol). The mixture was stirred at 60°C for 5 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 20:1 to 5:1) to afford the title compound as a white solid (4.0 g, 61% yield). LC-MS: m / z [M+H] + =280.

[0171] 2) Synthesis of tert-butyl 3-amino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0172] To a solution of tert-butyl 3-nitro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (2 g, 7.16 mmol) in methanol (50 mL) was added 10% palladium-on-carbon catalyst (0.3 g, CAS: 7440-05-3). The mixture was degassed, replaced with hydrogen three times, and stirred at 25°C under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered through celite, and the filter cake was washed once with methanol (20 mL). The filtrate was concentrated under reduced pressure to afford the title compound as a colorless, transparent oil (1.78 g, 100% yield). LC-MS: m / z [M+H] + =250.

[0173] 3) Synthesis of tert-butyl 3-amino-2-bromo-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0174] To a solution of tert-butyl 3-amino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (1.78 g, 7.14 mmol) in N,N-dimethylformamide (15 mL) at 0°C was added dropwise a solution of N-bromosuccinimide (1.27 g, 7.14 mmol) in N,N-dimethylformamide (10 mL). After completion of the addition, the reaction mixture was warmed to 25°C and stirred for 18 hours. The mixture was poured into water (150 mL) and extracted three times with ethyl acetate (100 mL). The combined organic phases were washed once with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (petroleum ether / ethyl acetate = 10:1 to 3:1) afforded the title compound as a white solid (1.8 g, 77% yield). LC-MS: m / z [M+H] + =328 / 330.

[0175] 4) Synthesis of tert-butyl 3-(bis(4-methoxybenzyl)amino)-2-bromo-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0176] To a solution of tert-butyl 3-amino-2-bromo-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (2 g, 6.09 mmol) and potassium tert-butoxide (1.709 g, 15.23 mmol) in N,N-dimethylformamide (30 mL) was added p-methoxybenzyl chloride (1.825 mL, 13.46 mmol, d = 1.155 g / mL), and the mixture was stirred at 80°C for 18 hours. The mixture was poured into water (80 mL) and extracted three times with ethyl acetate (60 mL). The combined organic phases were washed once with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (petroleum ether / ethyl acetate = 10:1 to 4:1) afforded the title compound as a yellow solid (3.4 g, 98% yield). LC-MS: m / z [M+H] + =568 / 570.

[0177] 5) Synthesis of tert-butyl 3-(bis(4-methoxybenzyl)amino)-2-((4-methylbenzyl)amino)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0178] Tert-butyl 3-(bis(4-methoxybenzyl)amino)-2-bromo-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (3.4 g, 5.98 mmol), 4-methoxybenzylamine (1.23 g, 8.97 mmol), cesium carbonate (3.9 g, 11.96 mmol), palladium acetate (134.26 mg, 0.60 mmol, CAS: 3375-31-3) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (372.37 mg, 0.60 mmol, CAS: 98327-87-8) were added to 1,4-dioxane (60 mL), the mixture was degassed, replaced with nitrogen three times, and stirred at 100 ° C. under a nitrogen atmosphere for 18 hours. The reaction mixture was filtered through celite, and the filter cake was washed three times with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 10:1 to 4:1) to obtain the title compound as a yellow oil (2.5 g, yield 67%). LC-MS: m / z [M+H] + =625.

[0179] 6)N 2 ,N 3 ,N 3 Synthesis of tris(4-methoxybenzyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2,3-diamine

[0180] Zinc bromide (1405.68 mg, 6.24 mmol) was added to a solution of tert-butyl 3-(bis(4-methoxybenzyl)amino)-2-((4-methylbenzyl)amine)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (780 mg, 1.25 mmol) in dichloromethane (35 mL), and the mixture was stirred at 25°C for 18 hours. The reaction solution was filtered through celite and washed three times with dichloromethane (20 mL). The filtrate was concentrated under reduced pressure and purified by preparative liquid chromatography (1% formic acid) to give the title compound as a yellow solid (547 mg, 83% yield). LC-MS: m / z [M+H] + =525.

[0181] Intermediate 10 Synthesis of a mixture of 3-bromo-2-chloro-6-(methoxy-d3)pyridine and 3-bromo-6-chloro-2-(methoxy-d3)pyridine

[0182] Under nitrogen at 0°C, sodium hydroxide (0.21 g, 5.29 mmol, 60% dispersion in mineral oil) was added to deuterated methanol (2 mL, 49.35 mmol, d = 0.888 g / mL, CAS: 811-98-3), and the mixture was stirred at room temperature for 0.5 hours. A solution of 3-bromo-2,6-dichloropyridine (1 g, 4.41 mmol, CAS: 866755-20-6) in deuterated methanol (6 mL) was added dropwise to the mixture, and the mixture was stirred at 60°C for 16 hours. The reaction mixture was quenched with saturated ammonium chloride solution (15 mL) and extracted three times with ethyl acetate (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to afford the title compound (950 mg as a white solid). LC-MS: m / z [M+H] + =225 / 227.

[0183] Intermediate 11 Synthesis of a mixture of 1-(difluoromethyl)-4-iodo-5-(trifluoromethyl)-1H-pyrazole and 1-(difluoromethyl)-4-iodo-3-(trifluoromethyl)-1H-pyrazole

[0184] Diethyl bromofluoromethylphosphonate (1450 mg, 5.43 mmol, CAS: 65094-22-6) was added to a mixture of 4-iodo-3-(trifluoromethyl)-1H-pyrazole (1050 mg, 4.01 mmol, CAS: 866638-72-4), potassium hydroxide (800 mg, 14.26 mmol), water (10 mL), and acetonitrile (12 mL) at 0°C and allowed to react at 60°C for 15 hours. The reaction mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 15:1) to afford the title compound (200 mg) as a yellow viscous liquid. LC-MS: m / z [M+H] + =313.

[0185] Intermediate 13 Synthesis of 5-bromo-4-chloro-3-(difluoromethyl)isoxazole

[0186] 1) Synthesis of ethyl 5-amino-4-chloroisoxazole-3-carboxylate

[0187] N-Chlorosuccinimide (4.49 g, 33.62 mmol, CAS: 128-09-6) was added to a solution of ethyl 5-aminoisoxazole-3-carboxylate (5 g, 32.02 mmol, CAS: 1629161-40-5) in N,N-dimethylformamide (50 mL). The mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water (500 mL) and extracted three times with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to afford the title compound as a pale yellow solid (5.77 g, 94.6% yield). LC-MS: m / z [M+H] + =191.

[0188] 2) Synthesis of ethyl 5-bromo-4-chloroisoxazole-3-carboxylate

[0189] Tert-butyl nitrite (2.52 mL, 20.9 mmol, d = 0.867 g / mL) was added dropwise to a solution of ethyl 5-amino-4-chloroisoxazole-3-carboxylate (2 g, 10.49 mmol) and copper bromide (2.34 g, 10.49 mmol) in acetonitrile (20 mL). The mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted three times with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to afford the title compound as a pale yellow oil (1.4 g, 52% yield). LC-MS: m / z [M+H] + =254 / 256.

[0190] 3) Synthesis of (5-bromo-4-chloroisoxazol-3-yl)methanol

[0191] Sodium borohydride (1.33 g, 35.19 mmol) was added to a solution of ethyl 5-bromo-4-chloroisoxazole-3-carboxylate (2.985 g, 11.73 mmol) in methanol (20 mL) at 0°C, and the mixture was stirred at 50°C for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (50 mL) and extracted three times with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound as a colorless oil (2 g, 80% yield). LC-MS: m / z [M+H] + =212 / 214.

[0192] 4) Synthesis of 5-bromo-4-chloroisoxazole-3-carboxaldehyde

[0193] Dess-Martin periodinane (4.55 g, 10.72 mmol, CAS: 87413-09-0) was added to a solution of (5-bromo-4-chloroisoxazol-3-yl)methanol in dichloromethane (25 mL), and the mixture was stirred at 25°C for 4 hours. The reaction was quenched with saturated aqueous sodium thiosulfate (20 mL) and extracted three times with dichloromethane (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 1:100) to afford the title compound (1.1 g, 54% yield) as a pale yellow solid. LC-MS: m / z [M+H] + =210 / 212.

[0194] 5) Synthesis of 5-bromo-4-chloro-3-(difluoromethyl)isoxazole

[0195] At -30°C under nitrogen, diethylaminosulfur trifluoride (DAST, 1.57 mL, 11.88 mmol, d = 1.22 g / mL, CAS: 38078-09-0) was added dropwise to a solution of 5-bromo-4-chloroisoxazole-3-carbaldehyde (500 mg, 2.38 mmol) in dichloromethane (10 mL). The mixture was stirred at 25°C for 18 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (10 mL) and extracted three times with dichloromethane (5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (petroleum ether / ethyl acetate = 2:1) afforded the title compound as a pale yellow solid (120 mg, 22% yield). 1 H NMR (400MHz, DMSO-d6) δ7.40 (t, J=51.6Hz, 1H); LC-MS: m / z[M+H] + =232 / 234.

[0196] Intermediate 15 Synthesis of 3-bromo-6-chloro-2-(difluoromethoxy)pyridine

[0197] 1) Synthesis of 6-(difluoromethoxy)pyridin-2-amine

[0198] To a solution of 6-aminopyridin-2-one (3000 mg, 27.24 mmol, CAS: 5154-00-7) and potassium carbonate (5647.48 mg, 40.86 mmol) in N,N-dimethylformamide (45 mL) was added sodium 2-chloro-2,2-difluoroacetate (8306.94 mg, 54.49 mmol, CAS: 1895-39-2). The mixture was stirred at 100°C under nitrogen for 3 hours. The reaction mixture was cooled to room temperature, poured into water (200 mL), and extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (petroleum ether / ethyl acetate = 10:1) afforded the title compound as a colorless, transparent oil (3.50 g, 80% yield). LC-MS: m / z [M+H] + =161.

[0199] 2) Synthesis of 5-bromo-6-(difluoromethoxy)pyridin-2-amine

[0200] To a solution of 6-(difluoromethoxy)pyridin-2-amine (2 g, 12.49 mmol) in N,N-dimethylformamide (10 mL) was added a solution of N-bromosuccinimide (2.22 g, 12.49 mmol) in N,N-dimethylformamide (10 mL). The mixture was stirred at 25°C for 18 hours. The reaction solution was poured into saturated sodium chloride solution (300 mL) and extracted three times with ethyl acetate (150 mL). The organic phases were combined, washed three times with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (petroleum ether / ethyl acetate = 5:1) afforded the title compound as a yellow solid (2090 mg, 70% yield). LC-MS: m / z [M+H] + =239 / 241.

[0201] 3) Synthesis of 3-bromo-6-chloro-2-(difluoromethoxy)pyridine

[0202] Under nitrogen, to a solution of 5-bromo-6-(difluoromethoxy)pyridin-2-amine (700 mg, 2.93 mmol) and benzyltriethylammonium chloride (3001.87 mg, 13.18 mmol, CAS: 56-37-1) in dichloromethane (30 mL) was added tert-butyl nitrite (3.51 mL, 29.29 mmol, d = 0.867 g / mL, CAS: 540-80-7). The mixture was stirred at 25°C for 3 hours. The reaction was quenched with saturated aqueous sodium thiosulfate (100 mL) and extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (petroleum ether / ethyl acetate = 20:1) afforded the title compound as a colorless, transparent oil (470 mg, 62% yield).

[0203] Synthesis of Intermediate 16a 5-Bromo-6-chloro-N-methylpyridin-2-amine

[0204] To a solution of 3-bromo-2,6-dichloropyridine (1000 mg, 4.46 mmol, CAS: 866755-20-6) in tetrahydrofuran (10 mL) was added a 2M solution of methylamine in tetrahydrofuran (11 mL, 22.3 mmol). The mixture was stirred at 70°C overnight. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to afford the title compound as a white solid (500 mg, 51% yield). LC-MS: m / z [M+H]+ = 221 / 223.

[0205] Intermediate 16b Synthesis of a mixture of 3-bromo-6-chloro-N-methylpyridin-2-amine

[0206] Dissolve 3-bromo-6-chloropyridin-2-amine (1000 mg, 4.85 mmol, CAS: 442127-50-6) and methyl trifluoromethanesulfonate (1171 mg, 7.27 mmol, CAS: 333-27-7) in hexafluoroisopropanol (10 mL, CAS: 920-66-1). Stir the mixture overnight at 25°C. Add water (20 mL) and extract twice with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (petroleum ether / ethyl acetate = 3:1) afforded the title compound as a white solid (200 mg, 18% yield). LC-MS: m / z [M+H] + =221 / 223.

[0207] Synthesis of Intermediate 17a 5-(difluoromethoxy)-1-(difluoromethyl)-4-iodo-1H-pyrazole

[0208] Synthesis of Intermediate 17b 3-(difluoromethoxy)-1-(difluoromethyl)-4-iodo-1H-pyrazole

[0209] 1) Synthesis of tert-butyl 3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate

[0210] To a solution of 1,2-dihydro-3H-pyrazol-3-one (5 g, 59.47 mmol, CAS: 137-45-1) and triethylamine (9.89 mL, 71.36 mmol, d = 0.728 g / mL) in dichloromethane (50 mL) was added di-tert-butyl dicarbonate (14.00 mL, 65.41 mmol, CAS: 24424-99-5). The mixture was stirred at 25°C for 5 hours. The reaction mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 10:1 to 2:1) to afford the title compound as a yellow solid (8.8 g, 51% yield).

[0211] 2) Synthesis of 3-(difluoromethoxy)-1H-pyrazole

[0212] tert-Butyl 3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate (7.8 g, 42.35 mmol) and potassium hydroxide (7.13 g, 127.04 mmol) were added to acetonitrile (80 mL) and water (80 mL), followed by diethyl bromofluoromethylphosphonate (22.61 g, 84.70 mmol, CAS: 65094-22-6). The mixture was stirred at 60°C for 5 hours. The reaction mixture was poured into saturated brine (300 mL) and extracted three times with ethyl acetate (200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (petroleum ether / dichloromethane = 10:1 to 1:1) afforded the title compound as a colorless, transparent oil (1.95 g, 34% yield). LC-MS: m / z [M+H] + =135.

[0213] 3) Synthesis of 3-(difluoromethoxy)-4-iodo-1H-pyrazole

[0214] 3-(Difluoromethoxy)-1H-pyrazole (2.04 g, 15.21 mmol) was dissolved in N,N-dimethylformamide (80 mL), followed by the addition of a solution of N-iodosuccinimide (3.42 g, 15.21 mmol, CAS: 516-12-1) in N,N-dimethylformamide (10 mL). The mixture was stirred at 25°C for 18 hours. The reaction mixture was poured into saturated brine (1000 mL) and extracted three times with ethyl acetate (500 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (petroleum ether / dichloromethane = 10:1 to 2:1) afforded the title compound as a yellow solid (3.5 g, 88% yield). LC-MS: m / z [M+H] + =261.

[0215] 4) Synthesis of 5-(difluoromethoxy)-1-(difluoromethyl)-4-iodo-1H-pyrazole and 3-(difluoromethoxy)-1-(difluoromethyl)-4-iodo-1H-pyrazole

[0216] 3-(Difluoromethoxy)-4-iodo-1H-pyrazole (1 g, 3.85 mmol) and potassium hydroxide (2.16 g, 38.46 mmol) were added to acetonitrile (20 mL) and water (20 mL), and then diethyl bromofluoromethylphosphonate (2.05 g, 7.69 mmol, CAS: 65094-22-6) was added, and the mixture was stirred at 60 ° C for 18 hours. The reaction mixture was poured into water (100 mL) and extracted three times with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (petroleum ether / ethyl acetate = 30:1) afforded 5-(difluoromethoxy)-1-(difluoromethyl)-4-iodo-1H-pyrazole (117 mg, Intermediate 17a) as a colorless, transparent oil, and 3-(difluoromethoxy)-1-(difluoromethyl)-4-iodo-1H-pyrazole (277 mg, Intermediate 17b) as a colorless, transparent oil. LC-MS: m / z [M+H] + =311.

[0217] Synthesis of Intermediate 18 (Methyl-d3) Boronic Acid

[0218] To a solution of trimethyl borate (1.63 mL, 14.40 mmol, CAS: 121-43-7) in tetrahydrofuran (15 mL) was slowly added methyl-d3-magnesium iodide (8 mL, 8.00 mmol, 1 M in diethyl ether) at -70 to -60°C. The reaction mixture was stirred at -70°C under nitrogen for 1 hour, then slowly warmed to room temperature and stirred at room temperature for 1 hour. Aqueous hydrochloric acid (5 mL, 1N) was slowly added dropwise to quench the reaction. Ethyl acetate (50 mL) was added, and the organic phase was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound (400 mg, crude) as a yellow oil, which was used directly in the next reaction.

[0219] Intermediate 19 Synthesis of 1-bromo-2-chloro-4-(difluoromethyl)benzene

[0220] Dissolve 4-bromo-3-chlorobenzaldehyde (2 g, 9.26 mmol, CAS: 120077-69-2) in dichloromethane (20 mL). Slowly add diethylaminosulfur trifluoride (DAST, 2.98 g, 18.52 mmol, CAS: 38078-09-0) at 0°C. After addition, warm to 25°C and stir overnight. Quench the reaction mixture with water (100 mL) and extract twice with dichloromethane (60 mL). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purify by column chromatography (petroleum ether / dichloromethane = 10:1) to afford the title compound as a yellow oil (2.0 g, 91% yield).

[0221] Intermediate 20: Synthesis of 7-bromo-8-fluoro-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0222] 1) Synthesis of 2-amino-6-fluorobenzaldehyde

[0223] Active manganese dioxide (6467.47 mg, 74.3 mmol) was added to a solution of (2-amino-6-fluorophenyl)methanol (2100 mg, 14.88 mmol, CAS: 221285-25-2) in dichloromethane (30 mL). The mixture was stirred at 25°C overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a light yellow solid (2000 mg, 97% yield). LC-MS: m / z [M+H] + =140.

[0224] 2) Synthesis of 6-amino-3-bromo-2-fluorobenzaldehyde

[0225] N-Bromosuccinimide (2.51 g, 14.09 mmol) was added to a solution of 2-amino-6-fluorobenzaldehyde (1.96 g, 14.09 mmol) in N,N-dimethylformamide (20 mL) at 0°C, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into ice water (50 mL), and the precipitated solid was collected by filtration. The filter cake was washed three times with water (10 mL) and dried to give the title compound as a light yellow solid (2.71 g, 88% yield). LC-MS: m / z [M+H] + =218 / 220.

[0226] 3) Synthesis of 5-(6-amino-3-bromo-2-fluorobenzylidene)imidazoline-2,4-dione

[0227] Sodium methoxide (3.30 mL, 17.75 mmol, 30 wt% methanol solution) was added dropwise to a solution of diethyl (2,5-dioxoimidazolin-4-yl)phosphonate (4.19 g, 17.75 mmol, CAS: 95378-36-2) in ethanol (10 mL). The mixture was stirred at 25°C for 20 minutes, followed by the addition of 6-amino-3-bromo-2-fluorobenzaldehyde (2.58 g, 11.83 mmol) in ethanol. After the addition was complete, the reaction mixture was stirred at 25°C for 1 hour. The reaction solution was used directly in the next reaction without further treatment. LC-MS: m / z [M+H] + =300 / 302.

[0228] 4) Synthesis of 7-bromo-8-fluoro-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0229] Acetic acid (15 mL) was added directly to the reaction mixture from the previous step and stirred at 25°C for 2 hours. A yellow solid precipitated. The reaction mixture was filtered and the filter cake was washed three times with ethanol (10 mL). The filter cake was collected and concentrated under reduced pressure to obtain the title compound as a yellow solid (2.77 g crude product). LC-MS: m / z [M+H] + =282 / 284.

[0230] 5) Synthesis of 7-bromo-8-fluoro-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0231] To a solution of 7-bromo-8-fluoro-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (2.1 g, 7.44 mmol, Intermediate 20) in N,N-dimethylformamide (30 mL) was added sodium hydride (1.19 g, 30 mmol, 60% w / w in mineral oil). The mixture was stirred at 25°C for 1 hour, followed by the addition of 2-(trimethylsilyl)ethoxymethyl chloride (3.30 mL, 18.61 mmol, d = 0.942 g / mL). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched by pouring into saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to afford the title compound as a yellow solid (711 mg, 18% yield). LC-MS: m / z[M+H] + =542 / 544.

[0232] Referring to the table below, the following intermediate 21 was prepared by following the preparation method of intermediate 20, except that the raw materials described in the "Raw Materials" column were used instead of the corresponding raw materials.

[0233] Synthesis of Intermediate 22N-bis(tert-butoxycarbonyl)-2-aminoacetonitrile

[0234] To a mixture of bis(tert-butyloxycarbonyl)amine (25.00 g, 115.07 mmol, CAS: 51779-32-9), sodium hydroxide (13.81 g, 345.21 mmol), and tetrabutylammonium bromide (3.71 g, 11.51 mmol) in tetrahydrofuran (200 mL) and water (200 mL) was added bromoacetonitrile (16.56 g, 138.08 mmol, CAS: 590-17-0). The mixture was stirred at 45°C for 2 hours. The organic phase was separated, and the aqueous phase was extracted once with ethyl acetate (300 mL). The combined organic phases were washed three times with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound as a black solid (26.4 g, 95% yield).

[0235] Intermediate 23 Synthesis of methyl 6-amino-3-bromo-2-methoxybenzoate

[0236] 1) Synthesis of 5-methoxy-2H-benzo[d][1,3]oxazine-2,4(1H)-dione

[0237] To a solution of 2-amino-6-methoxybenzoic acid (22 g, 131.61 mmol, CAS: 53600-33-2) and sodium hydroxide (14.48 g, 361.93 mmol) in water (500 mL) was slowly added dropwise a solution of triphosgene (8.78 mL, 52.64 mmol, 6 M solution in toluene) in 125 mL at 0°C. The reaction mixture was heated to 25°C and stirred for 18 hours. The precipitated solid was collected by filtration, and the filter cake was washed once with water (100 mL) and dried to afford the title compound as a white solid (16.5 g, 65% yield). LC-MS: m / z [MH] - =192.

[0238] 2) Synthesis of 6-bromo-5-methoxy-2H-benzo[d][1,3]oxazine-2,4(1H)-dione

[0239] To a solution of 5-methoxy-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (16.5 g, 85.42 mmol) in N,N-dimethylformamide (60 mL) and dichloromethane (360 mL) was slowly added dropwise a solution of N-bromosuccinimide (16.72 g, 93.96 mmol) in N,N-dimethylformamide (60 mL) at 0°C. The reaction mixture was heated to 25°C and stirred for 18 hours. The dichloromethane solvent was removed by concentration under reduced pressure, and the residue was poured into water (150 mL). The precipitated solid was collected by filtration, and the filter cake was washed once with water (30 mL) and dried to give the title compound as a white solid (37 g crude product). LC-MS: m / z [MH] - =270 / 272.

[0240] 3) Synthesis of methyl 6-amino-3-bromo-2-methoxybenzoate

[0241] A solution of 6-bromo-5-methoxy-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (37.2 g, 136.74 mmol) in methanol (300 mL) was stirred at 70°C for 18 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 100:1 to 10:1) to afford the title compound as a white solid (5.69 g, 16% yield). LC-MS: m / z [M+H] + =260 / 262.

[0242] Intermediate 24 Synthesis of 6-amino-3-bromo-2-(trifluoromethyl)benzaldehyde

[0243] 1) Synthesis of (2-amino-6-(trifluoromethyl)phenyl)methanol

[0244] Dissolve 2-amino-6-(trifluoromethyl)benzoic acid (5 g, 24.4 mmol) in anhydrous tetrahydrofuran (60 mL). Add lithium aluminum hydride (0.93 g, 24.4 mmol) at 0°C under nitrogen. The mixture is allowed to react at 0°C for 4 hours. The reaction solution is quenched with sodium sulfate decahydrate and extracted three times with dichloromethane (50 mL). The organic phases are combined, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to afford the title compound as a white solid (2 g, 43% yield). LC-MS: m / z [M+H] + =192.

[0245] 2) Synthesis of 2-amino-6-(trifluoromethyl)benzaldehyde

[0246] Active manganese dioxide (4.5 g, 52.3 mmol) was added to a solution of (2-amino-6-(trifluoromethyl)phenyl)methanol (2 g, 10.5 mmol) in dichloromethane (60 mL). The mixture was stirred at 25°C overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a colorless, transparent oil (1.5 g, 76% yield). LC-MS: m / z [M+H] + =190.

[0247] 3) Synthesis of 6-amino-3-bromo-2-(trifluoromethyl)benzaldehyde

[0248] N-Bromosuccinimide (1.4 g, 7.9 mmol) was added to a solution of 2-amino-6-(trifluoromethyl)benzaldehyde (1.5 g, 7.9 mmol) in N,N-dimethylformamide (20 mL) at 0°C, and the mixture was stirred at 25°C overnight. The reaction mixture was poured into ice water (50 mL), and the precipitated solid was collected by filtration. The filter cake was washed three times with water (10 mL) and dried to give the title compound as a yellow solid (1.0 g, 47% yield). LC-MS: m / z [M+H] + =268 / 270.

[0249] Intermediate 27 Synthesis of 8-chloro-7-iodo-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0250] 1) Synthesis of 6-amino-2-chloro-3-iodobenzaldehyde

[0251] To a solution of 2-chloro-6-aminobenzaldehyde (10 g, 64.28 mmol, CAS: 35490-90-5) in acetic acid (80 mL) was added portionwise N-iodosuccinimide (14.46 g, 64.28 mmol, CAS: 516-12-1) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, the filter cake collected, and concentrated under reduced pressure to dryness to afford the title compound as a yellow solid (10.9 g, 60% yield). LC-MS: m / z [M+H] + =282 / 284.

[0252] 2. Synthesis of tert-Butyl (2-amino-5-chloro-6-iodoquinolin-3-yl)carbamate

[0253] To a solution of 6-amino-2-chloro-3-iodobenzaldehyde (10.9 g, 38.72 mmol) and N-bis(tert-butoxycarbonyl)-2-aminoacetonitrile (12.9 g, 50.34 mmol, Intermediate 22) in tetrahydrofuran (200 mL) was added a 1M solution of potassium tert-butoxide in tetrahydrofuran (50.34 mL, 50.34 mmol) at room temperature. The mixture was stirred at room temperature overnight under nitrogen. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (petroleum ether / ethyl acetate = 5:1 to 1:1) afforded the title compound as a yellow solid (1.7 g, 10% yield). LC-MS: m / z [M+H] + =420 / 422.

[0254] 3) Synthesis of 8-chloro-7-iodo-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0255] Potassium tert-butoxide (721.95 mg, 6.43 mmol) was added to a solution of tert-butyl (2-amino-5-chloro-6-iodoquinolin-3-yl)carbamate (900 mg, 2.14 mmol) in tetrahydrofuran (25 mL). The mixture was stirred at 60°C for 16 hours. The reaction mixture was adjusted to pH 6 with 1N hydrochloric acid, filtered, and the filter cake was washed three times with water (15 mL). The filter cake was collected and concentrated under reduced pressure to give the title compound as a yellow solid (569 mg, 77% yield). LC-MS: m / z [M+H] + =346.

[0256] Intermediate 29 Synthesis of 6-bromo-5-chloro-1,3-dihydro-2H-imidazo[4,5-b]quinoxalin-2-one

[0257] 1) Synthesis of 4-bromo-3-chlorobenzene-1,2-diamine

[0258] Iron powder (2.22 g, 39.77 mmol) was added to a solution of 3-bromo-2-chloro-6-nitroaniline (2000 mg, 7.95 mmol, CAS: 2091859-73-1) and ammonium chloride (4.25 g, 79.54 mmol) in ethanol (20 mL) and water (10 mL) at room temperature. The mixture was stirred at 80°C under nitrogen for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound as a yellow solid (1300 mg, 74% yield).

[0259] 2) Synthesis of 6-bromo-5-chloro-1,4-dihydroquinoxaline-2,3-dione

[0260] Under ice-cooling conditions, 4-bromo-3-chlorobenzene-1,2-diamine (700 mg, 3.18 mmol) and dimethyl oxalate (563 mg, 4.77 mmol) were slowly added to 4M hydrochloric acid (2 mL). The mixture was stirred at room temperature for 5 minutes and then stirred at 80°C under nitrogen for 16 hours. The reaction solution was cooled to room temperature, and the brown filter cake was filtered, washed three times with water (1 mL), and dried. The dried solid was slurried with ethyl acetate (1 mL), collected by filtration, and the filter cake was rinsed with ethyl acetate (0.5 mL) and dried to obtain the title compound as a brown solid (800 mg, 92% yield). LC-MS: m / z [M+H] + =275 / 277.

[0261] 3) Synthesis of 6-bromo-2,3,5-trichloroquinoxaline

[0262] A suspension of 6-bromo-5-chloro-1,4-dihydroquinoxaline-2,3-dione (750 mg, 2.72 mmol) in phosphorus oxychloride (120 mL) was stirred at 110°C overnight under nitrogen. The reaction mixture was concentrated under reduced pressure to afford the title compound as a brown solid (850 mg, 100% yield).

[0263] 4) Synthesis of 6-bromo-5-chloroquinoxaline-2,3-diamine

[0264] 6-Bromo-2,3,5-trichloroquinoxaline (800 mg, 2.56 mmol), aqueous ammonia (5 mL), and tetrahydrofuran (10 mL) were added to a sealed jar and the mixture was reacted at 80°C overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (50 mL). The mixture was washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (petroleum ether / ethyl acetate = 9:1 to 1:9) afforded the title compound as a brown solid (140 mg, 20% yield). LC-MS: m / z [M+H] + =273 / 275.

[0265] 5) Synthesis of 6-bromo-5-chloro-1,3-dihydro-2H-imidazo[4,5-b]quinoxalin-2-one

[0266] To a solution of 6-bromo-5-chloroquinoxaline-2,3-diamine (120 mg, 0.44 mmol) and N,N-diisopropylethylamine (0.29 mL, 1.76 mmol, d = 0.742 g / mL) in tetrahydrofuran (6 mL) was added N,N'-carbonyldiimidazole (143 mg, 0.88 mmol) at room temperature. The mixture was stirred at 60°C overnight under nitrogen. The reaction mixture was directly concentrated under reduced pressure and dissolved in N,N-dimethylformamide (3 mL), then slowly added dropwise to water (30 mL). The precipitated solid was collected by filtration and dried to afford the title compound as a brown solid (120 mg, 73% yield). 1 H NMR (400MHz, DMSO-d6) δ12.19(s,2H),7.83(d,J=8.9Hz,1H),7.72(d,J=8.9Hz,1H); LC-MS:m / z[M+H] + =299 / 301.

[0267] Intermediate 30 Synthesis of 1-(difluoromethyl)-4-iodo-3-(methoxy-d3)-1H-pyrazole

[0268] 1) Synthesis of 1-acetyl-1,2-dihydro-3H-pyrazol-3-one

[0269] To a solution of 1,2-dihydro-3H-pyrazol-3-one (5000 mg, 59.47 mmol, CAS: 137-45-1) in pyridine (35 mL) was slowly added acetic anhydride (5.85 mL, 62.44 mmol) at room temperature. The mixture was stirred at 90°C under nitrogen for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was slurried with methyl tert-butyl ether (40 mL) to afford the title compound as a white solid (6500 mg, 87% yield). LC-MS: m / z [M+H] + =127.

[0270] 2) Synthesis of 1-(3-(methoxy-d3)-1H-pyrazol-1-yl)ethan-1-one

[0271] To a solution of 1-acetyl-1,2-dihydro-3H-pyrazol-3-one (4500 mg, 35.68 mmol) and potassium carbonate (7397.11 mg, 53.52 mmol) in N,N-dimethylformamide (40 mL) was added deuterated iodomethane (3.33 mL, 53.52 mmol, d = 2.330 g / mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (400 mL) and washed once with water (150 mL) and once with saturated brine (150 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (petroleum ether / ethyl acetate = 50:1 to 10:1) afforded the title compound as a colorless oil (2900 mg, 57% yield). LC-MS: m / z [M+H] + =144.

[0272] 3) Synthesis of 3-(methoxy-d3)-1H-pyrazole

[0273] To a solution of potassium hydroxide (2841.56 mg, 50.64 mmol) in ethanol (30 mL) and water (15 mL) was slowly added 1-(3-(methoxy-d3)-1H-pyrazol-1-yl)ethan-1-one (2900 mg, 20.26 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction solution was directly concentrated, and the residue was dissolved in ethyl acetate (150 mL) and washed once with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound as a colorless liquid (2000 mg, 98% yield). LC-MS: m / z [M+H] + =102.

[0274] 4) Synthesis of 4-iodo-3-(methoxy-d3)-1H-pyrazole

[0275] To a solution of 3-(methoxy-d3)-1H-pyrazole (2000 mg, 19.78 mmol) in N,N-dimethylformamide (30 mL) was added portionwise N-iodosuccinimide (4449.96 mg, 19.78 mmol) at 0-10°C. The mixture was stirred at room temperature under nitrogen for 2 hours. The reaction mixture was poured into water (200 mL) and extracted three times with ethyl acetate (60 mL). The organic phases were combined and washed once with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (petroleum ether / ethyl acetate = 10:1 to 5:1) afforded the title compound as a colorless oil (3000 mg, 67% yield). LC-MS: m / z [M+H] + =228.

[0276] 5) Synthesis of 1-(difluoromethyl)-4-iodo-3-(methoxy-d3)-1H-pyrazole

[0277] Diethyl bromofluoromethylphosphonate (1450 mg, 5.43 mmol, CAS: 65094-22-6) was added to a mixture of 4-iodo-3-(methoxy-d3)-1H-pyrazole (1100 mg, 4.85 mmol), potassium hydroxide (800 mg, 14.26 mmol), water (10 mL), and acetonitrile (12 mL) at 0°C. The mixture was reacted at 60°C for 15 hours. The reaction mixture was cooled to room temperature and extracted three times with ethyl acetate (40 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (petroleum ether / dichloromethane = 3:1) afforded the title compound as a yellow viscous liquid (240 mg, 18.5% yield). LC-MS: m / z [M+H] + =278.

[0278] Example 1 8-Chloro-7-(p-tolyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0279] 7-Bromo-8-chloro-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (60 mg, 0.2 mmol, Intermediate 1), cesium carbonate (128 mg, 0.4 mmol), and 4-methylphenylboronic acid (22.4 mg, 0.2 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.5 mL). Dichloro[1,1'-bis(di-tert-butylphosphino)ferrocenepalladium(II)] (8 mg, 0.02 mmol, CAS: 95408-45-0) was added. The mixture was purged with nitrogen three times and stirred at 100°C under nitrogen for 12 hours. The reaction mixture was filtered through a pad of Celite, and the filter cake was washed with dichloromethane (10 mL x 3). The filtrate was concentrated under reduced pressure and purified by reverse phase chromatography (5%-95% acetonitrile and water) to afford the title compound as a white solid (15 mg, 24% yield). 1 H NMR (400MHz, DMSO-d6) δ11.76 (s, 1H), 11.25 (s, 1H), 7.84 (d, J = 8Hz, 1H), 7.82 (s, 1H), 7. 51(d,J=8Hz,1H),7.39(d,J=8Hz,2H),7.31(d,J=8Hz,2H),2.39(s,3H); LC-MS:m / z[M+H] + =310.

[0280] Example 2 5-Chloro-6-(p-tolyl)-1,3-dihydropyrrolo[2,3-b]quinolin-2-one

[0281] 1) Synthesis of 4-amino-2-chloro-4'-methyl-[1,1'-biphenyl]-3-carbaldehyde

[0282] 6-Amino-3-bromo-2-chlorobenzaldehyde (500 mg, 2.12 mmol, synthesized according to the method provided in WO2019167000A1), p-methylphenylboronic acid (288 mg, 2.12 mmol), and sodium carbonate (449 mg, 4.24 mmol) were dissolved in 1,4-dioxane (8 mL) and water (2 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (154 mg, 0.21 mmol) was added. The atmosphere was purged with nitrogen three times, and the reaction mixture was heated to 90°C overnight. The reaction mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted twice with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title compound as a yellow solid (250 mg, 48% yield). LC-MS: m / z [M+H] + =246.

[0283] 2) Synthesis of 3-((4-amino-2-chloro-4'-methyl-[1,1'-biphenyl]-3-yl)methylene)-1-(4-methoxybenzyl)pyrrolidine-2,5-dione

[0284] Dissolve diethyl (1-(4-methoxybenzyl)-2,5-dioxopyrrolidin-3-yl)phosphonate (652 mg, 1.84 mmol, Intermediate 2) in methanol (5 mL) and add sodium methoxide (151 mg, 2.76 mmol). The reaction mixture was stirred at room temperature for 30 minutes, followed by the addition of 4-amino-2-chloro-4'-methyl-[1,1'-biphenyl]-3-carbaldehyde (220 mg, 0.92 mmol). The mixture was heated to 50°C and stirred overnight. The reaction mixture was cooled to room temperature and used directly in the next step without post-treatment. LC-MS: m / z [M+H] + =447.

[0285] 3) Synthesis of 5-chloro-1-(4-methoxybenzyl)-6-(p-tolyl)-1,3-dihydro-2H-pyrrolo[2,3-b]quinolin-2-one

[0286] Acetic acid (5 mL) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated directly, and saturated sodium bicarbonate solution (20 mL) and ethyl acetate (20 mL) were added to the residue. The organic phase was separated, and the aqueous phase was extracted once with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The mixture was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain the title compound as a white solid (60 mg, 15% yield over two steps). LC-MS: m / z [M+H] + =429.

[0287] 4) Synthesis of 5-chloro-6-(p-tolyl)-1,3-dihydropyrrolo[2,3-b]quinolin-2-one

[0288] 5-Chloro-1-(4-methoxybenzyl)-6-(p-tolyl)-1,3-dihydro-2H-pyrrolo[2,3-b]quinolin-2-one (60 mg, 0.14 mmol) was dissolved in trifluoroacetic acid (5 mL), heated to 150°C in a microwave oven and stirred for 1 hour. The reaction solution was cooled to room temperature and directly concentrated, dissolved in dimethyl sulfoxide (2 mL), and purified by preparative liquid chromatography (formic acid system) to give the title compound as a yellow solid (9 mg, yield 21%). 1H NMR (400MHz, DMSO-d6) δ11.43(s,1H),8.36(s,1H),7.80(d,J=8.6Hz,1H),7.61(d,J=8.6Hz,1H), 7.40(d,J=8.0Hz,2H),7.31(d,J=8.0Hz,2H),3.77(d,J=1.6Hz,2H),2.39(s,3H); LC-MS:m / z[M+H] + =309.

[0289] Example 3 7-(2-chloro-4-fluorophenyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0290] 7-Bromo-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (300.00 mg, 1.14 mmol, intermediate 3), 2-chloro-4-fluorophenylboronic acid (495.2 mg, 2.8 mmol, CAS: 313545-72-1), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2- A mixture of 2-(2-(2-(2-(2-dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl)) (48.1 mg, 0.06 mmol, CAS: 1445085-55-1), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (54.2 mg, 0.11 mmol, CAS: 564483-18-7), and potassium carbonate (392 mg, 2.8 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3.2 mL) and water (0.8 mL). The atmosphere was purged with nitrogen three times, and the reaction mixture was stirred and heated at 85°C overnight under a nitrogen atmosphere. The reaction mixture was concentrated and purified by column chromatography (dichloromethane / methanol = 50:1) to afford a white powder (131 mg). The powder was then slurried with methyl tert-butyl ether (3 mL) to afford the title compound as a white solid (44 mg, 12% yield). 1 H NMR (400MHz, DMSO-d6) δ11.59(s,1H),11.11(s,1H),7.93(d,J=1.6Hz,1H),7.85(d,J=8.4Hz,1H),7.67(s, 1H), 7.60 (dd, J=8.8, 2.4Hz, 1H), 7.56 (dd, J=8.4, 2.0Hz, 2H), 7.35 (td, J=8.4, 2.4Hz, 1H); LC-MS: m / z[M+H] + =314.

[0291] Example 4 7-(4-Fluoro-2-methylphenyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0292] 7-Bromo-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (100 mg, 0.38 mmol, intermediate 3), 4-fluoro-2-methylphenylboronic acid (120 mg, 0.78 mmol, CAS: 139911-29-8), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (32 mg, 0.039 mmol, CAS: 95464-05-4) and cesium carbonate (390 mg, 1.2 mmol) were dissolved in a mixed solvent of 1,4-dioxane (2 mL) and water (0.4 mL). The atmosphere was replaced with nitrogen three times, and the reaction solution was heated and stirred at 95 ° C under a nitrogen atmosphere overnight. The reaction solution was cooled to room temperature, diluted with water (20 mL), extracted twice with ethyl acetate (20 mL), and the organic phases were combined, washed twice with water (30 mL) and twice with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by preparative liquid chromatography (formic acid system) gave the title compound as a white solid (25 mg, yield 22.5%). 1 H NMR(400MHz,DMSO-d6)δ11.54(s,1H),11.07(s,1H),7.87-7.77(m,2H),7.64(s,1H),7 .50-7.46(m,1H),7.35-7.31(m,1H),7.25-7.00(m,2H),2.28(s,3H); LC-MS:m / z[M+H] + =294.

[0293] Example 5 7-(4-Fluoro-2-(trifluoromethylphenyl))-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0294] 7-Bromo-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (150 mg, 0.57 mmol, intermediate 3), 4-fluoro-2-trifluoromethylphenylboronic acid (236 mg, 1.14 mmol, CAS: 182344-16-7), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (14.47 The following 2-(2-(2-(2-(2-dicyclohexylphosphino-2',4',6'-triisopropyl)biphenyl)-1,4-dioxane (2 mL, 0.017 mmol, CAS: 1445085-55-1), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (16.21 mg, 0.034 mmol, CAS: 564483-18-7), and potassium carbonate (157 mg, 1,14 mmol) were dissolved in a mixed solvent of 1,4-dioxane (2 mL) and water (0.5 mL). The atmosphere was purged with nitrogen three times, and the reaction mixture was heated and stirred at 80°C under a nitrogen atmosphere for 16 hours. The reaction mixture was directly concentrated and the resulting solid was purified by column chromatography (dichloromethane / methanol = 50:1 to 30:1). The resulting solid was then slurried with methanol (1 mL) to afford the title compound (74 mg, 37% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ11.60(s,1H),11.12(s,1H),7.85-7.81(m,2H),7.78-7.75 (m,1H),7.68-7.61(m,2H),7.58-7.54(m,1H),7.45-7.42(m,1H); LC-MS:m / z[M+H] + =348.

[0295] Example 6 7-(4-fluoro-2-methoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0296] 7-Bromo-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (150 mg, 0.57 mmol, intermediate 3), 4-fluoro-2-methoxyphenylboronic acid (193 mg, 1.14 mmol, CAS: 179899-07-1), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (41 mg, 0.05 mmol, CAS: 95464-05-4) and potassium carbonate (235 mg, 1.7 mmol) were dissolved in a mixed solvent of 1,4-dioxane (1.6 mL) and water (0.4 mL). The atmosphere was replaced with nitrogen three times and the reaction solution was heated and stirred at 90 °C under a nitrogen atmosphere overnight. The reaction solution was cooled to room temperature, diluted with water (30 mL), extracted twice with ethyl acetate (30 mL), and the organic phases were combined, washed twice with water (30 mL), and twice with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (dichloromethane / methanol = 10:1) to give the title compound as a white solid (50 mg, yield 28%). 1 H NMR (400MHz, DMSO-d6) δ11.52(s,1H),11.05(s,1H),7.92(s,1H),7.78(d,J=8.4Hz,1H),7.63–7.58(m, 2H), 7.41 (t, J=7.2Hz, 1H), 7.06 (d, J=10.8Hz, 1H), 6.89 (t, J=7.2Hz, 1H), 3.81 (s, 3H); LC-MS: m / z[M+H] + =310.

[0297] Example 7 7-(2-chloro-6-methoxypyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0298] 1) Synthesis of 7-(2-chloro-6-methoxypyridin-3-yl)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0299] 7-Bromo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (156 mg, 0.3 mmol, intermediate 4), 2-chloro-6-methoxypyridine-3-boronic acid (236 mg, 1.26 mmol, CAS: 1072946-25-8), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (40 mg, 0.055 mmol, CAS: 72287-26-4) and potassium carbonate (115 mg, 0.83 mmol) were dissolved in a mixed solvent of 1,4-dioxane (1 mL) and water (0.2 mL). The atmosphere was replaced with nitrogen three times, and the reaction solution was stirred at 90 ° C under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature and diluted with water (30 mL). The mixture was extracted twice with ethyl acetate (30 mL). The organic phases were combined and washed twice with water (30 mL) and saturated brine (30 mL). The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The title compound (172 mg, 98% yield) was isolated by column chromatography (petroleum ether / ethyl acetate = 5:1) to afford the title compound as a colorless, transparent liquid. LC-MS: m / z [MH] - =585.

[0300] 2) Synthesis of 7-(2-chloro-6-methoxypyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0301] 7-(2-chloro-6-methoxypyridin-3-yl)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (172 mg, 0.29 mmol) was dissolved in trifluoroacetic acid (3 mL), and the mixture was reacted at 90°C overnight. Water (5 mL) was added to the reaction solution to quench the mixture, which was then concentrated under reduced pressure. The resulting solid was separated by column chromatography (dichloromethane / methanol = 50:1 to 30:1) and slurried with methanol (1 mL) to afford the title compound as a white solid (33 mg, 34% yield). 1 H NMR (400MHz, DMSO-d6) δ11.59(s,1H),11.11(s,1H),7.95(d,J=2.0Hz,1H),7.89(d,J=8.4Hz,1H),7.85(d, J=8.4Hz,1H),7.66(s,1H),7.59(dd,J=8.8,2.0Hz,1H),6.99(d,J=8.4Hz,1H),3.93(s,3H); LC-MS: m / z[MH] - =325.

[0302] Example 8 7-(4-chloro-6-methoxypyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0303] 1) Synthesis of 7-(4-chloro-6-methoxypyridin-3-yl)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0304] 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (130 mg, 0.23 mmol, intermediate 5), 5-bromo-4-chloro-2-methoxypyridine (51 mg, 0.23 mmol, CAS: 851607-27-7), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (17 mg, 0.023 mmol, CAS: 72287-26-4) and potassium carbonate (78 mg, 0.56 mmol) were dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (0.6 mL). The atmosphere was replaced with nitrogen three times, and the reaction solution was stirred at 90°C overnight under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and diluted with water (20 mL). The mixture was extracted twice with ethyl acetate (20 mL). The organic phases were combined and washed twice with water (20 mL) and saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The title compound (59 mg, 44% yield) was isolated by column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain a white solid. LC-MS: m / z [M+H] + =587.

[0305] 2) Synthesis of 7-(4-chloro-6-methoxypyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0306] 7-(4-chloro-6-methoxypyridin-3-yl)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (49 mg, 0.08 mmol) was dissolved in trifluoroacetic acid (3.5 mL), and the mixture was reacted at 90°C overnight. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted twice with ethyl acetate (20 mL). The organic phases were combined, washed twice with water (20 mL), and twice with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The title compound (15 mg, 55% yield) was isolated by column chromatography (dichloromethane / methanol = 10:1) as a white solid. 1 H NMR(400MHz, DMSO-d6)δ11.60(s,1H),11.12(s,1H),8.30(d,J=7.2Hz,1H),7.99–7.83(m,2H), 7.69–7.55(m,1H),7.18(d,J=4.4Hz,1H),6.54(t,J=7.2Hz,1H),3.94(s,3H); LC-MS:m / z[M+H] + =327.

[0307] Example 9 7-(4-Fluorophenyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0308] 7-Bromo-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (100 mg, 0.38 mmol, intermediate 3), 4-fluorophenylboronic acid (110 mg, 0.71 mmol, CAS: 1765-93-1), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (32 mg, 0.039 mmol, CAS: 95464-05-4) and cesium carbonate (390 mg, 1.2 mmol) were dissolved in a mixed solvent of 1,4-dioxane (2 mL) and water (0.4 mL). The atmosphere was replaced with nitrogen three times and the reaction solution was heated at 95 °C with stirring overnight under a nitrogen atmosphere. The reaction solution was cooled to room temperature, diluted with water (20 mL), extracted twice with ethyl acetate (20 mL), and the organic phases were combined, washed twice with water (30 mL) and twice with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by preparative liquid chromatography (formic acid system) gave the title compound as a white solid (6 mg, yield 6%). 1H NMR (400MHz, DMSO-d6) δ11.55(s,1H),11.07(s,1H),8.18(s,1H),7.75(brs,4H),7.66(s,1H),7.34(brs,2H); LC-MS: m / z[M+H] + =280.

[0309] Example 10 7-(3-chloro-5-fluoropyridin-2-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0310] The title compound was synthesized in a similar manner to Example 8, substituting 2-bromo-3-chloro-5-fluoropyridine (CAS: 1214326-94-9) for 5-bromo-4-chloro-2-methoxypyridine (CAS: 851607-27-7). 1 H NMR (400MHz, DMSO-d6) δ11.62(s,1H),11.13(s,1H),8.74(d,J=2.4Hz,1H),8.26(dd,J=8.8,2.8Hz,1H), 8.20(d,J=2.0Hz,1H),7.87(d,J=8.4Hz,1H),7.78(dd,J=8.4,2.0Hz,1H),7.72(s,1H); LC-MS:m / z[M+H] + =315.

[0311] Example 11 7-(1-(Difluoromethyl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0312] The title compound was synthesized in a manner similar to Example 9, using (1-(difluoromethyl)-1H-pyrazol-4-yl)boric acid (CAS: 1312693-57-4) instead of 4-fluorophenylboric acid (CAS: 1765-93-1) and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (CAS: 95408-45-0) instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (CAS: 95464-05-4) as the catalyst. 1 H NMR (400MHz, DMSO-d6) δ11.56(s,1H),11.06(s,1H),8.78(s,1H),8.35(s,1H),8.21(d,J=2.0Hz,1H),8.04-7.72(m,3H),7.55(s,1H); LC-MS: m / z[M+H] + =302.

[0313] Example 12 7-(3-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0314] Example 13 7-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0315] The two title compounds were synthesized in a manner similar to Example 8 by replacing 5-bromo-4-chloro-2-methoxypyridine (CAS: 851607-27-7) with a mixture of 3-chloro-1-(difluoromethyl)-4-iodo-1H-pyrazole and 5-chloro-1-(difluoromethyl)-4-iodo-1H-pyrazole (Intermediate 6), and then purified by preparative high performance liquid chromatography (24% to 54% (v / v) acetonitrile and water, 0.1% formic acid). Example 12: 1 H NMR (400MHz, DMSO-d6) δ11.59(s,1H),11.13(s,1H),8.76(s,1H),8.16(d,J=2.0Hz,1H),8.02–7.70(m,3H),7.65(s,1H); LC-MS: m / z[M+H] + =336. Example 13: 1 H NMR (400MHz, DMSO-d6) δ11.52(s,1H),11.23(s,1H),8.37(s,1H),8.20(d,J=2.0Hz ,1H),8.18–7.83(m,2H),7.80(dd,J=8.4,2.0Hz,1H),7.65(s,1H); LC-MS:m / z[M+H] + =336.

[0316] Example 14 7-(2-chloro-4-cyanophenyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0317] The title compound was synthesized in a similar manner to Example 8, substituting 2-chloro-4-cyanophenylboronic acid (CAS: 677743-50-9) for 5-bromo-4-chloro-2-methoxypyridine (CAS: 851607-27-7). 1H NMR (400MHz, DMSO-d6) δ11.63(s,1H),11.16(s,1H),8.23(s,1H),8.10-7.80(m,3H),7.75-7.60(m,3H); LC-MS: m / z[MH] - =319.

[0318] Example 15 7-(4-chloro-1-(difluoromethyl)-1H-pyrazol-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0319] Example 16 7-(4-chloro-1-(difluoromethyl)-1H-pyrazol-5-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0320] The two title compounds were synthesized in a manner similar to Example 8 by replacing 5-bromo-4-chloro-2-methoxypyridine (CAS: 851607-27-7) with a mixture of 3-bromo-4-chloro-1-(difluoromethyl)-1H-pyrazole and 5-bromo-4-chloro-1-(difluoromethyl)-1H-pyrazole (Intermediate 7), and then purified by preparative high performance liquid chromatography (32% to 62% (v / v) acetonitrile and water, 10 mM ammonium bicarbonate). Example 15: 1 H NMR (400MHz, DMSO-d6) δ11.40 (s, 2H), 8.74 (s, 1H), 8.40 (d, J = 2.0Hz, 1H), 8.04-7.71 (m, 4H); LC-MS: m / z [M+H] + =336. Example 16: 1 H NMR (400MHz, DMSO-d6) δ11.71(s,1H),11.22(s,1H),8.13(s,1H),8.05(d,J=2.0Hz,1H),7.94(d,J=8.7Hz,1H),7.84–7.54(m,3H); LC-MS: m / z[M+H] + =336.

[0321] Example 17 7-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0322] The title compound was synthesized in a manner similar to Example 9 by replacing 4-fluorophenylboric acid (CAS: 1765-93-1) with (2-chloro-6-(trifluoromethyl)pyridin-3-yl)boric acid (CAS: 205240-63-7) and replacing [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (CAS: 95408-45-0) with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (CAS: 95464-05-4) as the catalyst. 1 H NMR(400MHz,DMSO-d6)δ11.66(s,1H),11.18(s,1H),8.27(d,J=7.8Hz,1H),8 .12–8.06(m,2H),7.90(d,J=8.6Hz,1H),7.71-7.65(m,2H); LC-MS:m / z[M+H] + =365.

[0323] Example 18 7-(2,6-dichloropyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0324] The title compound was synthesized in a similar manner to Example 8, substituting 3-bromo-2,6-dichloropyridine (CAS: 866755-20-6) for 5-bromo-4-chloro-2-methoxypyridine (CAS: 851607-27-7). 1 H NMR (400MHz, DMSO-d6) δ8.05(d,J=8.0Hz,1H),8.01(d,J=2.0Hz,1H),7.88(d,J=8.4Hz ,1H),7.71(d,J=8.0Hz,1H),7.67(s,1H),7.63(dd,J=8.8,2.0Hz,1H); LC-MS:m / z[M+H] + =331.

[0325] Example 19 7-(6-amino-2-chloropyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0326] The title compound was synthesized in a similar manner to Example 8, substituting 2-chloro-3-bromo-6-aminopyridine (CAS: 866755-20-6) for 5-bromo-4-chloro-2-methoxypyridine (CAS: 358672-65-8). 1H NMR (400MHz, DMSO-d6) δ11.27(s,2H),7.86(d,J=2.0Hz,1H),7.79(d,J=8.8Hz,1H), 7.63(s,1H),7.57–7.50(m,2H),6.53(d,J=8.0Hz,1H),6.49(s,2H); LC-MS:m / z[M+H] + =312.

[0327] Example 20 7-phenyl-1,3,5,6,7,8-hexahydro-2H-imidazo[4,5-b][1,6]naphthyridin-2-one

[0328] 1)N 2 ,N 3 ,N 3 Synthesis of tris(4-methoxybenzyl)-6-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2,3-diamine

[0329] N 2 ,N 3 ,N 3 -Tris(4-methoxybenzyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2,3-diamine (550 mg, 1.05 mmol, intermediate 8), bromobenzene (165.70 μL, 1.57 mmol, d = 1.491 g / mL) and cesium carbonate (683.11 mg, 2.10 mmol) were added to tert-butyl alcohol (30 mL), and then 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (146 The mixture was degassed, replaced with nitrogen three times, and stirred at 100°C under a nitrogen atmosphere for 18 hours. The reaction mixture was filtered through celite, and the filter cake was washed three times with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 10:1 to 2:1) to afford the title compound as a yellow solid (350 mg, 55% yield). LC-MS: m / z [M+H] + =601.

[0330] 2) Synthesis of 6-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2,3-diamine

[0331] To N2 ,N 3 ,N 3 To a solution of 1,3-tris(4-methoxybenzyl)-6-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2,3-diamine (350 mg, 0.58 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL, 26 mmol, d = 1.489 g / mL), and the mixture was stirred at 25°C for 18 hours. The reaction mixture was directly concentrated under reduced pressure and purified by preparative liquid chromatography to afford the title compound as a yellow solid (78 mg, 56% yield). LC-MS: m / z [M+H] + =241.

[0332] 3) Synthesis of 7-phenyl-1,3,5,6,7,8-hexahydro-2H-imidazo[4,5-b][1,6]naphthyridin-2-one

[0333] To a solution of 6-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2,3-diamine (58 mg, 0.24 mmol) and triethylamine (1.5 mL, 10.8 mmol, d = 0.728 g / mL) in N,N-dimethylformamide (3 mL) was added N,N'-carbonyldiimidazole (233.50 mg, 1.44 mmol). The mixture was stirred at 60°C for 18 hours. The reaction mixture was purified by preparative liquid chromatography to afford the title compound (20 mg, 31% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ11.14(s,1H),10.72(s,1H),7.22(s,2H),7.08(s,1H),7 .02(s,2H),6.75(s,1H),4.36(s,2H),3.59(s,2H),2.88(s,2H); LC-MS:m / z[M+H] + =267.

[0334] Example 21 7-(2-chloro-4-fluorophenyl)-1,3,5,6,7,8-hexahydro-2H-imidazo[4,5-b][1,6]naphthyridin-2-one

[0335] The title compound is prepared by replacing bromobenzene with 1-bromo-2-chloro-4-fluorobenzene (CAS: 110407-59-5), and the catalyst (methanesulfonic acid {biscyclohexyl (3-isopropoxy-2', 4', 6'-triisopropyl-[1,1'-biphenyl]-2-yl) phosphine} (2'-methylamino-1,1'-biphenyl-2-yl) palladium (II) (CAS: 2132978-44-8) is replaced by [ ... -biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (CAS: 1599466-85-9), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (CAS: 2118959-55-8) replaced 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (CAS: 787618-22-8), and were synthesized in a similar manner to Example 20. 1 H NMR (400MHz, DMSO-d6) δ11.14(s,1H),10.71(s,1H),7.45(dd,J=8.4,2.8Hz,1H),7.28(dd,J=9.2,5.6Hz,1H) ,7.23-7.18(m,1H),7.01(s,1H),4.14(s,2H),3.30(t,J=5.8Hz,2H),2.92(t,J=5.8Hz,2H); LC-MS:m / z[M+H] + =319.

[0336] Example 22 7-(2-chloro-4-cyanophenyl)-1,3,5,6,7,8-hexahydro-2H-imidazo[4,5-b][1,6]naphthyridin-2-one

[0337] 1)N 2 ,N 3 ,N 3 Synthesis of tris(4-methoxybenzyl)-6-(2-chloro-4-cyanophenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2,3-diamine

[0338] To N 2 ,N 3 ,N 3To a solution of 4-tris(4-methoxybenzyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2,3-diamine (400 mg, 0.76 mmol, Intermediate 8) in N,N-dimethylformamide (10 mL) were added 3-chloro-4-fluorobenzonitrile (160 mg, 1.02 mmol, CAS: 117482-84-5) and cesium carbonate (600 mg, 1.84 mmol). The mixture was purged with nitrogen three times and stirred at 100°C overnight under nitrogen. The reaction mixture was cooled to room temperature, poured into water (50 mL), and extracted three times with ethyl acetate (20 mL). The combined organic phases were washed three times with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (petroleum ether / ethyl acetate = 7:1 to 4:1) afforded the title compound as a yellow oil (100 mg, 20% yield). LC-MS: m / z[M+H] + =660.

[0339] 2) Synthesis of 6-(2-chloro-4-cyanophenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2,3-diamine

[0340] To N 2 ,N 3 ,N 3 To a solution of 1-tris(4-methoxybenzyl)-6-(2-chloro-4-cyanophenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2,3-diamine (100 mg, 0.15 mmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.5 mL, 6.5 mmol, d = 1.489 g / mL), and the mixture was stirred at room temperature for 3 hours. The reaction solution was directly concentrated under reduced pressure to obtain the title compound (40 mg crude product, which was used directly in the next reaction without further purification). LC-MS: m / z [M+H] + =300.

[0341] 3) Synthesis of 7-(2-chloro-4-cyanophenyl)-1,3,5,6,7,8-hexahydro-2H-imidazo[4,5-b][1,6]naphthyridin-2-one

[0342] To a solution of 6-(2-chloro-4-cyanophenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2,3-diamine (40 mg crude) and triethylamine (0.5 mL, 3.6 mmol, d = 0.728 g / mL) in N,N-dimethylformamide (2 mL) was added N,N'-disuccinimidyl carbonate (200 mg, 0.78 mmol, CAS: 74124-79-1), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water (10 mL) and extracted three times with ethyl acetate (5 mL). The combined organic phases were washed three times with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by preparative liquid chromatography afforded the title compound (6.6 mg, 13.5% yield over two steps) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.18(s,1H),10.74(s,1H),7.99(d,J=2.0Hz,1H),7.78(dd,J=8.4,2.0Hz,1H),7.3 1(d,J=8.4Hz,1H),7.05(s,1H),4.33(s,2H),3.52(t,J=6.0Hz,2H),2.95(t,J=5.8Hz,2H); LC-MS:m / z[M+H] + =326.

[0343] Example 23 7-(3-chloro-5-fluoropyridin-2-yl)-1,3,6,7,8-hexahydro-2H-imidazo[4,5-b][1,6]naphthypyridin-2-one

[0344] The title compound was synthesized in a similar manner to Example 20, substituting 2-bromo-3-chloro-5-fluoropyridine (CAS: 1214326-94-9) for bromobenzene. 1 H NMR (400MHz, DMSO-d6) δ11.14(s,1H),10.71(s,1H),8.30(d,J=2.8Hz,1H),8.05(dd,J=8.0,2.8 Hz,1H),7.07(s,1H),4.39(s,2H),3.55(t,J=5.6Hz,2H),2.96(t,J=5.6Hz,2H); LC-MS:m / z[M+H] + =320.

[0345] Example 24 8-Chloro-7-(5-fluoropyridin-2-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0346] 1) Synthesis of 8-chloro-7-(5-fluoropyridin-2-yl)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0347] 8-Chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (210 mg, 0.35 mmol, intermediate 9), 2-bromo-5-fluoropyridine (140 mg, 0.80 mmol, CAS: 41404-58-4), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (60 mg, 0.09 mmol, CAS: 95408-45-0) and cesium carbonate (310 mg, 0.95 mmol) were dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (0.5 mL). The atmosphere was replaced with nitrogen three times, and the reaction solution was stirred at 100°C under a nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature and diluted with water (20 mL). The mixture was extracted twice with ethyl acetate (20 mL). The organic phases were combined and washed twice with water (20 mL) and saturated brine (20 mL). The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The title compound (125 mg, 63% yield) was isolated by column chromatography (petroleum ether / ethyl acetate = 6:1) to obtain a white solid. LC-MS: m / z [M+H] + =575.

[0348] 2) Synthesis of 8-chloro-7-(5-fluoropyridin-2-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0349] 8-Chloro-7-(5-fluoropyridin-2-yl)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (100 mg, 0.17 mmol) was dissolved in trifluoroacetic acid (2 mL) and microwave-treated at 130°C for 1 hour. The reaction mixture was concentrated, and the residue was dissolved in dichloromethane (1 mL), methanol (2 mL), and aqueous ammonia (1 mL). The reaction mixture was reacted at 20°C for 1 hour. The reaction mixture was concentrated and purified by preparative liquid chromatography (acetonitrile and water containing 0.1% formic acid) to afford the title compound as a white solid (31.1 mg, 57% yield). 1H NMR (400MHz, DMSO-d6) δ11.82(s,1H),11.34(s,1H),8.74(d,J=2.8Hz,1H),7.93–7.80(m,4H),7.67(d,J=8.4Hz,1H); LC-MS: m / z[M+H] + =315.

[0350] Example 25 7-(2-chloro-4-methylphenyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0351] The title compound was synthesized in a similar manner to Example 9, substituting 2-chloro-4-methylphenylboronic acid (CAS: 145349-62-8) for 4-fluorophenylboronic acid (CAS: 1765-93-1). 1 H NMR (400MHz, DMSO-d6) δ11.56(s,1H),11.09(s,1H),7.91(d,J=2.0Hz,1H),7.83(d,J=8.6Hz,1H),7.66(s,1H),7. 56(dd,J=8.6,2.0Hz,1H),7.43(s,1H),7.39(d,J=7.8Hz,1H),7.27(d,J=7.8Hz,1H),2.38(s,3H); LC-MS:m / z[M+H] + =310.

[0352] Example 26 7-(2-aminopyridin-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0353] The title compound (formate salt) was synthesized in a manner similar to Example 9 by replacing 4-fluorophenylboronic acid (CAS: 1765-93-1) with 2-aminopyridine-4-boronic acid (CAS: 903513-62-2) and replacing [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (CAS: 95464-05-4) with the catalyst tris(dibenzylideneacetone)dipalladium (CAS: 51364-51-3) and the ligand 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (CAS: 97739-46-3). 1H NMR (400MHz, DMSO-d6) δ11.60(s,1H),11.12(s,1H),8.23–8.16(m,2H),8.00(d,J=5.4Hz,1H),7.86(d,J=8.7Hz,1H),7. 77(dd,J=8.7,2.1Hz,1H),7.70(s,1H),6.90(dd,J=5.4,1.6Hz,1H),6.81(d,J=1.7Hz,1H),6.00(s,2H); LC-MS: m / z[M+H] + =278.

[0354] Example 27 7-(2-chloro-6-(methoxy-d3)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0355] Example 28 7-(6-chloro-2-(methoxy-d3)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0356] The two title compounds were synthesized in a manner similar to Example 8 by replacing 5-bromo-4-chloro-2-methoxypyridine (CAS: 851607-27-7) with a mixture of 3-bromo-2-chloro-6-(methoxy-d3)pyridine and 3-bromo-6-chloro-2-(methoxy-d3)pyridine (Intermediate 10). The mixture was then purified by preparative high performance liquid chromatography (32% to 62% (v / v) acetonitrile and water, 10 mM ammonium bicarbonate). Example 27: 1 H NMR (400MHz, DMSO-d6) δ11.38(s,2H),8.05(d,J=2.0Hz,1H),7.90(d,J=7.6Hz,1H),7.82(d,J =8.4Hz,1H),7.70(dd,J=8.4,2.0Hz,1H),7.64(s,1H),7.23(d,J=7.6Hz,1H); LC-MS:m / z[M+H] + =330. Example 28: 1 H NMR (400MHz, DMSO-d6) δ11.54(s,1H),11.13(s,1H),7.94(d,J=2.0Hz,1H),7.89(d,J=8.0Hz,1H),7. 84(d,J=8.4Hz,1H),7.65(s,1H),7.58(dd,J=8.4,2.0Hz,1H),6.98(d,J=8.0Hz,1H); LC-MS:m / z[M+H] + =330.

[0357] Example 29 7-(1-(Trifluoromethyl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0358] The title compound was synthesized in a manner similar to Example 9 by replacing 4-fluorophenylboronic acid (CAS: 1765-93-1) with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)-1H-pyrazole (CAS: 1046831-98-4) and replacing [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (CAS: 95408-45-0) with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (CAS: 95464-05-4) as the catalyst. 1 H NMR(400MHz,DMSO-d6)δ11.56(s,1H),11.05(s,1H),9.04(s,1H),8.54(s,1H),8.26 (s,1H),7.89(d,J=8.0Hz,1H),7.82(d,J=8.4Hz,1H),7.53(s,1H); LC-MS:m / z[M+H] + =320.

[0359] Example 30 7-(1-(difluoromethyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0360] Example 31 7-(1-(difluoromethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0361] The two title compounds were synthesized in a similar manner to Example 8 by replacing 5-bromo-4-chloro-2-methoxypyridine (CAS: 851607-27-7) with a mixture of 1-(difluoromethyl)-4-iodo-5-(trifluoromethyl)-1H-pyrazole and 1-(difluoromethyl)-4-iodo-3-(trifluoromethyl)-1H-pyrazole (Intermediate 11), and finally purified by chiral column to obtain the respective compounds. Example 30: 1H NMR (400MHz, DMSO-d6) δ11.63(s,1H),11.14(s,1H),8.23(s,1H),8.14(t,J=57.6Hz,1H),7.98(d ,J=2.0Hz,1H),7.86(d,J=8.4Hz,1H),7.66(s,1H),7.53(dd,J=8.4,2.0Hz,1H); LC-MS:m / z[M+H] + =370. Example 31: 1 H NMR (400MHz, DMSO-d6) δ11.62(s,1H),11.13(s,1H),8.83(s,1H),8.21–7.78(m,3H),7.64(s,1H),7.57(dd,J=8.4,2.0Hz,1H); LC-MS:m / z[M+H] + =370.

[0362] Example 32 7-(5-bromo-1-(difluoromethyl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0363] Example 33 7-(3-Bromo-1-(difluoromethyl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0364] The two title compounds were synthesized in a similar manner to Example 8 by replacing 5-bromo-4-chloro-2-methoxypyridine (CAS: 851607-27-7) with a mixture of 5-bromo-1-(difluoromethyl)-4-iodo-1H-pyrazole and 3-bromo-1-(difluoromethyl)-4-iodo-1H-pyrazole (Intermediate 12), and finally purified by chiral column to obtain the respective compounds. Example 32: 1 H NMR (400MHz, DMSO-d6) δ11.60(s,1H),11.11(s,1H),8.28(s,1H),8.17–7.83(m,3H),7.77(dd,J=8.8,2.1Hz,1H),7.64(s,1H); LC-MS: m / z[M+H] + =380 / 382. Example 33: 1 H NMR (400MHz, DMSO-d6) δ11.59(s,1H),11.11(s,1H),8.66(s,1H),8.12(d,J=2.0Hz,1H),8.05–7.68(m,3H),7.64(s,1H); LC-MS: m / z[M+H] +=380 / 382.

[0365] Example 34 7-(4-chloro-3-(difluoromethyl)isoxazol-5-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0366] The title compound was synthesized in a similar manner to Example 8, substituting 5-bromo-4-chloro-3-(difluoromethyl)isoxazole (Intermediate 13) for 5-bromo-4-chloro-2-methoxypyridine (CAS: 851607-27-7). 1 H NMR (400MHz, DMSO-d6) δ11.79(s,1H),11.28(s,1H),8.61(d,J=2.1Hz,1H),8.07(dd,J=8. 8,2.1Hz,1H),7.98(d,J=8.8Hz,1H),7.84(s,1H),7.45(t,J=51.7Hz,1H); LC-MS:m / z[M+H] + =337.

[0367] Example 35 7-(2-chloro-6-(difluoromethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0368] The title compound was synthesized in a similar manner to Example 8, substituting 3-bromo-2-chloro-6-(difluoromethyl)pyridine (CAS: 1805221-46-8) for 5-bromo-4-chloro-2-methoxypyridine (CAS: 851607-27-7). 1 H NMR (400MHz, DMSO-d6) δ11.07(s,2H),8.18(d,J=7.6Hz,1H),8.05(s,1H),7.89(d,J=8.8Hz,1H) ,7.86(d,J=8.0Hz,1H),7.69(s,1H),7.66(dd,J=8.8,2.4Hz,1H),7.07(s,1H); LC-MS:m / z[M+H] + =347.

[0369] Example 36 7-(2-chloro-4-(difluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0370] The title compound was synthesized in a similar manner to Example 8, substituting 1-bromo-2-chloro-4-(difluoromethyl)benzene (Intermediate 19) for 5-bromo-4-chloro-2-methoxypyridine (CAS: 851607-27-7).1 H NMR (400MHz, DMSO-d6) δ11.31(s,2H),7.98(d,J=2.4Hz,1H),7.86(d,J=8.8Hz,1H),7.82(s, 1H),7.70–7.65(m,3H),7.60(dd,J=8.8,2.4Hz,1H),7.13(t,J=55.6Hz,1H); LC-MS:m / z[M+H] + =346.

[0371] Example 37 7-(5-chloro-1-(difluoromethyl)-1H-imidazol-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0372] Example 38 7-(4-chloro-1-(difluoromethyl)-1H-imidazol-5-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0373] The two title compounds were synthesized in a similar manner to Example 8 by replacing 5-bromo-4-chloro-2-methoxypyridine (CAS: 851607-27-7) with a mixture of 5-chloro-1-(difluoromethyl)-4-iodo-1H-imidazole and 4-chloro-1-(difluoromethyl)-5-iodo-1H-imidazole (Intermediate 14), and finally obtained by chiral column separation. Example 37: 1 H NMR (400MHz, DMSO-d6) δ11.55(s,1H),11.13(s,1H),8.42–8.37(m,2H),8.10–7.75(m,3H),7.71(s,1H); LC-MS: m / z[M+H] + =336. Example 38: 1 H NMR (400MHz, DMSO-d6) δ11.65(s,1H),11.18(s,1H),8.35(s,1H),8.01(d,J=2.0Hz,1H),7.90(d,J=8.4Hz,1H),7.85–7.52(m,3H); LC-MS: m / z[M+H] + =336.

[0374] Example 39 7-(6-chloro-2-(difluoromethoxy)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0375] The title compound was synthesized in a similar manner to Example 8, substituting 3-bromo-6-chloro-2-(difluoromethoxy)pyridine (Intermediate 15) for 5-bromo-4-chloro-2-methoxypyridine (CAS: 851607-27-7). 1 H NMR (400MHz, DMSO-d6) δ11.61(s,1H),11.12(s,1H),8.13(d,J=8.0Hz,1H),8.06(d,J=2.4Hz,1H),7.93–7.50(m,5H); LC-MS: m / z[M+H] + =363.

[0376] Example 40 7-(2-chloro-6-(methylamino)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0377] The title compound was synthesized in a similar manner to Example 8, substituting 5-bromo-6-chloro-N-methylpyridin-2-amine (Intermediate 16a) for 5-bromo-4-chloro-2-methoxypyridine (CAS: 851607-27-7). 1 H NMR (400MHz, DMSO-d6) δ11.49(s,1H),11.07(s,1H),7.86(d,J=2.0Hz,1H),7.79(d,J=8.8Hz,1H),7.63(s,1 H),7.58–7.51(m,2H),7.01(q,J=5.2Hz,1H),6.54(d,J=8.4Hz,1H),2.80(d,J=4.8Hz,3H); LC-MS:m / z[M+H] + =326.

[0378] Example 41 7-(6-chloro-2-(methylamino)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0379] The title compound was synthesized in a similar manner to Example 8 by replacing 5-bromo-4-chloro-2-methoxypyridine (CAS: 851607-27-7) with a mixture of 3-bromo-6-chloro-N-methylpyridin-2-amine (Intermediate 16b) and finally purified by column chromatography to obtain the respective products. 1H NMR (400MHz, DMSO-d6) δ11.04(s,2H),7.90(d,J=2.0Hz,1H),7.85(d,J=8.4Hz,1H),7.64(s,1H),7.49(dd,J=8.4,2. 0Hz,1H),7.35(d,J=7.6Hz,1H),6.66(d,J=7.6Hz,1H),6.23(d,J=4.8Hz,1H),2.76(d,J=4.8Hz,3H); LC-MS: m / z[M+H] + =326.

[0380] Example 42 7-(5-(difluoromethoxy)-1-(difluoromethyl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0381] The title compound was synthesized in a similar manner to Example 8, substituting 5-(difluoromethoxy)-1-(difluoromethyl)-4-iodo-1H-pyrazole (Intermediate 17a) for 5-bromo-4-chloro-2-methoxypyridine (CAS: 851607-27-7). 1 H NMR (400MHz, DMSO-d6) δ11.57(s,1H),11.09(s,1H),8.31(s,1H),8.11(d,J=2.0 Hz,1H),8.03–7.68(m,3H),7.60(s,1H),7.24(t,J=70.4Hz,1H); LC-MS:m / z[M+H] + =368.

[0382] Example 43 7-(3-(difluoromethoxy)-1-(difluoromethyl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0383] The title compound was synthesized in a similar manner to Example 8 by replacing 5-bromo-4-chloro-2-methoxypyridine (CAS: 851607-27-7) with a mixture of 3-(difluoromethoxy)-1-(difluoromethyl)-4-iodo-1H-pyrazole (Intermediate 17b), and finally purified by column chromatography to obtain the respective products. 1 H NMR (400MHz, DMSO-d6) δ11.57(s,1H),11.09(s,1H),8.74(s,1H),8.11(d,J=1.8Hz,1H),7.96–7.34(m,5H); LC-MS:m / z[M+H] + =368.

[0384] Example 44 7-(1-(Difluoromethyl)-5-methyl-1H-pyrazol-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0385] 1) Synthesis of 7-(1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0386] 7-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (250 mg, 0.42 mmol, prepared from 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (Intermediate 5) and 5-chloro-1-(difluoromethyl)-4-iodo-1H-pyrazol-4-yl)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (Intermediate 5) were added. Intermediate 6) was synthesized using a method similar to that of Example 8, step 1. Trimethylboroxane (0.14 mL, 0.50 mmol, 3.5 M solution in tetrahydrofuran, CAS: 823-96-1), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (27.07 mg, 0.04 mmol, CAS: 95408-45-0), and cesium carbonate (409.86 mg, 1.26 mmol) were dissolved in a mixed solvent of 1,4-dioxane (6 mL) and water (1.5 mL). The atmosphere was purged with nitrogen three times, and the reaction mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (15 mL), and extracted three times with ethyl acetate (3 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The title compound (167 mg, 69% yield) was isolated by column chromatography (petroleum ether / ethyl acetate = 5:1) as a yellow solid. LC-MS: m / z[M+H] + =576.

[0387] 2) Synthesis of 7-(1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0388] 7-(1-(Difluoromethyl)-5-methyl-1H-pyrazol-4-yl)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (167 mg, 0.29 mmol) was dissolved in trifluoroacetic acid (2 mL), followed by the addition of trifluoromethanesulfonic acid (30 μL, 0.34 mmol, d = 1.696 g / mL). The mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure, followed by the addition of 7M ammonia in methanol (5 mL) and dichloromethane (5 mL), and stirred at room temperature for 0.5 hour. The mixture was filtered, and the filter cake was washed with dichloromethane (5 mL). The filter cake was dissolved in N,N-dimethylformamide (5 mL), and the solution was added dropwise to water (25 mL). The precipitated solid was collected by filtration and dried to afford the title compound as a white solid (23 mg, 25% yield). 1 H NMR (400MHz, DMSO-d6) δ11.55(s,1H),11.09(s,1H),8.06–7.75(m,4H),7.66–7.60(m,2H),2.59(s,3H); LC-MS: m / z[M+H] + =316.

[0389] Example 45 7-(1-(difluoromethyl)-5-(methyl-d3)-1H-pyrazol-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0390] The title compound was synthesized in a similar manner to Example 44 by substituting (methyl-d3)boronic acid (Intermediate 18) for trimethylboroxine (CAS: 823-96-1). 1 H NMR(400MHz, DMSO-d6)δ11.25(s,2H),8.07–7.72(m,4H),7.65–7.58(m,2H); LC-MS:m / z[M+H] + =319.

[0391] Example 46 7-(2-chloro-4-(difluoromethyl)phenyl)-1,3,5,6,7,8-hexahydro-2H-imidazo[4,5-b][1,6]naphthyridin-2-one

[0392] The title compound was synthesized in a similar manner to Example 20, substituting 1-bromo-2-chloro-4-(difluoromethyl)benzene (Intermediate 19) for bromobenzene. 1H NMR (400MHz, DMSO-d6) δ11.15(s,1H),10.72(s,1H),7.65(s,1H),7.53(d,J=7.3Hz,1H),7.33(d,J=8.4 Hz,1H),7.18–6.78(m,2H),4.25(s,2H),3.43(t,J=5.7Hz,2H),2.94(t,J=6.0Hz,2H); LC-MS:m / z[M+H] + =351.

[0393] Example 47 7-(2,4-dichlorophenyl)-1,3,5,6,7,8-hexahydro-2H-imidazo[4,5-b][1,6]naphthyridin-2-one

[0394] The title compound was synthesized in a similar manner to Example 20, using 2,4-dichlorobromobenzene (CAS: 1193-72-2) instead of bromobenzene. 1 H NMR (400MHz, DMSO-d6) δ11.15(s,1H),10.72(s,1H),7.58(d,J=2.5Hz,1H),7.39(dd,J=8.7,2.5Hz,1H),7.2 3(d,J=8.7Hz,1H),7.02(s,1H),4.18(s,2H),3.36(d,J=5.7Hz,2H),2.92(t,J=5.7Hz,2H); LC-MS:m / z[M+H] + =335.

[0395] Example 48 7-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-1,3,5,6,7,8-hexahydro-2H-imidazo[4,5-b][1,6]naphthypyridin-2-one

[0396] The title compound was synthesized in a similar manner to Example 20, substituting 3-bromo-2-chloro-6-(trifluoromethyl)pyridine (CAS: 1159512-34-1) for bromobenzene. 1 H NMR (400MHz, DMSO-d6) δ11.18(s,1H),10.74(s,1H),7.89(d,J=8.2Hz,1H),7.75(d,J=7.9Hz, 1H),7.04(s,1H),4.35(s,2H),3.56(t,J=6.1Hz,2H),2.96(t,J=5.5Hz,2H); LC-MS:m / z[M+H] + =370.

[0397] Example 49 7-(3-Fluorophenyl)-1,3,5,6,7,8-hexahydro-2H-imidazo[4,5-b][1,6]naphthyridin-2-one

[0398] The title compound was synthesized in a similar manner to Example 20 by replacing bromobenzene with m-bromofluorobenzene (CAS: 1073-06-9). 1 H NMR (400MHz, DMSO-d6) δ11.15(s,1H),10.73(s,1H),7.22(dd,J=15.9,8.2Hz,1H),7.09(s,1H),6.81(t,J=9 .7Hz,2H),6.51(t,J=7.5Hz,1H),4.40(s,2H),3.62(t,J=5.8Hz,2H),2.88(t,J=5.6Hz,2H); LC-MS:m / z[M+H] + =285.

[0399] Example 50 7-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-1,3,5,6,7,8-hexahydro-2H-imidazo[4,5-b][1,6]naphthyridin-2-one

[0400] Example 51 7-(3-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-1,3,5,6,7,8-hexahydro-2H-imidazo[4,5-b][1,6]naphthyridin-2-one

[0401] The two title compounds were synthesized in a similar manner to Example 20 by replacing bromobenzene with a mixture of 3-chloro-1-(difluoromethyl)-4-iodo-1H-pyrazole and 5-chloro-1-(difluoromethyl)-4-iodo-1H-pyrazole (Intermediate 6), and purified by preparative high performance liquid chromatography (acetonitrile and water, 0.1% formic acid). Example 50: 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),10.71(s,1H),7.84(s,1H),7.82(t,J=57.2Hz,1H) ,6.99(s,1H),4.20(s,2H),3.39(t,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H); LC-MS:m / z[M+H] + =341. Example 51: 1H NMR (400MHz, DMSO-d6) δ10.92(s,1H),10.50(s,1H),7.96(s,1H),7.60(t,J=59.2Hz,1H) ,6.96(s,1H),4.14(s,2H),3.35(t,J=6.0Hz,2H),2.90(t,J=6.0Hz,2H); LC-MS:m / z[M+H] + =341.

[0402] Example 52 7-(2-Fluoro-4-cyanophenyl)-1,3,5,6,7,8-hexahydro-2H-imidazo[4,5-b][1,6]naphthyridin-2-one

[0403] The title compound was synthesized in a similar manner to Example 22, substituting 3,4-difluorobenzonitrile (CAS: 64248-62-0) for 3-chloro-4-fluorobenzonitrile (CAS: 117482-84-5). 1 H NMR (400MHz, DMSO-d6) δ11.17(s,1H),10.74(s,1H),7.73(dd,J=13.6,2.0Hz,1H),7.57(dd,J=8.4,2.0Hz,1H), 7.17(t,J=8.4Hz,1H),7.07(s,1H),4.42(s,2H),3.62(t,J=6.0Hz,2H),2.90(t,J=6.0Hz,2H); LC-MS:m / z[M+H] + =310.

[0404] Example 53 7-(3-Fluoro-4-cyanophenyl)-1,3,5,6,7,8-hexahydro-2H-imidazo[4,5-b][1,6]naphthyridin-2-one

[0405] The title compound was synthesized in a similar manner to Example 22, substituting 2,4-difluorobenzonitrile (CAS: 3939-09-1) for 3-chloro-4-fluorobenzonitrile (CAS: 117482-84-5). 1 H NMR (400MHz, DMSO-d6) δ11.19(s,1H),10.75(s,1H),7.62(t,J=8.8Hz,1H),7.09(s,1H),6.98(dd,J=14.0,2.4H z,1H),6.90(dd,J=9.2,2.4Hz,1H),4.57(s,2H),3.75(t,J=6.0Hz,2H),2.91(t,J=6.0Hz,2H); LC-MS:m / z[M+H] +=310.

[0406] Example 54 7-(2-chloro-4-(trifluoromethoxy)phenyl)-1,3,5,6,7,8-hexahydro-2H-imidazo[4,5-b][1,6]naphthyridin-2-one

[0407] Example 55 7-(3-(trifluoromethoxy)phenyl)-1,3,5,6,7,8-hexahydro-2H-imidazo[4,5-b][1,6]naphthyridin-2-one

[0408] The two title compounds were synthesized in a similar manner to Example 20 by replacing bromobenzene with 1-bromo-2-chloro-4-(trifluoromethoxy)benzene (CAS: 892845-59-9), wherein Example 55 was synthesized from a by-product produced during the preparation of Example 54. Example 54: 1 H NMR (400MHz, DMSO-d6) δ11.16(s,1H),10.72(s,1H),7.57(d,J=2.2Hz,1H),7.44–7.26(m,2 H),7.02(s,1H),4.20(s,2H),3.37(t,J=5.6Hz,2H),2.93(t,J=5.4Hz,2H); LC-MS:m / z[M+H] + =385. Example 55: 1 H NMR (400MHz, DMSO-d6) δ11.15(s,1H),10.72(s,1H),7.31(t,J=8.3Hz,1H),7.11(d,J=11.4Hz,1H),7.02(d,J=8.6Hz ,1H),6.91(s,1H),6.67(d,J=9.5Hz,1H),4.42(s,2H),3.65(t,J=5.9Hz,2H),2.89(t,J=5.3Hz,2H); LC-MS:m / z[M+H] + =351.

[0409] Example 56 7-(3-chloro-5-cyanopyridin-2-yl)-1,3,5,6,7,8-hexahydro-2H-imidazo[4,5-b][1,6]naphthyridin-2-one

[0410] The title compound was synthesized in a similar manner to Example 22, substituting 5,6-dichloronicotinonitrile (CAS: 65189-15-3) for 3-chloro-4-fluorobenzonitrile (CAS: 117482-84-5). 1H NMR (400MHz, DMSO-d6) δ11.17(s,1H),10.74(s,1H),8.62(d,J=2.0Hz,1H),8.32(d,J=2.0Hz, 1H),7.10(s,1H),4.67(s,2H),3.86(t,J=5.6Hz,2H),2.98(t,J=5.6Hz,2H); LC-MS:m / z[M+H] + =327.

[0411] Example 57 7-(4-Fluorophenyl)-1,3,5,6,7,8-hexahydro-2H-imidazo[4,5-b]quinolin-2-one

[0412] 1) Synthesis of 8-(4-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene

[0413] To a solution of p-fluoroiodobenzene (1.55 mL, 13.51 mmol, CAS: 352-34-1, d = 1.925 g / mL), 1,4-dioxa-spiro[4,5]dec-7-ene-8-boronic acid pinacol ester (3596.49 mg, 13.51 mmol, CAS: 680596-79-6) and cesium carbonate (8805.95 mg, 27.03 mmol) in dioxane (40 mL) and water (8 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (988.80 mg, 1.35 mmol, CAS: 72287-26-4) at room temperature, and the mixture was stirred at 80 °C overnight under nitrogen protection. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The mixture was separated and purified by column chromatography (petroleum ether / ethyl acetate = 50:1-10:1) to give the title compound (1900 mg, yield 60%) as a light yellow solid.

[0414] 2) Synthesis of 8-(4-fluorophenyl)-1,4-dioxaspiro[4.5]decane

[0415] To a solution of 8-(4-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene (4500 mg, 19.21 mmol) in tetrahydrofuran (100 mL) was added portionwise 10% palladium-on-carbon catalyst (0.98 g, CAS: 7440-05-3) at room temperature. The mixture was stirred at 35°C overnight under a hydrogen balloon atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to afford the title compound as a colorless oil (3800 mg crude product), which was used directly in the next reaction.

[0416] 3) Synthesis of 4-(4-fluorophenyl)cyclohexan-1-one

[0417] Trifluoroacetic acid (5 mL, 67.09 mmol, d = 1.489 g / mL) was added to a solution of 8-(4-fluorophenyl)-1,4-dioxaspiro[4.5]decane (3.8 g, 16.08 mmol) in dichloromethane (30 mL). The mixture was stirred at 25°C for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to afford the title compound as a pale yellow oil (3 g, 15.61 mmol, 97% yield).

[0418] 4) Synthesis of 2-((dimethylamino)methyl)-4-(4-fluorophenyl)cyclohexan-1-one

[0419] N,N-Dimethylchlorobenzeneimide (146.00 mg, 1.56 mmol, CAS: 30354-18-8) was added to a solution of 4-(4-fluorophenyl)cyclohexan-1-one (200 mg, 1.04 mmol) in acetonitrile (15 mL). The mixture was stirred at 70°C for 3 hours. The reaction solution was directly concentrated under reduced pressure to obtain the title compound as a yellow oil (260 mg crude product), which was used directly in the next reaction. LC-MS: m / z [M+H] + =250.

[0420] 5) Synthesis of 6-(4-fluorophenyl)-3-nitro-5,6,7,8-tetrahydroquinolin-2-amine

[0421] To a solution of 2-((dimethylamino)methyl)-4-(4-fluorophenyl)cyclohexan-1-one (260 mg, 1.04 mmol) in N,N-dimethylformamide (4 mL) at room temperature was added 2-nitroethylene-1,1-diamine (107.49 mg, 1.04 mmol, CAS: 71090-35-2). The mixture was stirred at 130°C for 4 hours. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted three times with ethyl acetate (5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 1:100) to afford the title compound (100 mg, 33% yield) as a yellow solid. LC-MS: m / z [M+H] + =288.

[0422] 6) Synthesis of 6-(4-fluorophenyl)-5,6,7,8-tetrahydroquinoline-2,3-diamine

[0423] To a solution of 6-(4-fluorophenyl)-3-nitro-5,6,7,8-tetrahydroquinolin-2-amine (80 mg, 0.28 mmol) in methanol (4 mL) was added portionwise 10% palladium-carbon catalyst (9 mg, CAS: 7440-05-3) at room temperature. The mixture was stirred at 25°C overnight under a hydrogen balloon atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to afford the title compound (65 mg crude product) as a yellow oil, which was used directly in the next reaction.

[0424] 7) Synthesis of 7-(4-fluorophenyl)-1,3,5,6,7,8-hexahydro-2H-imidazo[4,5-b]quinolin-2-one

[0425] To a solution of 6-(4-fluorophenyl)-5,6,7,8-tetrahydroquinoline-2,3-diamine (71.65 mg, 0.28 mmol) and N,N-diisopropylethylamine (138.43 μL, 0.84 mmol, d = 0.742 g / mL) in N,N-dimethylformamide (2 mL) was added N,N'-carbonyldiimidazole (135.46 mg, 0.84 mmol). The mixture was stirred at 60°C for 16 hours. The reaction solution was separated and purified by preparative HPLC (acetonitrile and water containing 0.1% formic acid) to afford the title compound as a pale yellow solid (23.3 mg, 29.5% yield). 1 H NMR(400MHz,DMSO-d6)δ11.05(s,1H),10.63(s,1H),7.40–7.32(m,2H),7.18–7 .09(m,2H),6.93(s,1H),3.01–2.79(m,5H),2.09–1.89(m,2H); LC-MS:m / z[M+H] + =284.

[0426] Example 58 7-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5,6,7,8-hexahydro-2H-imidazo[4,5-b][1,6]naphthyridin-2-one

[0427] The title compound was synthesized in a similar manner to Example 22, substituting 2-fluoro-6-(trifluoromethyl)pyridine (CAS: 94239-04-0) for 3-chloro-4-fluorobenzonitrile (CAS: 117482-84-5). 1H NMR (400MHz, DMSO-d6) δ11.17(s,1H),10.74(s,1H),7.78(t,J=8.0Hz,1H),7.19(d,J=8.8Hz,1H),7.12( s,1H),7.05(d,J=7.2Hz,1H),4.71(s,2H),3.93(t,J=6.0Hz,2H),2.90(t,J=6.0Hz,2H); LC-MS:m / z[M+H] + =336.

[0428] Example 59 7-(3-chlorophenyl)-1,3,5,6,7,8-hexahydro-2H-imidazo[4,5-b][1,6]naphthyridin-2-one

[0429] The title compound was synthesized in a similar manner to Example 20 by replacing bromobenzene with m-chlorobromobenzene (CAS: 108-37-2). 1 H NMR (400MHz, DMSO-d6) δ11.14(s,1H),10.71(s,1H),7.22(t,J=8.4Hz,1H),7.10(s,1H),7.04–6.94( m,2H),6.78–6.72(m,1H),4.40(s,2H),3.63(t,J=6.0Hz,2H),2.88(t,J=6.0Hz,2H); LC-MS:m / z[M+H] + =301.

[0430] Example 60 7-(3-Fluoro-6-(trifluoromethyl)pyridin-2-yl)-1,3,5,6,7,8-hexahydro-2H-imidazo[4,5-b][1,6]naphthyridin-2-one

[0431] The title compound was synthesized in a similar manner to Example 22, substituting 2-chloro-3-fluoro-6-(trifluoromethyl)pyridine (CAS: 1159512-39-6) for 3-chloro-4-fluorobenzonitrile (CAS: 117482-84-5). 1 H NMR (400MHz, DMSO-d6) δ11.16(s,1H),10.75(s,1H),7.75(dd,J=13.2,8.0Hz,1H),7.29(dd,J=8.0, 2.4Hz,1H),7.12(s,1H),4.68(s,2H),3.85(t,J=6.0Hz,2H),2.95(t,J=6.0Hz,2H); LC-MS:m / z[M+H] + =354.

[0432] Example 61 7-(5-fluoro-6-(trifluoromethyl)pyridin-2-yl)-1,3,5,6,7,8-hexahydro-2H-imidazo[4,5-b][1,6]naphthyridin-2-one

[0433] Example 62 7-(6-chloro-2-(trifluoromethyl)pyridin-3-yl)-1,3,5,6,7,8-hexahydro-2H-imidazo[4,5-b][1,6]naphthyridin-2-one

[0434] The two title compounds were synthesized in a similar manner to Example 22 by replacing 3-chloro-4-fluorobenzonitrile (CAS: 117482-84-5) with 6-chloro-3-fluoro-2-(trifluoromethyl)pyridine (CAS: 1227511-58-1). Example 62 was synthesized from a by-product produced during the preparation of Example 61. Example 61: 1 H NMR (400MHz, DMSO-d6) δ11.17(s,1H),10.73(s,1H),7.83(t,J=9.6Hz,1H),7.28(dd,J=9.2,2.4 Hz,1H),7.10(s,1H),4.67(s,2H),3.89(t,J=6.0Hz,2H),2.89(t,J=6.0Hz,2H); LC-MS:m / z[M+H] + =354. Example 62: 1 H NMR (400MHz, DMSO-d6) δ11.17(s,1H),10.72(s,1H),8.13(d,J=8.8Hz,1H),7.85(d,J=8.8Hz, 1H), 6.99 (s, 1H), 4.16 (s, 2H), 3.29 (t, J=6.0Hz, 2H), 2.90 (t, J=6.0Hz, 2H); LC-MS: m / z[M+H] + =370.

[0435] Example 63 7-(3-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-1,3,5,6,7,8-hexahydro-2H-imidazo[4,5-b]quinolin-2-one

[0436] Example 64 7-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-1,3,5,6,7,8-hexahydro-2H-imidazo[4,5-b]quinolin-2-one

[0437] The two title compounds were synthesized in a similar manner to Example 57 by replacing p-fluoroiodobenzene (CAS: 352-34-1) with a mixture of 3-chloro-1-(difluoromethyl)-4-iodo-1H-pyrazole and 5-chloro-1-(difluoromethyl)-4-iodo-1H-pyrazole (Intermediate 6), and then purified by column chromatography to obtain the respective compounds. Example 63: 1 H NMR (400MHz, DMSO-d6) δ11.06(s,1H),10.63(s,1H),8.18(s,1H),7.72(t,J=58.8Hz,1H),6.94(s,1H),3.01(dd ,J=14.8,3.8Hz,1H),2.94–2.76(m,4H),2.10(d,J=13.0Hz,1H),1.88(qd,J=11.0,5.6Hz,1H); LC-MS:m / z[M+H] + =340. Example 64: 1 H NMR (400MHz, DMSO-d6) δ11.06(s,1H),10.62(s,1H),8.06–7.72(m,2H),6.94(s,1H),2.99–2.76(m,5H),2.10–1.88(m,2H); LC-MS: m / z[M+H] + =340.

[0438] Example 64-A (*S)-7-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-1,3,5,6,7,8-hexahydro-2H-imidazo[4,5-b]quinolin-2-one

[0439] Example 64-B (*R)-7-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-1,3,5,6,7,8-hexahydro-2H-imidazo[4,5-b]quinolin-2-one

[0440] 223 mg of the racemic compound 7-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-1,3,5,6,7,8-hexahydro-2H-imidazo[4,5-b]quinolin-2-one (Example 64) was subjected to chiral resolution to give Example 64-A(*S)-7-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-1,3,5,6,7,8-hexahydro-2H-imidazo[4,5-b]quinolin-2-one (first eluting peak, RT = 2.496 minutes, tentatively designated as "S" ABS) (83.1 mg, % ee 100, white solid) and Example 64-B (*R)-7-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-1,3,5,6,7,8-hexahydro-2H-imidazo[4,5-b]quinolin-2-one (second eluting peak, RT = 2.887 minutes, tentatively designated as 'R'ABS) (66.2 mg, %ee100, white solid).

[0441] Analytical separation method:

[0442] Instrument: Waters UPC2 analytical SFC (SFC-H)

[0443] Column: ChiralPak IG, 100×4.6mm ID, 3μm

[0444] Mobile phase: A for CO2 and B for Ethanol (0.05% DEA)

[0445] Isocratic: B 50%

[0446] Flow rate: 2.0 mL / min

[0447] Column temperature: 35°C

[0448] Wavelength: 220nm

[0449] Chiral preparation method (Preparative separation method):

[0450] Instrument: WATERS 150 preparative SFC (SFC-26)

[0451] Column: ChiralPak IG, 250×30mm ID, 10μm

[0452] Mobile phase: A for CO2 and B for Ethanol (0.1% NH3.H2O)

[0453] Isocratic elution: B 40%

[0454] Flow rate: 120 mL / min

[0455] Back pressure: 100bar

[0456] Column temperature: 38°C

[0457] Wavelength: 220nm

[0458] Cycle time: ~3min

[0459] Example 64-A: 1 H NMR (400MHz, DMSO-d6) δ11.07(s,1H),10.63(s,1H),8.06–7.72(m,2H),6.94(s,1H),2.99–2.77(m,5H),2.10–1.88(m,2H); LC-MS: m / z[M+H] + =340.

[0460] Example 64-B: 1 H NMR (400MHz, DMSO-d6) δ11.07(s,1H),10.63(s,1H),8.06–7.74(m,2H),6.94(s,1H),3.00–2.76(m,5H),2.10–1.88(m,2H); LC-MS: m / z[M+H] + =340.

[0461] Example 65 8-Chloro-7-phenyl-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0462] 1) Synthesis of 8-chloro-7-phenyl-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0463] Under nitrogen atmosphere, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (50 mg, 0.06 mmol, CAS: 72287-26-4) was added to a mixture of 7-bromo-8-chloro-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (140 mg, 0.25 mmol, intermediate 1a), cesium carbonate (300 mg, 0.92 mmol), phenylboronic acid (40 mg, 0.33 mmol), water (0.5 mL) and 1,4-dioxane (2.5 mL), and the reaction mixture was reacted at 100°C for 3 hours. The reaction mixture was cooled to room temperature and diluted with water (20 mL). The mixture was extracted twice with ethyl acetate (20 mL). The organic phases were combined and washed twice with water (20 mL) and saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The title compound (110 mg, 79% yield) was isolated by column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain a yellow oil. LC-MS: m / z [M+H] + =556.

[0464] 2) Synthesis of 8-chloro-7-phenyl-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0465] 8-Chloro-7-phenyl-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (100 mg, 0.20 mmol) was dissolved in trifluoroacetic acid (2 mL) and microwave-treated at 130°C for 1 hour. The reaction mixture was concentrated, and the residue was dissolved in dichloromethane (1 mL), 7M ammonia in methanol (1 mL), and aqueous ammonia (1 mL). The reaction mixture was reacted at 20°C for 1 hour. The reaction mixture was concentrated and purified by preparative liquid chromatography (acetonitrile and water containing 0.1% ammonium bicarbonate) to afford the title compound as a white solid (7.5 mg, 13% yield). 1 H NMR (400MHz, DMSO-d6) δ11.49 (s, 2H), 7.85 (d, J = 8.7Hz, 1H), 7.82 (s, 1H), 7.57–7.47 (m, 5H), 7.47–7.39 (m, 1H); LC-MS: m / z [M+H] + =296.

[0466] Example 66 8-Chloro-7-(4-fluorophenyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0467] The title compound was synthesized in a similar manner to Example 65, substituting 4-fluorophenylboronic acid for phenylboronic acid. 1 H NMR (400MHz, DMSO-d6) δ11.78(s,1H),11.27(s,1H),7.85(d,J=8.6Hz,1H),7.82(s,1H),7.59–7.49(m,3H),7.33(t,J=8.9Hz,2H); LC-MS: m / z[M+H] + =314.

[0468] Example 67 8-chloro-7-(4-(difluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0469] The title compound was synthesized in a similar manner to Example 65, substituting 4-(difluoromethyl)phenylboronic acid (CAS: 946525-43-5) for phenylboronic acid. 1 H NMR (400MHz, DMSO-d6) δ11.84(s,1H),11.33(s,1H),7.88(d,J=8.6Hz,1H),7.83(s,1H),7.71(d,J =8.1Hz,2H),7.66(d,J=8.2Hz,2H),7.55(d,J=8.6Hz,1H),7.13(t,J=55.9Hz,1H); LC-MS:m / z[M+H] + =346.

[0470] Example 68 8-Fluoro-7-(p-tolyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0471] The title compound was synthesized in a similar manner to Example 65 by replacing 7-bromo-8-chloro-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (Intermediate 1a) with 7-bromo-8-fluoro-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (Intermediate 20). 1 H NMR (400MHz, DMSO-d6) δ11.72(s,1H),11.22(s,1H),7.71(d,J=8.8Hz,1H),7.66–7 .59(m,2H),7.58–7.51(m,2H),7.33(d,J=7.9Hz,2H),2.38(s,3H); LC-MS:m / z[M+H] + =294.

[0472] Example 69 6-Chloro-7-(p-tolyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0473] The title compound was synthesized in a similar manner to Example 65 by replacing 7-bromo-8-chloro-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (Intermediate 1a) with 7-bromo-6-chloro-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (Intermediate 21). 1 H NMR (400MHz, DMSO-d6) δ11.58(s,1H),11.21(s,1H),7.92(d,J=4.5Hz,2H),7.66( s,1H),7.39(d,J=7.8Hz,2H),7.30(d,J=7.9Hz,2H),2.38(s,3H); LC-MS:m / z[M+H] + =310.

[0474] Example 70 8-chloro-7-(5-methylpyridin-2-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0475] The title compound was synthesized in a similar manner to Example 65, substituting 5-methylpyridine-2-boronic acid (CAS: 372963-49-0) for phenylboronic acid. 1 H NMR (400MHz, DMSO-d6) δ11.24(s,2H),8.56(s,1H),7.87(d,J=8.8Hz,1H),7.8 4(s,1H),7.78–7.72(m,1H),7.70–7.62(m,2H),2.39(s,3H); LC-MS:m / z[M+H] + =311.

[0476] Example 71 8-Chloro-7-(5-fluoropyrimidin-2-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0477] The title compound was synthesized in a similar manner to Example 24, substituting 2-chloro-5-fluoropyrimidine (CAS: 62802-42-0) for 2-bromo-5-fluoropyridine (CAS: 41404-58-4). 1H NMR (400MHz, DMSO-d6) δ11.47(s,2H),9.10(s,2H),7.99–7.84(m,2H),7.79(d,J=8.7Hz,1H); LC-MS:m / z[M+H] + =316.

[0478] Example 72 8-chloro-7-(6-methoxypyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0479] The title compound was synthesized in a similar manner to Example 1, substituting 2-methoxy-5-pyridineboronic acid (CAS: 163105-89-3) for 4-methylphenylboronic acid. 1 H NMR(400MHz, DMSO-d6)δ11.55(br.s,2H),8.30(d,J=2.3Hz,1H),7.93–7.84(m,2H),7. 81(s,1H),7.56(d,J=8.6Hz,1H),6.96(d,J=8.6Hz,1H),3.92(s,3H); LC-MS:m / z[M+H] + =327.

[0480] Example 73 8-Chloro-7-(6-chloropyridazin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0481] The title compound was synthesized in a similar manner to Example 24, substituting 3-chloro-6-iodopyridazine (CAS: 135034-10-5) for 2-bromo-5-fluoropyridine (CAS: 41404-58-4). 1 H NMR (400MHz, DMSO-d6) δ11.50(br.s,2H),8.19(d,J=8.9Hz,1H),8.10(d,J=8.9Hz ,1H),7.96(d,J=8.5Hz,1H),7.86(s,1H),7.76(d,J=8.7Hz,1H); LC-MS:m / z[M+H] + =332.

[0482] Example 74 8-chloro-7-(5-(difluoromethyl)pyridin-2-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0483] The title compound was synthesized in a similar manner to Example 24, substituting 2-bromo-5-(difluoromethyl)pyridine (CAS: 1221272-81-6) for 2-bromo-5-fluoropyridine (CAS: 41404-58-4). 1 H NMR (400MHz, DMSO-d6) δ11.84(s,1H),11.30(s,1H),8.94(s,1H),8.16(d,J=7.9Hz,1H),7.91 (t,J=8.4Hz,2H),7.85(s,1H),7.71(d,J=8.6Hz,1H),7.26(t,J=55.3Hz,1H); LC-MS:m / z[M+H] + =347.

[0484] Example 75 8-chloro-7-(4-cyanophenyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0485] The title compound was synthesized in a similar manner to Example 24, substituting 4-iodocyanobenzene (CAS: 3058-39-7) for 2-bromo-5-fluoropyridine (CAS: 41404-58-4). 1 H NMR (400MHz, DMSO-d6) δ11.73(s,1H),11.37(s,1H),7.98(d,J=8.3Hz,2H),7.89(d,J= 8.8Hz,1H),7.82(s,1H),7.73(d,J=8.3Hz,2H),7.55(d,J=8.6Hz,1H); LC-MS:m / z[M+H] + =321.

[0486] Example 76 8-Chloro-7-(2-azaspiro[3.3]hept-2-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0487] 1) Synthesis of 8-chloro-7-(2-azaspiro[3.3]hept-2-yl)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0488] Under nitrogen atmosphere, a solution of 7-bromo-8-chloro-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (200 mg, 0.36 mmol, intermediate 1a), cesium carbonate (300 mg, 0.92 mmol) and 2-azaspiro[3.3]heptane hemioxalate (56 mg, 0.20 mmol, CAS: 1365639-13-9) in tert-butanol (5 mL) was added. 2-Dicyclohexylphosphino-2',6'-diisopropyloxy-1,1'-biphenyl (50 mg, 0.11 mmol, CAS: 787618-22-8) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (50 mg, 0.06 mmol, CAS: 1599466-85-9) were added, and the mixture was reacted at 90°C for 3 hours. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted twice with ethyl acetate (20 mL). The organic phases were combined, washed twice with water (20 mL), and twice with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (petroleum ether / ethyl acetate = 5:1) to afford the title compound (110 mg, 43% yield) as a white solid. LC-MS: m / z[M+H] + =575.

[0489] 2) Synthesis of 8-chloro-7-(2-azaspiro[3.3]hept-2-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0490] 8-Chloro-7-(2-azaspiro[3.3]hept-2-yl)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (100 mg, 0.17 mmol) was dissolved in trifluoroacetic acid (2 mL), trifluoromethanesulfonic acid (0.4 mL) was added, and the mixture was reacted at 20°C for 1 hour. The reaction mixture was concentrated directly, and the residue was dissolved in dichloromethane (2 mL), methanol solution (2 mL), and aqueous ammonia (1 mL), and the reaction mixture was reacted at 20°C for 1 hour. The reaction mixture was concentrated directly and purified by preparative liquid chromatography (acetonitrile and water containing 0.1% ammonium bicarbonate) to obtain the title compound as a white solid (14.2 mg, 26% yield). 1H NMR (400MHz, DMSO-d6) δ11.46(s,1H),11.05(s,1H),7.64(d,J=8.9Hz,1H),7.57(s,1H),6. 93(d,J=9.1Hz,1H),4.07(s,4H),2.19(t,J=7.6Hz,4H),1.89–1.78(m,2H); LC-MS:m / z[M+H] + =315.

[0491] Example 77 8-(Difluoromethoxy)-7-(4-fluorophenyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0492] 1) Synthesis of (6-amino-3-bromo-2-methoxyphenyl)methanol

[0493] To a solution of methyl 6-amino-3-bromo-2-methoxybenzoate (3.5 g, 13.46 mmol, Intermediate 23) in tetrahydrofuran (50 mL) was added lithium borohydride (0.59 g, 26.91 mmol). The reaction mixture was heated to 50°C and stirred for 3 hours. The reaction mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride (200 mL), and extracted three times with ethyl acetate (100 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (petroleum ether / ethyl acetate = 10:1 to 1:1) afforded the title compound as a yellow solid (3.1 g, 99% yield). LC-MS: m / z [M+H] + =232 / 234.

[0494] 2) Synthesis of 3-amino-6-bromo-2-(hydroxymethyl)phenol

[0495] To a solution of (6-amino-3-bromo-2-methoxyphenyl)methanol (2.79 g, 12.02 mmol) in dichloromethane (100 mL) was added anhydrous aluminum chloride (12.82 g, 96.17 mmol). The mixture was purged with nitrogen three times and stirred at 25°C under a nitrogen atmosphere for 18 hours. The reaction mixture was poured into saturated aqueous potassium tartrate (500 mL), stirred at room temperature for 2 hours, and extracted three times with ethyl acetate (300 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (dichloromethane / methanol = 100:1 to 20:1) afforded the title compound as a brownish-red solid (1585 mg, 60.5% yield). LC-MS: m / z [M+H] + =218 / 220.

[0496] 3) Synthesis of (6-amino-3-bromo-2-(difluoromethoxy)phenyl)methanol

[0497] To a mixture of 3-amino-6-bromo-2-(hydroxymethyl)phenol (1600 mg, 7.34 mmol) and potassium hydroxide (8234.44 mg, 146.76 mmol) in acetonitrile (40 mL) and water (40 mL) was added diethyl bromofluoromethylphosphonate (3918.51 mg, 14.68 mmol, CAS: 65094-22-6). The mixture was stirred at 60°C for 5 hours. The reaction mixture was poured into saturated brine (100 mL) and extracted three times with ethyl acetate (150 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (petroleum ether / ethyl acetate = 10:1 to 2:1) afforded the title compound as a yellow solid (520 mg, 26% yield). LC-MS: m / z [M+H] + =268 / 270.

[0498] 4) Synthesis of 6-amino-3-bromo-2-(difluoromethoxy)benzaldehyde

[0499] To a solution of (6-amino-3-bromo-2-(difluoromethoxy)phenyl)methanol (840 mg, 3.13 mmol) in dichloromethane (30 mL) was added activated manganese dioxide (1362.19 mg, 15.67 mmol). The reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was filtered through Celite, and the filter cake was washed three times with dichloromethane (30 mL). The filtrate was concentrated under reduced pressure to afford the title compound as a yellow solid (750 mg, 89.96%). LC-MS: m / z [M+H] + =266 / 268.

[0500] 5. Synthesis of tert-Butyl (2-amino-6-bromo-5-(difluoromethoxy)quinolin-3-yl)carbamate

[0501] To a solution of 6-amino-3-bromo-2-(difluoromethoxy)benzaldehyde (740 mg, 2.78 mmol) and N-bis(tert-butoxycarbonyl)-2-aminoacetonitrile (1425.82 mg, 5.56 mmol, Intermediate 22) in tetrahydrofuran (30 mL) was added dropwise a 1M solution of potassium tert-butoxide in tetrahydrofuran (5.56 mL, 5.56 mmol) at 0°C. The reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was poured into water (100 mL) and extracted three times with ethyl acetate (80 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (petroleum ether / ethyl acetate = 10:1 to 1:1) afforded the title compound as a yellow solid (145 mg, 13% yield). LC-MS: m / z [M+H] + =404 / 406.

[0502] Synthesis of tert-butyl (6) (2-amino-5-(difluoromethoxy)-6-(4-fluorophenyl)quinolin-3-yl)carbamate

[0503] tert-Butyl (2-amino-6-bromo-5-(difluoromethoxy)quinolin-3-yl)carbamate (125 mg, 0.31 mmol), 4-fluorophenylboronic acid (43.27 mg, 0.31 mmol), cesium carbonate (201.52 mg, 0.62 mmol), and [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (40.43 mg, 0.06 mmol, CAS: 95408-45-0) were added to a mixed solvent of 1,4-dioxane (5 mL) and water (0.5 mL). The atmosphere was replaced with nitrogen three times and stirred at 90°C under a nitrogen atmosphere for 18 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (petroleum ether / ethyl acetate = 10:1 to 1:1) afforded the title compound as a yellow solid (55 mg, 42% yield). LC-MS: m / z [M+H] + =420.

[0504] 7) Synthesis of 8-(difluoromethoxy)-7-(4-fluorophenyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0505] To tert-butyl (2-amino-5-(difluoromethoxy)-6-(4-fluorophenyl)quinolin-3-yl)carbamate (45 mg, 0.11 mmol) was added a 1 M solution of potassium tert-butoxide in tetrahydrofuran (321.89 μL, 0.32 mmol). The reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was purified by preparative liquid chromatography to afford the title compound as a white solid (12.8 mg, 34.6% yield). 1H NMR (400MHz, DMSO-d6) δ11.75 (s, 1H), 11.20 (s, 1H), 7.84 (d, J = 8.7Hz, 1H), 7.7 3–7.53(m,4H),7.33(t,J=8.9Hz,2H),6.72(t,J=73.5Hz,1H); LC-MS:m / z[M+H] + =346.

[0506] Example 78 8-(Methyloxy)-7-(4-fluorophenyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0507] The title compound was synthesized in a similar manner to Example 77 starting from methyl 6-amino-3-bromo-2-methoxybenzoate (Intermediate 23). 1 H NMR (400MHz, DMSO-d6) δ11.60(s,1H),11.08(s,1H),7.79–7.60(m,4H),7.51(d,J=8.4Hz,1H),7.35–7.30(m,2H),3.50(s,3H); LC-MS: m / z[M+H] + =310.

[0508] Example 79 7-(p-Tolyl)-8-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0509] The title compound was synthesized in a similar manner to Example 1 by replacing 7-bromo-8-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (Intermediate 1) with 7-bromo-8-chloro-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (Intermediate 25). 1 H NMR (400MHz, DMSO-d6) δ11.82(s,1H),11.20(s,1H),8.05(d,J=8.4Hz,1H),7.70(d,J =2.0Hz,1H),7.39(d,J=8.8Hz,1H),7.29–7.21(m,4H),2.38(s,3H); LC-MS:m / z[M+H] + =344.

[0510] Example 80 7-phenyl-8-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0511] The title compound was synthesized in a similar manner to Example 1 by replacing 7-bromo-8-chloro-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (Intermediate 1) with 7-bromo-8-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (Intermediate 25) and replacing 4-methylphenylboronic acid with phenylboronic acid. 1 H NMR (400MHz, DMSO-d6) δ11.83(s,1H),11.22(s,1H),8.07(d,J=8.4Hz,1H),7.71(d,J=2.0Hz,1H),7.50–7.33(m,6H); LC-MS:m / z[M+H] + =330.

[0512] Example 81 8-chloro-7-(6-azaspiro[2.5]octan-6-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0513] Example 82 8-chloro-7-(4-ethyl-3,6-dihydropyridin-1(2H)-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0514] The two title compounds were synthesized in a similar manner to Example 76 by replacing 2-azaspiro[3.3]heptane hemioxalate (CAS: 1365639-13-9) with 6-azaspiro[2.5]octane hydrochloride (CAS: 1037834-62-0). Example 82 is a by-product produced during the preparation of Example 81. Example 81: 1 H NMR (400MHz, DMSO-d6) δ11.60(s,1H),11.15(s,1H),7.76(d,J=9.0Hz,1H),7.71(s,1H), 7.49(d,J=9.0Hz,1H),3.06(t,J=5.3Hz,4H),1.54(s,4H),0.36(s,4H); LC-MS:m / z[M+H] + =329. Example 82: 1H NMR (400MHz, DMSO-d6) δ11.60(s,1H),11.15(s,1H),7.76(d,J=9.0Hz,1H),7.70(s,1H),7.49(d,J=9.1Hz,1H),5.52(dt,J=3.6,2.0Hz, 1H),3.66–3.54(m,2H),3.20(t,J=5.5Hz,2H),2.19(d,J=7.0Hz,2H),2.04(q,J=8.1,7.5Hz,2H),1.03(t,J=7.4Hz,3H); LC-MS:m / z[M+H] + =329.

[0515] Example 83 8-Chloro-7-(2-chloro-4-fluorophenyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0516] The title compound was synthesized in a similar manner to Example 1, substituting 2-chloro-4-fluorophenylboronic acid (CAS: 313545-72-1) for 4-methylphenylboronic acid. 1 H NMR (400MHz, DMSO-d6) δ11.70(s,1H),11.34(s,1H),7.86(d,J=8.7Hz,1H),7.78(s,1H),7.64(d ,J=8.8Hz,1H),7.53–7.47(m,1H),7.44(d,J=8.4Hz,1H),7.36(t,J=7.8Hz,1H); LC-MS:m / z[M+H] + =348.

[0517] Example 84 7-(4-Fluorophenyl)-8-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0518] The title compound was synthesized in a similar manner to Example 1, using 7-bromo-8-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (Intermediate 25) instead of 7-bromo-8-chloro-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (Intermediate 1) and 4-methylphenylboronic acid instead of p-fluorophenylboronic acid. 1 H NMR (400MHz, DMSO-d6) δ11.83(s,1H),11.22(s,1H),8.07(d,J=8.4Hz,1H),7.71(d,J=2.0Hz,1H),7.45–7.25(m,5H); LC-MS:m / z[M+H] + =348.

[0519] Example 85 7-(2-chloro-4-fluorophenyl)-8-methoxy-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0520] The title compound was synthesized in a similar manner to Example 77 starting from methyl 6-amino-3-bromo-2-methoxybenzoate (Intermediate 23) and replacing 4-fluorophenylboronic acid with 2-chloro-4-fluorophenylboronic acid (CAS: 313545-72-1). 1 H NMR (400MHz, DMSO-d6) δ11.65(s,1H),11.13(s,1H),7.69–7.59(m,3H),7.53(dd,J=8.6,6.3Hz,1H),7.40–7.26(m,2H),3.49(s,3H); LC-MS: m / z[M+H] + =344.

[0521] Example 86 8-chloro-7-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0522] Example 87 8-chloro-7-(3-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0523] The title compound was synthesized in a similar manner to Example 24 by replacing 2-bromo-5-fluoropyridine (CAS: 41404-58-4) with a mixture of 3-chloro-1-(difluoromethyl)-4-iodo-1H-pyrazole and 5-chloro-1-(difluoromethyl)-4-iodo-1H-pyrazole (Intermediate 6), and finally purified by chiral column to obtain the respective products. Example 86: 1 H NMR (400MHz, DMSO-d6) δ11.82(s,1H),11.31(s,1H),8.19(s,1H),8.04(t,J=56.8H z,1H),7.88(d,J=8.8Hz,1H),7.80(s,1H),7.58(d,J=8.8Hz,1H); LC-MS:m / z[M+H] + =370. Example 87: 1H NMR (400MHz, DMSO-d6) δ11.81(s,1H),11.31(s,1H),8.65(s,1H),8.07–7.68(m,3H),7.57(d,J=8.8Hz,1H); LC-MS:m / z[M+H] + =370.

[0524] Example 88 6-chloro-7-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0525] Example 89 6-chloro-7-(3-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0526] The title compound was prepared by replacing 8-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (Intermediate 26) with 6-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one. 1-(4-(2-(2-chloro-1-methyl)-2-thiazolyl)-1H-imidazo[4,5-b]quinolin-2-one (Intermediate 9), a mixture of 3-chloro-1-(difluoromethyl)-4-iodo-1H-pyrazole and 5-chloro-1-(difluoromethyl)-4-iodo-1H-pyrazole (Intermediate 6) was used to replace 2-bromo-5-fluoropyridine (CAS: 41404-58-4) and synthesized in a similar manner to Example 24. Finally, the products were purified by chiral column to obtain the following products: Example 88: 1 H NMR (400MHz, DMSO-d6) δ11.75(s,1H),11.21(s,1H),8.20–7.87(m,4H),7.68(s,1H); LC-MS:m / z[M+H] + =370. Example 89: 1 H NMR (400MHz, DMSO-d6) δ11.75(s,1H),11.21(s,1H),8.64(s,1H),8.05(s,1H),8.03–7.71(m,2H),7.68(s,1H); LC-MS: m / z[M+H] + =370.

[0527] Example 90 8-Chloro-7-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0528] 1) Synthesis of 8-chloro-7-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0529] Cuprous oxide (25.21 mg, 0.17 mmol) was added to a solution of 8-chloro-7-iodo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (351 mg, 0.58 mmol, Intermediate 28), 3-(trifluoromethyl)pyrazole (102.46 mg, 0.75 mmol, CAS: 20154-03-4), potassium phosphate (307.33 mg, 1.45 mmol) and N1,N2-bis(furan-2-ylmethyl)oxamide (43.13 mg, 0.17 mmol, CAS: 69010-90-8) in dimethyl sulfoxide (10 mL), and the mixture was replaced with nitrogen three times and stirred at 130°C for 18 hours. The reaction mixture was diluted with water (50 mL) and extracted three times with ethyl acetate (10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (petroleum ether / ethyl acetate = 3:1) to afford the title compound as a yellow solid (172 mg, 48% yield). LC-MS: m / z [M+H] + =614.

[0530] 2) Synthesis of 8-chloro-7-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0531] 8-Chloro-7-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (152 mg, 0.25 mmol) was dissolved in trifluoroacetic acid (1 mL), trifluoromethanesulfonic acid (0.1 mL) was added, and the mixture was reacted at room temperature for 1 hour. The reaction solution was directly concentrated, and the residue was dissolved in dichloromethane (10 mL) and aqueous ammonia (1 mL), and the mixture was stirred at room temperature for 0.5 hour. The reaction solution was directly concentrated and purified by preparative liquid chromatography (36% to 66% (v / v) acetonitrile and water with 0.1% formic acid) to obtain the title compound as a white solid (27.6 mg, 31.5% yield). 1 H NMR (400MHz, DMSO-d6) δ11.96(s,1H),11.42(s,1H),8.47(s,1H),7.95(d,J=8.8H z,1H),7.81(s,1H),7.73(d,J=8.8Hz,1H),7.07(d,J=2.4Hz,1H); LC-MS:m / z[M+H] + =354.

[0532] Example 91 7-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-1,3,5,6,7,8-hexahydro-2H-imidazo[4,5-b][1,6]naphthypyridin-2-one

[0533] The title compound was synthesized in a similar manner to Example 20, using 2-methoxy-3-(trifluoromethyl)-5-bromopyridine (CAS: 1214377-42-0) instead of bromobenzene. 1 H NMR (400MHz, DMSO-d6) δ11.16(s,1H),10.74(s,1H),8.17(d,J=2.6Hz,1H),7.79(d,J=2.8Hz,1H),7 .07(s,1H),4.37(s,2H),3.90(s,3H),3.59(t,J=5.9Hz,2H),2.89(t,J=5.7Hz,2H); LC-MS:m / z[M+H] + =366.

[0534] Example 92 5-Chloro-6-(p-tolyl)-1,3-dihydro-2H-imidazo[4,5-b]quinoxalin-2-one

[0535] The title compound was synthesized in a similar manner to Example 1 by replacing 7-bromo-8-chloro-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (Intermediate 1) with 6-bromo-5-chloro-1,3-dihydro-2H-imidazo[4,5-b]quinoxalin-2-one (Intermediate 29). 1 H NMR (400MHz, DMSO-d6) δ12.19(s,1H),12.08(s,1H),7.83(d,J=8.6Hz,1H),7.52(d,J= 8.5Hz, 1H), 7.41 (d, J=7.7Hz, 2H), 7.31 (d, J=7.7Hz, 2H), 2.39 (s, 3H); LC-MS: m / z[M+H] + =311.

[0536] Example 93 8-Chloro-7-(4-fluorophenyl)-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0537] 1) Synthesis of 8-chloro-7-(4-fluorophenyl)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0538] Under a nitrogen atmosphere, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (60 mg, 0.08 mmol, CAS: 72287-26-4) was added to a mixture of 7-bromo-8-chloro-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (150 mg, 0.27 mmol, Intermediate 1a), 4-fluorophenylboric acid (40 mg, 0.27 mmol), potassium carbonate (150 mg, 1.08 mmol), water (0.4 mL), and 1,4-dioxane (4 mL). The reaction mixture was reacted at 100°C for 3 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to afford the title compound as a white solid (110 mg, 71% yield). LC-MS: m / z[M+H] + =574.

[0539] 2) Synthesis of 8-chloro-7-(4-fluorophenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0540] 8-Chloro-7-(4-fluorophenyl)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (100 mg, 0.17 mmol) was added to a 1N tetrabutylammonium fluoride solution in tetrahydrofuran (2 mL), and the mixture was reacted at 80°C for 3 hours. The reaction mixture was directly concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound as a yellow solid (6 mg, 84% yield). LC-MS: m / z [M+H] + =444.

[0541] 3) Synthesis of 8-chloro-7-(4-fluorophenyl)-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0542] To a solution of 8-chloro-7-(4-fluorophenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (65 mg, 0.15 mmol) and sodium hydride (50 mg, 1.25 mmol, 60% w / w in mineral oil) in tetrahydrofuran (3 mL) was added iodomethane (50 mg, 0.35 mmol), and the mixture was reacted at 20°C for 2 hours. The reaction solution was slowly poured into saturated aqueous ammonium chloride (15 mL) and extracted twice with ethyl acetate (10 mL). The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 6:1) to afford the title compound (60 mg, 89% yield) as a yellow solid. LC-MS: m / z [M+H] + =458.

[0543] 4) Synthesis of 8-chloro-7-(4-fluorophenyl)-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0544] To a mixture of 8-chloro-7-(4-fluorophenyl)-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (60 mg, 0.13 mmol) and trifluoroacetic acid (2 mL) was added trifluoromethanesulfonic acid (0.3 mL), and the mixture was reacted at 20°C for 1 hour. The reaction solution was directly concentrated under reduced pressure, and then dichloromethane (1 mL), methanol (1 mL), and aqueous ammonia (1 mL, 25.96 mmol) were added, and the mixture was reacted at 20°C for 1 hour. The mixture was concentrated under reduced pressure and purified by preparative liquid chromatography (acetonitrile and water containing 0.1% ammonium bicarbonate) to afford the title compound as a white solid (1.3 mg, 3% yield). 1H NMR (400MHz, DMSO-d6) δ9.99 (s, 1H), 8.01 (s, 1H), 7.88 (d, J = 8.6Hz, 1H), 7.56 (dd,J=11.6,6.4Hz,3H),7.34(t,J=8.9Hz,2H),3.43(s,3H); LC-MS:m / z[M+H] + =328.

[0545] Example 94 8-chloro-7-(p-tolyl)oxazolo[4,5-b]quinolin-2(3H)-one

[0546] 1) Synthesis of 2-(4-methoxybenzyl)oxy)acetonitrile

[0547] To a solution of sodium hydroxide (1.88 g, 47.04 mmol, 60% dispersion in mineral oil) in tetrahydrofuran (60 mL) was added dropwise a solution of 4-methoxybenzyl alcohol (4.50 mL, 36.19 mmol, CAS: 105-13-5, d = 1.113 g / mL) in tetrahydrofuran (10 mL) at -78°C under nitrogen. The mixture was stirred at 0°C for 2 hours, followed by the addition of bromoacetonitrile (3.03 mL, 43.42 mmol, d = 1.722 g / mL) at 0°C. The reaction mixture was warmed to 25°C and stirred for 18 hours. Saturated aqueous ammonium chloride (50 mL) was added to the reaction mixture to quench the reaction. The mixture was filtered through celite, the filter cake was washed three times with ethyl acetate (30 mL), and the filtrate was extracted three times with ethyl acetate (30 mL). The organic phases were combined, washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10:1 to 4:1) to give the title compound (2.26 g, yield 35%) as a colorless transparent oil.

[0548] 2) Synthesis of 6-bromo-5-chloro-3-((4-methoxybenzyl)oxy)quinolin-2-amine

[0549] To a solution of 2-(4-methoxybenzyl)oxy)acetonitrile (997.54 mg, 5.63 mmol) and 6-amino-3-bromo-2-chlorobenzaldehyde (1200 mg, 5.12 mmol, synthesized according to the method provided in WO2019167000A1) in dimethyl sulfoxide (10 mL) was slowly added potassium tert-butoxide (861.39 mg, 7.68 mmol). The mixture was purged with nitrogen three times and stirred at 25°C under nitrogen protection for 18 hours. The reaction solution was poured into water (100 mL) and extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (petroleum ether / ethyl acetate = 10:1 to 1:1) gave the title compound as a yellow solid (380 mg, yield 19%). LC-MS: m / z[M+H] + =393 / 395.

[0550] 3) Synthesis of 5-chloro-3-((4-methoxybenzyl)oxy)-6-(p-tolyl)quinolin-2-amine

[0551] Under a nitrogen atmosphere, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (92.01 mg, 0.13 mmol, CAS: 72287-26-4) was added to a mixture of 6-bromo-5-chloro-3-((4-methoxybenzyl)oxy)quinolin-2-amine (330 mg, 0.84 mmol), 4-tolueneboronic acid (113.97 mg, 0.84 mmol), potassium carbonate (231.70 mg, 1.68 mmol), water (1 mL), and 1,4-dioxane (4 mL). The reaction mixture was stirred at 100°C for 18 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (petroleum ether / ethyl acetate = 10:1 to 1:1) afforded the title compound as a yellow solid (250 mg, 74% yield). LC-MS: m / z [M+H] + =405.

[0552] 4) Synthesis of 2-amino-5-chloro-6-(p-tolyl)quinolin-3-ol

[0553] To a solution of 5-chloro-3-((4-methoxybenzyl)oxy)-6-(p-tolyl)quinolin-2-amine (230 mg, 0.57 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1 mL), and the mixture was stirred at 25°C for 18 hours. The reaction solution was directly concentrated to give the title compound (340 mg crude product), which was used directly in the next reaction. LC-MS: m / z [M+H] + =285.

[0554] 5) Synthesis of 8-chloro-7-(p-tolyl)oxazolo[4,5-b]quinolin-2(3H)-one

[0555] To a solution of 2-amino-5-chloro-6-(p-tolyl)quinolin-3-ol (295 mg, 1.04 mmol) and N,N-diisopropylethylamine (0.86 mL, 5.18 mmol, d = 0.742 g / mL) in tetrahydrofuran (10 mL) was added N,N'-carbonyldiimidazole (503.98 mg, 3.11 mmol) at room temperature. The mixture was stirred at 70°C under nitrogen for 2 hours. The reaction solution was directly purified by preparative liquid chromatography (acetonitrile and water containing 0.1% formic acid) to afford the title compound as a white solid (41 mg, 13% yield). 1 H NMR (400MHz, DMSO-d6) δ12.89(s,1H),8.24(s,1H),7.89(d,J=8.6Hz,1H),7.62(d,J=8 .6Hz, 1H), 7.40 (d, J=8.0Hz, 2H), 7.32 (d, J=7.9Hz, 2H), 2.39 (s, 3H); LC-MS: m / z[M+H] + =311.

[0556] Example 95 5-Chloro-6-(p-tolyl)-1H-pyrrolo[2,3-b]quinoline-2,3-dione

[0557] 1) Synthesis of 5-chloro-1-(4-methoxybenzyl)-6-(p-tolyl)-1H-pyrrolo[2,3-b]quinoline-2,3-dione

[0558] To a solution of 5-chloro-1-(4-methoxybenzyl)-6-(p-tolyl)-1,3-dihydro-2H-pyrrolo[2,3-b]quinolin-2-one (110 mg, 0.26 mmol, the product from the third step in Preparation Example 2) in dimethyl sulfoxide (1 mL) was added N-bromosuccinimide (45.65 mg, 0.26 mmol) at room temperature. The mixture was stirred at 100°C overnight under nitrogen. The reaction mixture was filtered, and the filtrate was purified by C18 column chromatography to afford the title compound as a yellow solid (55 mg, 48% yield). LC-MS: m / z [M+H] + =443.

[0559] 2) Synthesis of 5-chloro-6-(p-tolyl)-1H-pyrrolo[2,3-b]quinoline-2,3-dione

[0560] To a solution of 5-chloro-1-(4-methoxybenzyl)-6-(p-tolyl)-1H-pyrrolo[2,3-b]quinoline-2,3-dione (55 mg, 0.12 mmol) in trifluoroacetic acid (2 mL) was added trifluoromethanesulfonic acid (0.11 mL) at room temperature, and the mixture was stirred at 80°C for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by C18 column chromatography to afford the title compound as a brown solid (4.9 mg, 12% yield). 1 H NMR (400MHz, DMSO-d6) δ12.04(s,1H),8.66(s,1H),7.88–7.76(m,2H),7.41(d,J=8.0Hz,2H),7.33(d,J=8.0Hz,2H),2.40(s,3H); LC-MS: m / z[M+H] + =323.

[0561] Example 96 7-(1-(difluoromethyl)-3-(methoxy-d3)-1H-pyrazol-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one

[0562] The title compound was synthesized in a similar manner to Example 8, substituting 1-(difluoromethyl)-4-iodo-3-(methoxy-d3)-1H-pyrazole (Intermediate 30) for 5-bromo-4-chloro-2-methoxypyridine (CAS: 851607-27-7). 1 H NMR (400MHz, DMSO-d6) δ11.51(s,1H),11.05(s,1H),8.57(s,1H),8.17(d,J=1.8Hz,1H),7.84–7.78(m,2H),7.78–7.51(m,2H); LC-MS: m / z[M+H] + =335.

[0563] Biological activity test examples

[0564] Experimental Example 1. SK-MEL-3 cell proliferation assay

[0565] 1. Experimental purpose: To detect the inhibitory activity of compounds on SK-MEL-3 cell proliferation.

[0566] 2. Experimental Materials:

[0567] 2.1 Drugs: (Promega; G7573); McCoy's 5A Medium (GIBCO; 16600-082); Fetal bovine serum (ExCell Bio; FND500) and Dimethyl sulfoxide (DMSO; Solarbio; D8371).

[0568] 2.2 Compounds: Compounds prepared in Examples of this application

[0569] 2.3 Experimental instruments / materials: 37°C incubator (Thermo; HERA cell vios 160i), clean bench (AIRTECH; VS-1300L-U), inverted microscope (OPTEC; BDS400); cell counter (Count star; IC1000); microplate reader (Molecular Devices; SpectraMax Paradigm); 96-well plate (Biosahrp; BS-MP-96W).

[0570] 3. Experimental Methods

[0571] SK-MEL-3 cells were purchased from Nanjing Kebai Biotechnology Co., Ltd. The cells were placed in McCoys-5A (Gibco) medium (containing 10% fetal bovine serum; ExCell bio) and supplemented with 1% penicillin and streptomycin and cultured in a cell culture incubator at 37°C, 5% CO2, and saturated humidity.

[0572] After the cells are fully grown, the cells are subcultured into 96-well plates (5000 cells / well). After overnight culture, the compounds are added to the cells at concentrations of 0.001nM, 0.005nM, 0.026nM, 0.128nM, 0.64nM, 3.2nM, 16nM, 80nM, 400nM and 2000nM. 0.1% DMSO and culture medium are set as solvents and negative controls, respectively. Each sample has two replicate wells. After the compounds are mixed, they are cultured in a 37°C, 5% CO2 incubator for 72h. After treatment, the 96-well plate is placed at room temperature for 30min, and 50μL of (Promega), and placed on an orbital shaker for 2 minutes, and then incubated at room temperature in the dark for 10 minutes. The 96-well plate was placed in a SpectraMax Paradigm (Molecular Devices) to measure the luminance signal value.

[0573] Cell activity inhibition rate (%) = 100-(RLUcompound-RLUblank) / (RLUcontrol-RLUblank)*100%, where Control represents the 0.1% DMSO-treated group and Blank represents the culture medium-treated group. The IC50 of the compound was calculated and the dose-effect curve was plotted using the nonlinear regression function "Dose-Response-Inhibition" in Graphpad Prism 7.0.

[0574] Experimental Example 2. A2058 cell proliferation assay

[0575] A2058 cells were purchased from Shanghai Fuheng Biotechnology. The cells were resuspended in RPMI160 medium + 10% fetal bovine serum (Giboco) and cultured in a cell culture incubator at 37°C, 5% CO2 and saturated humidity. When the growth density of A2058 cells reached 80%-90%, the cells were digested and counted. The counted cells were plated into a 96-well plate (2000 cells / well). After 24 hours of cell culture, compounds with concentrations of 2000nM, 400nM, 80nM, 16nM, 3.2nM, 0.64nM, 0.128nM, 0.0256nM and 0.00512nM were added. The final DMSO concentration was 0.2%. Each sample had 2 replicate wells. 0.2% DMSO and culture medium controls were set. The compounds were mixed and placed in a cell culture incubator for 96 hours. After compound treatment, 50μL of (Promega), vortexed for 2 minutes, and then incubated at room temperature in the dark for 10 minutes. Luminance signals in 96-well plates were measured using a SpectraMax Paradigm (Molecular Devices). Cell viability inhibition rate (%) = 100 - (RLUcompound - RLUblank) / (RLUcontrol - RLUblank) * 100%, where control represents the 0.2% DMSO-treated group and blank represents the culture medium.

[0576] Table 1: In vitro anti-proliferative IC values ​​of several examples in SK-MEL-3 cells and A2058 cells 50 value

[0577] Note: “-” means not determined.

[0578] Experimental Example 3. PDE3A enzyme activity inhibition experiment

[0579] The present invention uses isotope-labeled [3H]cAMP as a substrate to test the inhibitory activity (IC50) of compounds against PDE3A. A stock solution of tritiated cAMP substrate was diluted 100-fold with purified water to prepare a stock solution. The stock solution was then diluted with assay buffer (50 mM Tris-HCl, 10 mM MgCl2, 0.5 mM DTT, pH 8.0) to a cpm value of 20,000-30,000 on a liquid scintillation counter. 58 μL of the diluted substrate solution was added to a 1 mL EP tube. 2 μL of a series of compound solutions (50 μM, 12.5 μM, 3.125 μM, 781.25 nM, 195.31 nM, 48.83 nM, 12.21 nM, 3.05 nM, 0.76 nM, and 0.19 nM) were slowly added and mixed thoroughly. A control group was treated with 2 μL of 0.1% DMSO. Add 40 μL of PDE3A protein solution diluted to the appropriate concentration in assay buffer. Add 40 μL of assay buffer to the negative control group and incubate at room temperature for 15 minutes. Then, add 200 μL of 0.2 M ZnSO₄ and 200 μL of 0.2 M BaOH₂ solution sequentially to terminate the reaction. Vortex to mix thoroughly, and centrifuge for 5 minutes. Transfer 430 μL of the supernatant to a scintillation vial containing 2.5 mL of scintillation fluid, mix thoroughly, and measure the radioactivity in the supernatant using a liquid scintillation counter to determine enzyme activity. Enzyme activity inhibition (%) = 100 - (RLUcompound - RLUblank) / (RLUcontrol - RLUblank) * 100%, where control is the DMSO-treated group and blank is the negative control group. Compound IC₅₀ values ​​(IC₅₀) and dose-response curves were calculated using the "Dose-Response-Inhibition" function in Graphpad Prism 7.0, using nonlinear regression.

[0580] Table 2: PDE3A enzyme activity inhibition IC 50 value

[0581] It is to be understood that the above detailed description and accompanying examples are merely exemplary and should not be considered to limit the scope of the present application, which is defined only by the appended claims and their equivalents. It will be readily apparent to those skilled in the art that various changes and modifications to the disclosed embodiments may be made. Such changes and modifications may be made without departing from the spirit and scope thereof, including but not limited to those related to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and / or methods of use of the present application. All publications, patents and patent applications cited herein are incorporated herein by reference in their entirety for various purposes. These publications are provided only because they are disclosed prior to the filing date of the present application. All statements regarding the dates of these documents or the representations of the contents of these documents are based on information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Moreover, any reference to these publications herein does not constitute an admission that the publications are part of the common general knowledge in the art in any country.

Claims

1. A compound of formula (I), a pharmaceutically acceptable salt thereof, a deuterated substance thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof: in, Z is selected from CR1 or N; W is selected from C=O, CR2R7, NR3 or O; R1 is selected from H, halogen, hydroxy, cyano, alkynyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; R2 and R7 are each independently selected from H, a deuterium atom, a C1-C3 alkyl group or a C1-C3 haloalkyl group; or, R2 and R7 together with the connected carbon atom form a C3-C6 cycloalkyl group; R3 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl; n is selected from any integer between 0 and 6; R a Each independently selected from H, halogen, cyano, alkynyl, optionally substituted C1-C6 alkoxy, C1-C6 haloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C9 cycloalkyl, optionally substituted C4-C9 cycloalkenyl, or optionally substituted 3-10 membered heterocyclyl; Ring A is selected from C6-C 10 Aryl, 5-10 membered heteroaryl, C4-C 10 carbocyclic group or 4-10 membered heterocyclic group.

2. The compound according to claim 1, its pharmaceutically acceptable salt, its deuterated form, its stereoisomer, its tautomer or a mixture thereof, wherein: The R a Each independently selected from H, halogen, cyano, optionally substituted C1-C3 alkoxy, C1-C3 haloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C3-C6 cycloalkyl or optionally substituted 3- to 10-membered heterocyclyl.

3. The compound according to claim 1 or 2, its pharmaceutically acceptable salt, its deuterated product, its stereoisomer, its tautomer or a mixture thereof, wherein: Ring A is selected from a benzene ring, a C4-C6 carbocyclic group or a 5-6 membered heterocyclic group; Preferably, the ring A is selected from wherein k is selected from 1 or 2.

4. The compound according to any one of claims 1 to 3, its pharmaceutically acceptable salt, its deuterated product, its stereoisomer, its tautomer or a mixture thereof, wherein: The compound has a structure represented by formula (II), formula (II') or formula (II"): in, p is selected from 0, 1, 2 or 3; R1 is selected from H, halogen, hydroxy, cyano, alkynyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; R3 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl; R4 and R5 are each independently selected from H, halogen, cyano, alkynyl, optionally substituted C1-C3 alkoxy, C1-C3 haloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl, optionally substituted C4-C6 cycloalkenyl, optionally substituted 3-10 membered heterocyclyl; Indicates a single bond or a double bond.

5. The compound according to claim 4, its pharmaceutically acceptable salt, its deuterated form, its stereoisomer, its tautomer or a mixture thereof, wherein: Each R4 is independently selected from H, halogen, cyano, C1-C3 haloalkyl or optionally substituted C1-C3 alkoxy; R5 is selected from optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, cyano, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 10-membered heterocyclyl.

6. The compound according to claim 5, its pharmaceutically acceptable salt, its deuterated product, its stereoisomer, its tautomer or a mixture thereof, wherein: R5 is selected from cyano, wherein m is selected from 0, 1, 2 or 3; R6 is each independently selected from H, C1-C3 alkyl, C1-C3 haloalkyl, halogen, cyano, amino or optionally substituted C1-C3 alkoxy; the optionally substituted C1-C3 alkoxy is selected from -OCH3, -OCD3, -OCHD2, -OCH2D, ethoxy, -OCH2F, -OCHF2, -OCF3 or -OCH2CF3.

7. The compound according to claim 1, its pharmaceutically acceptable salt, its deuterated form, its stereoisomer, its tautomer or a mixture thereof, wherein: n is selected from any integer between 1 and 5, R a Each independently selected from halogen, optionally substituted C1-C6 alkoxy, C1-C6 haloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl or optionally substituted 3-10 membered heterocyclyl, the optionally substituted C1-C6 alkoxy, aryl, heteroaryl or heterocyclyl being unsubstituted or substituted by one or more independently selected from deuterium, halogen, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, hydroxyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, C6-C 10 substituted by aryl, 5-10 membered heteroaryl, or C1-C6 hydroxyalkyl; Preferably, n is selected from any integer between 1 and 3, R a Each independently selected from halogen, optionally substituted C1-C6 alkoxy, C1-C6 haloalkyl, optionally substituted C6-C 10 aryl, optionally substituted 5-10 membered heteroaryl or optionally substituted 3-10 membered heterocyclyl, the optionally substituted C1-C6 alkoxy is unsubstituted or substituted by halogen, the optionally substituted aryl, heteroaryl or heterocyclyl is unsubstituted or substituted by one or more substituents independently selected from halogen, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino; More preferably, n is 1 or 2, R a each independently selected from F, Cl, Br, optionally substituted C1-C5 alkoxy, C1-C5 haloalkyl, optionally substituted C6 aryl, optionally substituted 5-6 membered heteroaryl or optionally substituted 6-8 membered heterocyclyl, the optionally substituted C1-C6 alkoxy is unsubstituted or substituted by F, Cl, Br, the optionally substituted aryl, heteroaryl or heterocyclyl is unsubstituted or substituted by one or more substituents independently selected from F, Cl, Br, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 alkylamino.

8. The compound according to claim 1 or 7, its pharmaceutically acceptable salt, its deuterated product, its stereoisomer, its tautomer or a mixture thereof, wherein: Ring A is selected from C6-C 10 Aryl, 6-10 membered heteroaryl, C5-C8 carbocyclyl or 5-8 membered heterocyclyl; Preferably, ring A is selected from C6 aryl, 6-8 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, C5-C7 carbocyclic group or 5-7 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S.

9. The compound according to any one of claims 1 and 7-8, its pharmaceutically acceptable salt, its deuterated product, its stereoisomer, its tautomer or a mixture thereof, wherein: Z is selected from CR1 or N, R1 is selected from H, halogen, hydroxy or C1-C3 alkyl; Preferably, Z is selected from CH or N.

10. The compound according to any one of claims 1 and 7 to 9, its pharmaceutically acceptable salt, its deuterated product, its stereoisomer, its tautomer or a mixture thereof, wherein: W is selected from C=O, CR2R7, NR3 or O, R2 and R7 are each independently selected from H, a deuterium atom or a C1-C3 alkyl group, and R3 is selected from H, a C1-C6 alkyl group or a C1-C6 haloalkyl group; Preferably, W is selected from C=O, CH2, NR3 or O, and R3 is selected from H or C1-C6 alkyl.

11. [Corrected 30.01.2024 in accordance with Rule 26] The compound according to claim 1, its pharmaceutically acceptable salt, its deuterated form, its stereoisomer, its tautomer or a mixture thereof, wherein: The compound has a structure shown in formula (IV): wherein X is selected from C, CH or N; R a are independently selected from halogen, substituted or unsubstituted C1-C6 alkoxy, C1-C6 haloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-8 membered heteroaryl, substituted or unsubstituted 5-10 membered heterocyclic group, the C1-C6 alkoxy group may be substituted with halogen, the aryl, heteroaryl or heterocyclic group may be substituted with one or more substituents independently selected from deuterium, halogen, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, and the heteroaryl or heterocyclic group contains 1-3 heteroatoms selected from N, O or S; Z is selected from CH or N, W is selected from C=O, CH2, NR3 or O, R3 is selected from H or C1-C6 alkyl; Indicates a single bond or a double bond; --- indicates the presence or absence of the bond.

12. The compound according to claim 11, its pharmaceutically acceptable salt, its deuterated product, its stereoisomer, its tautomer or a mixture thereof, wherein: The compound has the structure shown in formula (IV-1): X is C or CH; R a is selected from substituted or unsubstituted C6 aryl, substituted or unsubstituted 5-6 membered heteroaryl, wherein the aryl or heteroaryl may be substituted by 1-3 substituents independently selected from F, Cl, Br, C1-C6 alkyl, C1-C6 haloalkyl, and the heteroaryl or heterocyclic group contains 1-3 heteroatoms selected from N, O or S; Z is CH, W is NH; Indicates a single bond or a double bond; --- indicates the presence or absence of the bond.

13. The compound according to any one of claims 1 to 11, its pharmaceutically acceptable salt, its deuterated form, its stereoisomer, its tautomer or a mixture thereof, wherein: The compound is selected from:

14. A compound according to any one of claims 1 to 13, a pharmaceutically acceptable salt thereof, a deuterated substance thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof for use as a drug for regulating the interaction between PDE3A and SLFN12; preferably, the drug can enhance and / or promote the interaction between PDE3A and SLFN12.

15. A compound according to any one of claims 1 to 13, a pharmaceutically acceptable salt thereof, a deuterated substance thereof, a stereoisomer thereof, a tautomer thereof or a mixture thereof for use in treating and / or preventing a disease, wherein the disease is a hyperproliferative disease, preferably, the hyperproliferative disease is a cancer disease, more preferably, the cancer disease is brain cancer, breast cancer, cervical cancer, AML, lung cancer, skin cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer and sarcoma.

Images