Pyridino-pyridone MAT2A inhibitor as well as pharmaceutical composition and medical application thereof

Abstract

The invention provides a compound as shown in a formula I and an isomer thereof, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof and a pharmaceutical application of the compound as an MAT2A inhibitor. The invention provides an MAT2A inhibitor compound which is novel in structure, strong in activity, good in selectivity and good in oral absorption in a rat body, and the compound has a good application prospect in prevention and / or treatment of indications related to MAT2A inhibition, such as cancers, autoimmune diseases and the like. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and particularly relates to a pyridopyridone compound as a MAT2A inhibitor, its stereoisomers, or its pharmaceutically acceptable salts, a preparation method thereof, a pharmaceutical composition, and uses in the preparation for use in a subject suffering from diseases such as cancer. Background Art

[0002] Methionine adenosyltransferase (MAT) (also known as S-adenosylmethionine synthetase) is a cellular enzyme that catalyzes the synthesis of S-adenosylmethionine (SAM or AdoMet) from methionine and ATP; this catalysis is considered to be the rate-limiting step of the methionine cycle. SAM is the propylamino donor in polyamine biosynthesis and is the main methyl donor for DNA methylation, and it is involved in gene transcription, cell proliferation, and the production of secondary metabolites.

[0003] Three subtypes of human MAT include MAT1 and MAT3 expressed in liver tissue, while MAT2A is ubiquitously expressed in human cell types and is the main form in human tumors. Crystal structure and mechanism studies have shown that although they have 85% identity in amino acid sequence, their mechanisms of action are significantly different. MAT2A forms functional homodimers in its purified active form and binds to the regulatory protein MAT2B. MAT2B regulates the activity of MAT2A by increasing the sensitivity of MAT2A to ADOMet product inhibition, but does not provide a significant rate enhancement. Cellular localization studies have shown that MAT2A is present in both the cytoplasm and the nucleus. It has been reported that nuclear condensation of MAT2A occurs during replication and subsequent G2 phase, meeting the high methylation requirements of the DNA and histone methylation processes in the S-phase nucleus. The activity of ADOMet in transmethylation reactions has been identified as a rate-limiting factor in the development of lung cancer stem cells, making MAT2A and related enzymes of the methionine cycle targets for anti-cancer drugs. The methionine for producing ADOMet by MAT2A comes from dietary sources or the polyamine cycle, in which 5-methylthio-D-ribose 1-phosphate produced by S-methyl-5'-thioadenosine phosphorylase is recycled to methionine. It has been reported that MAT2A protein is overexpressed in cancers such as colon cancer, liver cancer, gastric cancer, blood, and liver. Approximately 15% of human cancers show deletion of the MTAP (S-methyl-5'-thioadenosine phosphorylase) gene and thus lack the methionine recycling pathway for polyamine synthesis. Deletion of MTAP in chr9p21 usually includes deletion of the CDKN2a tumor suppressor gene locus. Comprehensive genetic lethality studies of MATP− / − cancer cells have shown that these cancer cells are more sensitive to the inhibition of MAT2A, PRMT5, and PRMT1.

[0004] In hepatocellular carcinoma (HCC), downregulation of MAT1A and upregulation of MAT2A occur, which is referred to as the MAT1A:MAT2A switch. The switch accompanied by upregulation of MAT2B results in lower SAM content, which provides a growth advantage for liver cancer cells. Since MAT2A plays a crucial role in promoting the growth of liver cancer cells, it is a target for anti-tumor therapy. Recent studies have shown that silencing by using small interfering RNA essentially inhibits the growth of liver cancer cells and induces apoptosis. See, for example, T. Li et al., J. Cancer 7(10)(2016)1317-1327.

[0005] Some MTAP-deficient cancer cell lines are particularly sensitive to inhibition of MAT2A, Marjon et al. (Cell Reports 15(3)(2016)574–587). MTAP (methylthioadenosine phosphorylase) is an enzyme that is widely expressed in normal tissues and catalyzes the conversion of methylthioadenosine (MTA) to adenine and 5-methylthioribose-1-phosphate. Adenine is salvaged to produce adenosine monophosphate, and 5-methylthioribose-1-phosphate is converted to methionine and formate. Due to this salvage pathway, when de novo synthesis of purines is blocked by, for example, an antimetabolite such as L-alanosine, MTA can serve as an alternative purine source.

[0006] In other cancers lacking MTAP deletion, including hepatocellular carcinoma and leukemia, MAT2A is dysregulated. J. Cai et al., Cancer Res. 58(1998)1444-1450; T. S. Jani et al., Cell. Res. 19(2009)358-369. Silencing MAT2A expression by RNA interference can produce anti-proliferative effects in multiple cancer models, H. Chen et al., Gastroenterology 133(2007)207-218; Q. Liu et al. Hepatol. Res. 37(2007)376-388.

[0007] Many human and murine malignant cells lack MTAP activity. MTAP deficiency exists not only in tissue culture cells, but also in primary leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, and mesothelioma. The gene encoding human MTAP is located in the region 9p21 on human chromosome 9. This region also contains the tumor suppressor genes p16INK4A (also known as CDKN2A) and p15INK4B. These genes encode p16 and p15, which are inhibitors of cyclin D-dependent kinases cdk4 and cdk6, respectively.

[0008] Optionally, the p16INK4A transcript can be an alternative reading frame (ARF) that is spliced into a transcript encoding p14ARF. p14ARF binds to MDM2 and prevents the degradation of p53 (Pomerantz et al. (1998) Cell 92: 713-723). The chromosomal region 9p21 is of interest because it is frequently homozygously deleted in a variety of cancers, including leukemia, NSCLC, pancreatic cancer, glioma, melanoma, and mesothelioma. Deletions typically inactivate more than one gene. For example, Cairns et al. ((1995) Nat. Gen. 11: 210-212) reported that after studying more than 500 primary tumors, almost all deletions identified in these tumors involved a 170 kb region containing MTAP, p14ARF, and p16INK4A. Carson et al. (WO99 / 67634) reported a correlation between the stage of tumor development and the loss of homozygosity of the gene encoding MTAP and the gene encoding p16. For example, it has been reported that the deletion of the MTAP gene rather than p16INK4A predicts cancer at an early stage of development, while the deletion of the genes encoding p16 and MTAP predicts cancer at a more advanced stage of cancer development. In some osteosarcoma patients, the MTAP gene was present at diagnosis but was deleted at a later time point (Garcia-Castellano et al., Clin. Cancer Res. 8(3) 2002 782-787).

[0009] MAT2A enzyme inhibitors for treating cancer are disclosed in WO2018039972; MAT2A inhibitors for treating autoimmune or inflammatory diseases are mentioned in WO2021158792; MAT2A enzyme inhibitors for treating diseases or disorders mediated by overexpression of MAT2A are described in WO2018045071; the compound 3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-3-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one for treating MTAP-deficient non-small cell lung cancer (NSCLC) in patients in need is also disclosed in CN202080014106.0; a MAT2A inhibitor with a 6-fused-6 ring core is disclosed in CN114874207A; a polycyclic compound that inhibits cancer cells with MTAP deletion is disclosed in CN113999232A.

[0010] Discovering and finding MAT2A inhibitors with novel structures and good oral absorption in rats has become a major focus in the research and development of drugs for treating MTAP-deleted tumors. Summary of the Invention Summary of the Invention

[0012] The present invention meets a significant need for safe and effective compounds and methods for treating, preventing, and controlling cancer while reducing or avoiding the toxicity and / or side effects associated with conventional therapies. To solve the above technical problems, the present invention adopts the following technical solutions:

[0013] On the one hand, the present invention provides a compound represented by Formula I, its stereoisomers, or its pharmaceutically acceptable salts,

[0014]

[0015] wherein, R1 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl;

[0016] R2 and R3 are each independently selected from a 5- to 12-membered monocyclic or bicyclic aromatic or heteroaryl ring, and the aromatic or heteroaryl is optionally substituted with one or more identical or different substituents R a substituted;

[0017] The heteroaryl contains 1-3 heteroatoms selected from N, O, S, and the ring system includes saturated or partially unsaturated ring systems such as spiro rings, bridged rings, fused rings, and annelated rings;

[0018] R a is selected from hydrogen, deuterium, halogen, cyano, -C(O)NH2, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 monoalkylamino, C1-C6 dialkylamino, alkenyl, alkynyl, 3- to 8-membered cycloalkyl or heterocycloalkyl;

[0019] R4 and R5 are each independently selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxyl, C1-C 12 alkyl, 3- to 12-membered cycloalkyl or heterocycloalkyl, 3- to 12-membered halocycloalkyl or haloheterocycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 monoalkylamino, C1-C6 dialkylamino, -NH-(CH2) n -C1-C6 haloalkyl, -NH-(CH2) n -C3-C8 heterocycloalkyl, -NH-(CH2) n -NR b R c 、-NH-(CH2) n -O-C1-C6 alkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -O-(CH2) n -heterocycloalkyl, -O-(CH2) n -cycloalkyl, -O-(CH2) n -C3-C6 heterocycloalkyl, -O-(CH2) n-O-C1-C6 alkyl;

[0020] The C1-C6 monoalkylamino, C1-C6 dialkylamino, -NH-(CH2) n -C1-C6 haloalkyl, -NH-(CH2) n -C3-C8 heterocycloalkyl, -NH-(CH2) n -NR b R c 、-NH-(CH2) n -O-C1-C6 alkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -O-(CH2) n -heterocyclic group, -O-(CH2) n -cycloalkyl, -O-(CH2) n -C3-C6 heterocycloalkyl, -O-(CH2) n -O-C1-C6 alkyl is optionally substituted by one or more substituents selected from the group consisting of: halogen, hydroxy, amino, oxo, C1-C6 alkylamino, C1-C6 alkyl, C1-C6 alkoxy, oxo, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl;

[0021] R b 、R c are each independently selected from H, C1-C6 alkyl.

[0022] N is an integer from 0 to 3, including 0.

[0023] As a preferred technical solution, R1 is selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl.

[0024] As a preferred technical solution, R2 is selected from a 5- to 12-membered bicyclic heteroaryl ring optionally substituted by one or more identical or different R a substituents, more preferably

[0025] As a preferred technical solution, R3 is selected from a 5- to 12-membered monocyclic aryl or heteroaryl ring optionally substituted by one or more identical or different R a substituents, more preferably

[0026] As a preferred technical solution, R4 is selected from Cl, methyl, methoxy, trifluoroethylamino, difluoromethyl, amino, trifluoroethoxy, trifluoromethyl,

[0027]

[0028] As a preferred technical solution, R5 is selected from F, hydrogen, methoxy.

[0029] As a preferred technical solution, the compounds provided by the present invention have the structures shown in the following formulas (Ia), (Ib), (Ic), (Id), and (Ie),

[0030]

[0031] wherein,

[0032] R6 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl;

[0033] R7 and R8 are each independently selected from hydrogen, deuterium, halogen, cyano, -C(O)NH2, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 monoalkylamino, C1-C6 dialkylamino, alkenyl, alkynyl, 3-8 membered cycloalkyl or heterocycloalkyl.

[0034] As a preferred technical solution, R7 and R8 are each independently selected from hydrogen, chlorine, fluorine, methoxy, trifluoromethoxy, cyano, trifluoromethyl, methyl.

[0035] As a preferred technical solution, R6 is selected from methyl.

[0036] The present invention also provides the compounds shown below, their stereoisomers, or their pharmaceutically acceptable salts:

[0037]

[0038]

[0039] The present invention also provides a pharmaceutical composition, which comprises the compound described in any one of the above, its stereoisomers or its pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0040] The present invention also provides the use of the compound described in any one of the above, its stereoisomers, or its pharmaceutically acceptable salts and drug combinations in the preparation of a drug for a subject suffering from a disease or disorder related to the activity or expression of MAT2a or MTAP protein, wherein the disease or disorder is preferably cancer or an autoimmune disease, and the cancer is preferably selected from lung cancer, pancreatic cancer, liver cancer, colorectal cancer, cholangiocarcinoma, gallbladder cancer, brain cancer, gastric cancer, leukemia, lymphoma, melanoma, thyroid cancer, nasopharyngeal cancer, glioma, bladder cancer, astrocytoma, basal cell carcinoma, osteosarcoma, head and neck cancer, chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma and mesothelioma, etc.; the autoimmune disease is preferably selected from thyroiditis, inflammatory bowel disease, lupus erythematosus, fibrosis, myasthenia gravis, vasculitis, psoriasis, arthritis, scleroderma, dermatitis, etc.

[0041] The present invention also provides important intermediate compounds as shown below, their stereoisomers or pharmaceutically acceptable salts,

[0042]

[0043] On the other hand, the present invention provides a method for preparing the compound shown in formula (1), which is characterized by including the following steps:

[0044]

[0045] (1) The starting material (i-1) is prepared into the intermediate compound (i-2) through a substitution reaction;

[0046] (2) The intermediate compound (i-2) is prepared into the intermediate compound (i-3) through substitution and decarboxylation reactions;

[0047] (3) The intermediate compound (i-3) is prepared into the intermediate compound (i-4) through an amine transesterification reaction;

[0048] (4) The intermediate compound (i-4) is prepared into the intermediate compound (i-5) through a halogenation reaction;

[0049] (5) The intermediate compound (i-5) is prepared into the intermediate compound (i-6) through a substitution reaction;

[0050] (6) The intermediate compound (i-6) is prepared into the intermediate compound (i-7) through an electrophilic substitution reaction;

[0051] (7) The intermediate compound (i-7) is prepared into the compound (1) through a Buchwald coupling reaction.

[0052] Finally, the present invention also provides a method for preparing the compound shown in formula (II), and this method includes the following steps:

[0053]

[0054] The general formula compound (IIA) is reacted with other compounds through a substitution reaction to obtain the general formula (II) compound;

[0055] Wherein,

[0056] R6 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl;

[0057] R7 and R8 are each independently selected from hydrogen, deuterium, halogen, cyano, -C(O)NH2, hydroxy, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 monoalkylamino, C1-C6 dialkylamino, alkenyl, alkynyl, 3- to 8-membered cycloalkyl or heterocycloalkyl;

[0058] R1, R4 and R5 are as defined above.

[0059] As a preferred technical solution, R6 is selected from methyl.

[0060] As a preferred technical solution, R1 is selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl.

[0061] As a preferred technical solution, R4 is selected from Cl, methyl, methoxy, trifluoroethylamino, difluoromethyl, amino, trifluoroethoxy, trifluoromethyl,

[0062]

[0063] As a preferred technical solution, R5 is selected from F, hydrogen, methoxy.

[0064] As a preferred technical solution, R7 and R8 are each independently selected from hydrogen, chlorine, fluorine, methoxy, trifluoromethoxy, cyano, trifluoromethyl, methyl.

[0065] The inventors have found that such compounds are highly efficient MAT2A inhibitors with extremely strong MAT2A inhibitory activity and can be used for preparing prophylactic and / or therapeutic agents for MAT2A inhibition-related indications, including cancers and autoimmune diseases caused by reduction or deletion of MTAP expression, deletion of MTAP gene, and reduction of MTAP protein function. The present invention has been completed based on the above findings. Detailed Description of the Invention

[0067] The following further describes various aspects and features of the present invention.

[0068] The compounds according to the present invention may exist in stereoisomeric forms, and the present invention includes all stereoisomeric forms.

[0069] The compounds of the present invention have asymmetric centers, and compounds containing asymmetrically substituted atoms in the present invention can be separated into optically active or racemic forms. Those skilled in the art know how to prepare optically active forms, such as by resolution of racemates or synthesis from optically active starting materials. Unless specifically indicating a particular stereochemistry or isomeric form, the present invention includes all chiral, diastereoisomers, and racemates. The methods for preparing the compounds of the present invention and their intermediates are part of the present invention. All stereoisomers of the compounds of the present invention also belong to the present invention.

[0070] The term "optionally" or "optionally" means that the subsequent described event or situation may or may not occur, and this description includes the occurrence and non-occurrence of the described event or situation.

[0071] "Alkyl" refers to a group of straight-chain or branched-chain saturated hydrocarbon groups having 1 to 10 carbon atoms ("C1-C10 alkyl"). In some embodiments, the alkyl has 1 to 8 carbon atoms ("C1-C8 alkyl"). In some embodiments, the alkyl has 1 to 6 carbon atoms ("C1-C6 alkyl"), the alkyl has 1 to 5 carbon atoms ("C1-C5 alkyl"), the alkyl has 1 to 4 carbon atoms ("C1-C4 alkyl"), the alkyl has 1 to 3 carbon atoms ("C1-C3 alkyl"), the alkyl has 1 to 2 carbon atoms ("C1-C2 alkyl"), and the alkyl has 1 carbon atom ("C1 alkyl"). In some embodiments, the alkyl has 2 to 6 carbon atoms ("C2-C6 alkyl"). Examples of C1-C6 alkyl include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). Additional examples of alkyl include n-heptyl (C7), n-octyl (C8), etc. Each instance of alkyl can be independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted by one or more substituents; for example, substituted by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, the alkyl is unsubstituted C1-C10 alkyl (e.g., -CH3). In certain embodiments, the alkyl is substituted C1-C6 alkyl. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).

[0072] The term "alkenyl" means a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and being connected to the rest of the molecule by a single bond, such as, but not limited to, vinyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl, etc.

[0073] The term "alkynyl" means a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and being connected to the rest of the molecule by a single bond, such as, but not limited to, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl, etc.

[0074] As used herein, the terms "halogen", "halo", "halo group", etc. denote fluorine, chlorine, bromine or iodine, particularly denote fluorine, chlorine, bromine, and particularly preferably fluorine, chlorine.

[0075] "Haloalkyl" refers to an alkyl group as described herein (e.g., C1-C6 alkyl) in which one or more hydrogen atoms are replaced by a halogen (e.g., monohaloalkyl, dihaloalkyl, and trihaloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloro-fluoroalkyl, chloro-difluoroalkyl, and 2-fluoroisobutyl.

[0076] "Alkoxy" refers to an alkyl group as described herein (e.g., C1-C6 alkyl) that is connected to the molecule through an oxygen atom. This includes moieties in which the alkyl portion may be straight-chain or branched, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, and n-hexyloxy.

[0077] "Cycloalkyl" refers to a monocyclic saturated cycloalkyl group having 3 to 10 ring carbon atoms ("C3-10 cycloalkyl" or "C3-C10 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C3-8 cycloalkyl" or "C3-C8 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C3-6 cycloalkyl" or "C3-C6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 6 ring carbon atoms ("C5-6 cycloalkyl" or "C5-C6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 10 ring carbon atoms ("C5-10 cycloalkyl" or "C5-C10 cycloalkyl"). Examples of C5-C6 cycloalkyl include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-C6 cycloalkyl include the aforementioned C5-C6 cycloalkyl, as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-C8 cycloalkyl include the aforementioned C3-C6 cycloalkyl, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of cycloalkyl is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, the cycloalkyl is an unsubstituted C3-C10 cycloalkyl. In certain embodiments, the cycloalkyl is a substituted C3-C10 cycloalkyl.

[0078] "Heterocycloalkyl" refers to a group in which one or more C atoms in the above "cycloalkyl" are replaced by heteroatoms such as N, O, S, P, etc.

[0079] The term "alkylamino" means an -alkyl-NH2 structure or a substituted amino -NRdRe, where Rd and Re are each independently hydrogen or an alkyl as described above. For example, the term "monoalkylamino" refers to a substituted amino -NRdRe, where one of Rd and Re is hydrogen and the other is an alkyl as described above; "dialkylamino" refers to a substituted amino -NRdRe, where Rd and Re are each independently an alkyl as described above.

[0080] The term "haloalkylamino" means an -alkyl-NH2 structure or a substituted amino -NRdRe, where Rd and Re are each independently hydrogen or a haloalkyl as described above. For example, the term "monohaloalkylamino" refers to a substituted amino -NRdRe, where one of Rd and Re is hydrogen and the other is a haloalkyl as described above; "dihaloalkylamino" refers to a substituted amino -NRdRe, where Rd and Re are each independently a haloalkyl as described above.

[0081] The term "heterocyclic group" means a stable 3- to 20-membered non-aromatic cyclic group composed of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen, and sulfur. Unless otherwise specifically indicated in this specification, the heterocyclic group can be a monocyclic, bicyclic, tricyclic, or more-ringed ring system, which can include a fused ring system, a bridged ring system, or a spiro ring system; the nitrogen, carbon, or sulfur atoms in the heterocyclic group can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclic group can be partially or fully saturated. The heterocyclic group can be connected to the rest of the molecule via a carbon atom or a heteroatom by a single bond. In a heterocyclic group containing fused rings, one or more rings can be an aryl or heteroaryl group as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom. For the purposes of the present invention, the heterocyclic group is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged, or spiro group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged, or spiro group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. Examples of the heterocyclic group include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]nonan-7-yl, 2-oxa-6-aza-spiro[3.3]heptan-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuryl, oxazinyl, dioxolanyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinuclidinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, dihydroindolyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimido, etc.

[0082] The term "aryl" means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms (preferably having 6 to 10 carbon atoms). For the purposes of the present invention, the aryl can be a monocyclic, bicyclic, tricyclic, or more-ringed ring system, and can also be fused with a cycloalkyl or heterocyclic group as defined above, provided that the aryl is connected to the rest of the molecule via an atom on the aromatic ring by a single bond. Examples of the aryl include, but are not limited to: phenyl, naphthyl, anthryl, phenanthryl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7-yl, etc.

[0083] The term "heteroaryl" means a 5- to 16-membered conjugated ring system group having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur within the ring. Unless otherwise specifically indicated in this specification, the heteroaryl can be a monocyclic, bicyclic, tricyclic, or more-ring ring system, and can also be fused with the cycloalkyl or heterocyclic group defined above, provided that the heteroaryl is connected to the rest of the molecule through a single bond via an atom on the aromatic ring. The nitrogen, carbon, or sulfur atoms in the heteroaryl can be optionally oxidized; the nitrogen atom can be optionally quaternized. For the purposes of the present invention, the heteroaryl is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur, more preferably a stable 5- to 10-membered aromatic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered aromatic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolinyl, isoquinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxatriazolyl, cinnolinyl, quinazolinyl, phenylthio, indolizinyl, phenanthrolinyl, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridyl, [1,2,4]triazolo[4,3-b]pyridazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1,2,4]triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrazine, etc.

[0084] Unless otherwise specified, when referring to a specifically named aryl (e.g., phenyl), heterocyclic group (e.g., pyrrolidinyl, piperidinyl, and morpholinyl), or heteroaryl (e.g., tetrazolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, and furyl), the reference is intended to include the ring having 0 to 3, preferably 0 to 2 substituents, which are selected from the substituents listed above for aryl, heterocyclic group, and / or heteroaryl, as appropriate.

[0085] As described herein, the term "pharmaceutically acceptable salt" refers to a salt that is not only physiologically acceptable to a subject but also a synthetic substance that has pharmaceutical utility, such as a salt formed as an intermediate during chiral resolution. Although such an intermediate salt cannot be directly administered to a subject, it can play a role in obtaining the end product of the present invention. Specifically included are acid (organic and inorganic acid) addition salts or base addition salts (including organic and inorganic bases).

[0086] "Pharmaceutically acceptable carrier" includes but is not limited to any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent or emulsifying agent that is permitted by the relevant government regulatory authorities for use in humans or livestock.

[0087] The "tumors", "diseases associated with abnormal cell proliferation", etc. described in the present invention include but are not limited to diseases such as leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, squamous cell lung cancer, adenocarcinoma of the lung, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer, etc.

[0088] As described herein, the term "disease" refers to a physical state of the subject that is related to the diseases described in the present invention. For example, the arterial peripheral diseases and neurodegenerative-related diseases described in the present invention.

[0089] The cancers of the present invention include standard treatments such as surgery, radiotherapy, chemotherapy, and hormone therapy, etc.

[0090] "Cancer" or "malignant tumor" refers to any one of a variety of diseases characterized by uncontrolled abnormal cell proliferation, the ability of affected cells to spread locally or through the bloodstream and lymphatic system to other parts of the body (i.e., metastasis), and any one of a number of characteristic structural and / or molecular features. "Cancer cells" refer to cells that have undergone an early, intermediate, or late stage of multi-step tumor progression. Cancers include mesothelioma, neuroblastoma, rectal cancer, colon cancer, familial adenomatous polyposis carcinoma, and hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine body cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, testicular cancer, breast cancer, urinary tract cancer, melanoma, brain tumor, head and neck cancer, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hepatocellular carcinoma, gallbladder cancer, bronchial tumor, advanced solid tumor, small cell lung cancer, metastatic non-small cell lung cancer, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma, lymphoma, pancreatic ductal adenocarcinoma.

[0091] The compounds or pharmaceutical compositions containing them in the present invention can be administered in unit dosage form, and the administration routes can be enteral or parenteral, such as oral, intravenous injection, intramuscular injection, intravenous drip, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum, etc.

[0092] The dosage forms can be liquid dosage forms, solid dosage forms or semi-solid dosage forms. Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including o / w type, w / o type and multiple emulsions), suspensions, injections (including aqueous injections, powder injections and infusions), eye drops, nasal drops, lotions and liniments, etc.; solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, dripping pills, suppositories, films, patches, aerosols (powder aerosols), sprays, etc.; semi-solid dosage forms can be ointments, gels, pastes, etc.

[0093] For the purpose of achieving the medication goal and enhancing the therapeutic effect, the drugs or pharmaceutical compositions of the present invention can be administered by any well-known administration methods.

[0094] The compounds or compositions of the present invention can be taken alone or in combination with other therapeutic drugs or symptomatic drugs. When there is a synergistic effect between the compounds of the present invention and other therapeutic drugs, the dosage should be adjusted according to the actual situation.

[0095] Advantageous Technical Effects

[0096] The inventors of the present invention have found that the compounds in the present invention have good MAT2A inhibitory activity and selectivity, and the IC50 is less than that of the positive control drug AG270 and compound A (compound 167 in WO2020123395). The present invention provides a class of MAT2A inhibitor compounds with novel structures, strong activities and good oral absorption in rats. Such compounds have good application prospects in the prevention and / or treatment of MAT2A inhibition-related indications such as cancer, autoimmune diseases, etc. Detailed implementation modes

[0097] The following listed examples are helpful for those skilled in the art to better understand the technical solutions of the present invention, but the protection scope of the present invention includes but is not limited to this.

[0098] For all the following examples, standard operations and methods known to those skilled in the art can be used. Unless otherwise specified, all temperatures are expressed in °C (degrees Celsius). The structures of the compounds are determined by nuclear magnetic resonance spectroscopy (NMR) and / or mass spectrometry (MS).

[0099] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or / and liquid-mass spectrometry (LC-MS). The NMR chemical shift (δ) is in parts per million (ppm). Nuclear magnetic resonance was measured using a Bruker avance-400 nuclear magnetic resonance instrument, and the solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3), and the internal standard was tetramethylsilane (TMS).

[0100] For the liquid chromatography-mass spectrometry LC-MS measurement, the liquid phase part uses an ACQUITY UPLC ultra-high pressure liquid chromatography, and the mass spectrometry part uses an Xevo G2-SQtof mass spectrometer.

[0101] The starting materials in the examples of the present invention are known and can be purchased on the market, or can also be used or synthesized according to methods known in the art.

[0102] Example 1: Synthesis of 7-chloro-1-(4-chlorophenyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one (Compound 1)

[0103]

[0104] Step 1: Synthesis of 6-chloro-2-[(4-chlorophenyl)amino]-5-fluoronicotinic acid

[0105] Dissolve 4-chloroaniline (20.00 g, 156.80 mmol, 2.0 eq) in ultradry tetrahydrofuran (200 mL), cool to -78 °C, slowly add lithium bis(trimethylsilyl)amide (235.20 mL, 235.20 mmol, 3.0 eq), continue the reaction for 1 hour after the addition is complete. Then dissolve 2,6-dichloro-5-fluoronicotinic acid (16.46 g, 78.40 mmol, 1.0 eq) in ultradry tetrahydrofuran (60 mL), slowly add it to the reaction system at -78 °C. After the addition is complete, transfer the reaction to room temperature and react for 1 hour. After the reaction is completed, quench the reaction with saturated ammonium chloride solution, extract with ethyl acetate (200 mL), combine the organic phases, dry and concentrate, add an appropriate amount of methanol for washing and slurrying, and filter to obtain a pale yellow solid 6-chloro-2-[(4-chlorophenyl)amino]-5-fluoronicotinic acid (20.1 g, yield 85.0%). LCMS (TOF MS ES+) m / z [M + H]+: 178. 1 1H NMR (400 MHz, DMSO) δ 10.40 (s, 1H), 8.27–8.17 (m, 1H), 7.70–7.58 (m, 2H), 7.44–7.33 (m, 2H).

[0106] Step 2: Synthesis of ethyl 3-{6-chloro-2-[(4-chlorophenyl)amino]-5-fluoropyridin-3-yl}-3-oxopropionate

[0107] Potassium 3-ethoxy-3-oxopropionate (8.28 g, 48.66 mmol, 2.0 eq), magnesium chloride (6.73 g, 72.99 mmol, 3.0 eq) and triethylamine (9.85 g, 97.32 mmol, 4.0 eq) were dissolved in acetonitrile solution (150 mL), and stirred at room temperature for 4 hours. 6-Chloro-2-{(4-chlorophenyl)amino}-5-fluoronicotinic acid (7.3 g, 24.33 mmol, 1.0 eq) and super dry dichloromethane (150 mL) were added to another reaction flask, and a small amount of N,N-dimethylformamide was added as a catalyst. Then, at 0 °C, oxalyl chloride (5.07 g, 39.99 mmol, 1.5 eq) was slowly added dropwise. After the addition was completed, the reaction was transferred to room temperature and reacted for 2 hours. After monitoring the reaction to completion by TLC, the reaction solution was directly concentrated to obtain a yellow solid, which was then dissolved in tetrahydrofuran solution (100 mL). At 0 °C, it was slowly added dropwise to the reaction system of potassium 3-ethoxy-3-oxopropionate, and the reaction continued at room temperature for 2 hours. After the reaction was completed, the reaction solution was directly concentrated, and purified by normal-phase column chromatography to obtain yellow solid ethyl 3-{6-chloro-2-[(4-chlorophenyl)amino]-5-fluoropyridin-3-yl}-3-oxopropionate (6.3 g, yield 70%). LCMS (TOF MS ES+) m / z [M+H]+: 371. 1 1H NMR (400 MHz, DMSO) δ 10.76 (s, 1H), 8.54 (d, J = 9.2 Hz, 1H), 7.77–7.60 (m, 2H), 7.50–7.25 (m, 2H), 4.29 (s, 2H), 4.14 (m, J = 7.1 Hz, 2H), 1.21 (t, J = 7.1 Hz, 3H).

[0108] Step 3: Synthesis of 7-chloro-1-(4-chlorophenyl)-6-fluoro-4-hydroxy-1,8-naphthyridin-2(1H)-one

[0109] Ethyl 3-{6-chloro-2-[(4-chlorophenyl)amino]-5-fluoropyridin-3-yl}-3-oxopropionate (6.30 g, 17.02 mmol, 1.0 eq) and potassium carbonate (4.70 g, 34.05 mmol, 2.0 eq) were dissolved in absolute ethanol (120 mL), and reacted at 70 °C for 3 hours. After the reaction was completed, it was filtered through diatomaceous earth, and the filtrate was purified by normal-phase column chromatography to obtain solid 7-chloro-1-(4-chlorophenyl)-6-fluoro-4-hydroxy-1,8-naphthyridin-2(1H)-one (5.1 g, yield 92.5%). LCMS (TOF MS ES+) m / z [M+H]+: 325. 11H NMR (400 MHz, DMSO) δ 12.28 (s, 1H), 8.27 (d, J = 8.1 Hz, 1H), 7.65–7.50 (m, 2H), 7.41–7.22 (m, 2H), 5.98 (s, 1H).

[0110] Step 4: Synthesis of 4,7-dichloro-1-(4-chlorophenyl)-6-fluoro-1,8-naphthyridin-2(1H)-one

[0111] 7-Chloro-1-(4-chlorophenyl)-6-fluoro-4-hydroxy-1,8-naphthyridin-2(1H)-one (5.1 g, 15.74 mmol, 1.0 eq) and phosphorus oxychloride (50 mL) were added to a reaction flask and reacted at 80 °C for 16 h. After completion of the reaction, phosphorus oxychloride was removed by concentration under reduced pressure, ethyl acetate was added for pulping, and filtration gave the yellow solid 4,7-dichloro-1-(4-chlorophenyl)-6-fluoro-1,8-naphthyridin-2(1H)-one (4.5 g, yield 83.6%). LCMS (TOF MS ES+) m / z [M+H]+: 343. 1 1H NMR (400 MHz, DMSO) δ 8.51 (d, J = 8.2 Hz, 1H), 7.70–7.53 (m, 2H), 7.43–7.32 (m, 2H), 7.26 (s, 1H).

[0112] Step 5: Synthesis of 7-chloro-1-(4-chlorophenyl)-6-fluoro-4-(methylamino)-1,8-naphthyridin-2(1H)-one

[0113] 4,7-Dichloro-1-(4-chlorophenyl)-6-fluoro-1,8-naphthyridin-2(1H)-one (1.0 g, 2.91 mmol, 1.0 eq), methylamine hydrochloride (294 mg, 4.35 mmol, 1.5 eq) and N,N-diisopropylethylamine (1.5 g, 11.6 mmol, 4.0 eq) were dissolved in acetonitrile (20 mL) and reacted at 80 °C for 2 h. After completion of the reaction, the reaction solution was concentrated to obtain a pale yellow solid, and pulping with ethyl acetate and filtration gave the yellow solid 7-chloro-1-(4-chloromethyl)-6-fluoro-4-(methylamino)-1,8-naphthyridin-2(1H)-one (410 mg, yield 41.6%), which was directly used for the next step. LCMS (TOF MS ES+) m / z [M+H]+: 338.

[0114] Step 6: Synthesis of 3-bromo-7-chloro-1-(4-chlorophenyl)-6-fluoro-4-(methylamino)-1,8-naphthyridin-2(1H)-one

[0115] 7-Chloro-1-(4-chloromethyl)-6-fluoro-4-(methylamino)-1,8-naphthyridin-2(1H)-one (400 mg, 1.18 mmol, 1.0 eq) and N-bromosuccinimide (232.4 mg, 1.30 mmol, 1.1 eq) were added to an acetonitrile solution (8 mL), and the reaction was carried out at room temperature for 4 hours. After the reaction was completed, the reaction solution was directly concentrated, and purified by normal phase separation (dichloromethane / methanol = 20:1) to obtain a pale yellow solid 3-bromo-7-chloro-1-(4-chloromethyl)-6-fluoro-4-(methylamino)-1,8-naphthyridin-2(1H)-one (350 mg, yield 70.85%). LCMS (TOF MS ES+) m / z [M+H]+: 416. 1 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 10.7 Hz, 1H), 7.54–7.39 (m, 2H), 7.22–7.13 (m, 2H), 5.14 (s, 1H), 2.72–2.68 (m, 3H).

[0116] Step 7: Synthesis of 7-chloro-1-(4-chlorophenyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one

[0117] 3-Bromo-7-chloro-1-(4-chloromethyl)-6-fluoro-4-(methylamino)-1,8-naphthyridin-2(1H)-one (297.0 mg, 0.71 mmol, 1.0 eq), 2-methyl-2H-indazole-5-boronic acid (188.0 mg, 1.07 mmol, 1.5 eq) and potassium phosphate (379.8 mg, 1.79 mmol, 2.5 eq) were added to a mixed solvent of dioxane (6 mL) and water (0.6 mL), and finally 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (52.3 mg, 0.07 mmol, 0.1 eq) was added. The reaction was carried out at 80 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was directly concentrated, and purified by preparative separation to obtain a yellow solid 7-chloro-1-(4-chlorophenyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one (40.4 mg, yield 12.05%). LCMS (TOF MS ES+) m / z [M+H]+: 468.0816. 11H NMR (400 MHz, DMSO) δ 8.36 (s, 1H), 7.86 (d, J = 11.2 Hz, 1H), 7.72 (d, J = 5.3 Hz, 1H), 7.69 (s, 1H), 7.58 (t, J = 8.3 Hz, 3H), 7.38 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 8.9 Hz, 1H), 4.18 (s, 3H), 2.52 (d, J = 4.6 Hz, 3H).

[0118] Example 2: Synthesis of 7-chloro-1-(2-chlorophenyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one (Compound 2)

[0119]

[0120] Step 1: Synthesis of 6-chloro-2-[(2-chlorophenyl)amino]-5-fluoronicotinic acid

[0121] A mixture of 2-chloroaniline (24.3 g, 190.5 mmol, 2.0 eq) and tetrahydrofuran (120 mL) was added to a three-necked flask. After purging with nitrogen, the mixture was cooled to -78 °C, and lithium bis(trimethylsilyl)amide (286 mL, 285.7 mmol, 3.0 eq) was slowly added dropwise. After stirring at -78 °C for 1.5 h, a solution of 2,6-dichloro-5-fluoronicotinic acid (20 g, 95.2 mmol, 1.0 eq) in tetrahydrofuran was added dropwise. After the addition was complete, the reaction mixture was transferred to room temperature and reacted for 2 h. After the reaction was completed, the reaction was quenched by adding dilute hydrochloric acid solution under an ice bath. The mixture was extracted three times with water and ethyl acetate. The organic phases were combined, dried, concentrated, and then washed with an appropriate amount of methanol and triturated. After filtration, yellow powdery solid 6-chloro-2-[(2-chlorophenyl)amino]-5-fluoronicotinic acid (12 g, yield 42.02%) was obtained. LCMS (TOF MS ES+) m / z [M+H]+: 300.9. 1H NMR (400 MHz, DMSO) δ 10.80 (s, 1H), 8.42 (dd, J = 8.4, 1.5 Hz, 1H), 8.28 (d, J = 8.4 Hz, 1H), 7.53 (dd, J = 8.0, 1.5 Hz, 1H), 7.38 (m, J = 7.9, 1.5 Hz, 1H), 7.09 (m, J = 7.7, 1.5 Hz, 1H).

[0122] Step 2: Synthesis of ethyl 3-{6-chloro-2-[(2-chlorophenyl)amino]-5-fluoropyridin-3-yl}-3-oxopropionate

[0123] Potassium 3-ethoxy-3-oxopropionate (8.48 g, 49.8 mmol, 1.5 eq), magnesium chloride (9.48 g, 99.6 mmol, 3.0 eq) and triethylamine (15.12 g, 149 mmol, 4.5 eq) were dissolved in acetonitrile solvent (180 mL), and stirred at room temperature for 4 hours. 6-Chloro-2-[(2-chlorophenyl)amino]-5-fluoronicotinic acid (10 g, 33.2 mmol, 1.0 eq), N,N-dimethylformamide (1.3 mL, 1.66 mmol, 0.05 eq) and dichloromethane (140 mL) were added to another reaction flask, and then oxalyl chloride (6.33 g, 49.8 mmol, 1.5 eq) was slowly added dropwise until no bubbles were generated. After stirring the reaction at room temperature for 2 hours, the reaction solution was directly concentrated. The obtained solid was dissolved in dichloromethane (60 mL), and slowly added dropwise to the potassium 3-ethoxy-3-oxopropionate system at 0 °C. After the addition was completed, the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated, extracted three times with ethyl acetate and water, the organic phases were combined, and purified by normal-phase column chromatography to obtain yellow solid ethyl 3-{6-chloro-2-[(2-chlorophenyl)amino]-5-fluoropyridin-3-yl}-3-oxopropionate (11.0 g, yield 89.5%). LCMS (TOF MS ES+) m / z [M+H]+: 371.03. 1H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 8.61 (d, J = 9.2 Hz, 1H), 8.37 (dd, J = 8.3, 1.5 Hz, 1H), 7.56 (dd, J = 8.0, 1.5 Hz, 1H), 7.41 (m, J = 7.9, 1.5 Hz, 1H), 7.15 (m, J = 7.7, 1.5 Hz, 1H), 4.32 (s, 2H), 4.16 (m, J = 7.1 Hz, 2H), 1.21 (t, J = 7.1 Hz, 3H).

[0124] Step 3: Synthesis of 7-chloro-1-(2-chlorophenyl)-6-fluoro-4-hydroxy-1,8-naphthyridin-2(1H)-one

[0125] Ethyl 3-{6-chloro-2-[(2-chlorophenyl)amino]-5-fluoropyridin-3-yl}-3-oxopropionate (11.5 g, 31.1 mmol, 1.0 eq) and potassium carbonate (8.59 g, 62.2 mmol, 2.0 eq) were added to anhydrous ethanol (250 mL), and the reaction was carried out at 70 °C for 3 hours. After the reaction was completed, the mixture was filtered, and the filtrate was separated by normal-phase column chromatography to obtain a yellow powdery solid, 7-chloro-1-(2-chlorophenyl)-6-fluoro-4-hydroxy-1,8-naphthyridin-2(1H)-one (7.56 g, yield 75.1%). LCMS (TOF MS ES+) m / z [M+H]+: 324.9. 1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J = 8.5 Hz, 1H), 7.61–7.52 (m, 1H), 7.47–7.36 (m, 2H), 7.34–7.25 (m, 1H), 4.96 (s, 1H), 4.47 (s, 1H).

[0126] Step 4: Synthesis of 4,7-dichloro-1-(2-chlorophenyl)-6-fluoro-1,8-naphthyridin-2(1H)-one

[0127] 7-Chloro-1-(2-chlorophenyl)-6-fluoro-4-hydroxy-1,8-naphthyridin-2(1H)-one (7.55 g, 23.3 mmol, 1.0 eq) was added to phosphorus oxychloride (80 mL), and the reaction was refluxed at 70 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated, the pH was adjusted to alkaline with sodium bicarbonate, and the mixture was extracted three times with ethyl acetate and water. The organic phases were combined, dried, and concentrated to obtain a yellow solid, 4,7-dichloro-1-(2-chlorophenyl)-6-fluoro-1,8-naphthyridin-2(1H)-one (5.35 g, yield 67.2%). LCMS (TOF MS ES+) m / z [M+H]+: 342.9. 1H NMR (400 MHz, DMSO) δ 8.57 (d, J = 8.2 Hz, 1H), 7.78–7.69 (m, 1H), 7.61–7.52 (m, 3H), 7.35 (s, 1H).

[0128] Step 5: Synthesis of 7-chloro-1-(2-chlorophenyl)-6-fluoro-4-(methylamino)-1,8-naphthyridin-2(1H)-one

[0129] 4,7-Dichloro-1-(2-chlorophenyl)-6-fluoro-1,8-naphthyridin-2(1H)-one (1.5 g, 4.39 mmol, 1.0 eq), methylamine hydrochloride (441 mg, 6.59 mmol, 1.5 eq) and triethylamine (1.77 g, 17.6 mmol, 4.0 eq) were dissolved in acetonitrile (30 mL), and the reaction was carried out at 80 °C for 3 h. After the reaction was completed, it was concentrated, extracted with aqueous sodium bicarbonate solution and ethyl acetate, and separated by normal-phase column chromatography to obtain the yellow solid 7-chloro-1-(2-chlorophenyl)-6-fluoro-4-(methylamino)-1,8-naphthyridin-2(1H)-one (1.4 g, yield 94.7%). LCMS (TOF MS ES+) m / z [M+H]+: 338.1.

[0130] Step 6: Synthesis of 3-bromo-7-chloro-1-(2-chlorophenyl)-6-fluoro-4-(methylamino)-1,8-naphthyridin-2(1H)-one

[0131] 7-Chloro-1-(2-chlorophenyl)-6-fluoro-4-(methylamino)-1,8-naphthyridin-2(1H)-one (1.54 g, 4.57 mmol, 1.0 eq) and N-bromosuccinimide (895 mg, 5.05 mmol, 1.1 eq) were dissolved in acetonitrile (40 mL), and the mixture was stirred at room temperature for 4 h. After the reaction was completed, it was separated by normal-phase column chromatography to obtain the yellow solid 3-bromo-7-chloro-1-(2-chlorophenyl)-6-fluoro-4-(methylamino)-1,8-naphthyridin-2(1H)-one (1.5 g, yield 79.1%). LCMS (TOF MS ES+) m / z [M+H]+: 415.9; 1H NMR (400 MHz, DMSO) δ 7.92–7.83 (m, 2H), 7.68 (m, J = 7.2, 3.7 Hz, 1H), 7.50 (dd, J = 6.9, 3.4 Hz, 2H), 2.43 (d, J = 4.5 Hz, 3H).

[0132] Step 7: Synthesis of 7-chloro-1-(2-chlorophenyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one

[0133] 3-Bromo-7-chloro-1-(2-chlorophenyl)-6-fluoro-4-(methylamino)-1,8-naphthyridin-2(1H)-one (1.00 g, 2.41 mmol, 1.0 eq), (2-methyl-2H-indazol-5-yl)boronic acid (506 mg, 2.89 mmol, 1.2 eq), and potassium phosphate (1.28 g, 6.03 mmol, 2.5 eq) were dissolved in 1,4-dioxane (15 mL) and water (1.5 mL). Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) (176 mg, 0.24 mmol, 0.1 eq) was added, and the mixture was stirred at 80 °C for 12 h under a nitrogen atmosphere. After completion of the reaction, the mixture was filtered, concentrated, extracted with dichloromethane and water, and the organic phase was concentrated. The product was isolated by reverse-phase column chromatography to obtain 7-chloro-1-(2-chlorophenyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one as a white powder (670 mg, yield 59.6%). LCMS (TOF MS ES+) m / z [M+H]+: 468.1. 1H NMR (400 MHz, DMSO) δ 8.37 (s, 1H), 7.88 (d, J = 11.1 Hz, 1H), 7.75 (d, J = 5.0 Hz, 1H), 7.72–7.63 (m, 2H), 7.60 (d, J = 9.0 Hz, 1H), 7.50 (m, J = 2.4 Hz, 3H), 7.16 (dd, J = 8.5, 1.6 Hz, 1H), 4.18 (s, 3H), 2.47 (d, J = 4.5 Hz, 3H).

[0134] Example 3: Synthesis of 1-(4-chlorophenyl)-6-fluoro-7-methoxy-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one (Compound 3)

[0135]

[0136] Step 1: Synthesis of 1-(4-chlorophenyl)-6-fluoro-7-methoxy-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one

[0137] 7-Chloro-1-(4-chlorophenyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one (60 mg, 0.13 mmol, 1.0 eq) prepared in Example 1 was added to methanol (1 mL), and then sodium hydride (51.4 mg, 1.28 mmol, 10.0 eq) was added. The mixture was stirred at 80 °C for 5 hours. After the reaction was completed, the insoluble matter was removed by filtration, and white solid 1-(4-chlorophenyl)-6-fluoro-7-methoxy-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one (8.2 mg, yield 13.8%) was prepared and purified. LCMS (TOF MS ES+) m / z [M+H] + : 464.1202. 1 H NMR (400 MHz, DMSO) δ 8.32 (s, 1H), 7.76–7.68 (m, 2H), 7.55 (dd, J = 12.3, 8.5 Hz, 4H), 7.33 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 9.0 Hz, 1H), 4.16 (s, 3H), 3.43 (s, 3H), 2.51 (s, 3H).

[0138] Example 4: Synthesis of 1-(4-chlorophenyl)-6-fluoro-7-methyl-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one (Compound 4)

[0139]

[0140] Step 1: Synthesis of 1-(4-chlorophenyl)-6-fluoro-7-methyl-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one (Compound 4)

[0141] 7-chloro-1-(4-chlorophenyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one (50 mg, 0.11 mmol, 1.0 eq) prepared in Example 1, methylboronic acid (13.2 mg, 0.22 mmol, 2.0 eq), tetrakis(triphenylphosphine)palladium (12.3 mg, 0.01 mmol, 0.1 eq) and potassium carbonate (44.2 mg, 0.33 mmol, 3.0 eq) were dissolved in 1,4-dioxane (1.5 mL) and water (0.3 mL). The system was purged with nitrogen and stirred at 120 °C for 2 h. After completion of the reaction, the insoluble matters were removed by filtration, and yellow solid 1-(4-chlorophenyl)-7-cyclopropyl-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one (13.2 mg) was prepared by purification. LCMS (TOF MS ES+) m / z [M+H]+: 448.1288. 1 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.84 (d, J = 12.0 Hz, 1H), 7.61–7.53 (m, 4H), 7.34–7.29 (m, 3H), 7.10 (dd, J = 8.9, 1.6 Hz, 1H), 4.17 (s, 3H), 2.49 (s, 3H), 2.23 (s, 3H).

[0142] Example 5: Synthesis of 1-(4-chlorophenyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-7-[(2,2,2-trifluoroethyl)amino]-1,8-naphthyridin-2(1H)-one (Compound 5)

[0143]

[0144] Step 1: Synthesis of 1-(4-chlorophenyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-7-[(2,2,2-trifluoroethyl)amino]-1,8-naphthyridin-2(1H)-one

[0145] 7-chloro-1-(4-chlorophenyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one (60 mg, 0.128 mmol, 1.0 eq) prepared in Example 1, 2,2,2-trifluoroethylamine (127 mg, 1.28 mmol, 10.0 eq), (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (11.6 mg, 0.012 mmol, 0.1 eq) and sodium tert-butoxide (61.5 mg, 0.64 mmol, 5.0 eq) were dissolved in 1,4-dioxane (2 mL). The system was purged with nitrogen three times and stirred at 90 °C for 1 h. After completion of the reaction, the insoluble matter was removed by filtration. The filtrate was concentrated and purified by preparative method to obtain a yellow solid 1-(4-chlorophenyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-7-[(2,2,2-trifluoroethyl)amino]-1,8-naphthyridin-2(1H)-one (11.2 mg, yield 16.4%). LCMS (TOF MS ES+) m / z [M+H] + : 531.10. 1 H NMR (400 MHz, DMSO) δ 8.33 (s, 1H), 7.78 (d, J = 12.5 Hz, 1H), 7.66–7.53 (m, 3H), 7.48–7.34 (m, 4H), 7.11 (d, J = 8.9 Hz, 1H), 6.37 (s, 1H), 4.21 (s, 3H), 3.34 (s, 2H), 2.42 (d, J = 4.6 Hz, 3H).

[0146] Example 6: Synthesis of 1-(4-chlorophenyl)-7-(difluoromethyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one (Compound 6)

[0147]

[0148] Step 1: Synthesis of 1-(4-chlorophenyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-7-ethenyl-1,8-naphthalen-2(1H)-one

[0149] 7-Chloro-1-(4-chlorophenyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one (200 mg, 0.427 mmol, 1.0 eq) prepared in Example 1, potassium vinyltrifluoroborate (85.9 mg, 0.641 mmol, 1.5 eq), tetrakis(triphenylphosphine)palladium (49.3 mg, 0.042 mmol, 0.1 eq) and potassium carbonate (176.9 mg, 1.28 mmol, 3.0 eq) were dissolved in 1,4-dioxane (4 mL) and water (0.8 mL), and the reaction was carried out at 110 °C. After the reaction was completed, dichloromethane and water were added for extraction, and purification by normal-phase column chromatography gave the yellow solid 1-(4-chlorophenyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-7-vinyl-1,8-naphthalen-2(1H)-one (181 mg, yield 92.1%). LCMS (TOF MS ES+) m / z + : 460.1. 1 H NMR (400 MHz, DMSO) δ 8.32 (s, 1H), 7.76 (d, J = 12.0 Hz, 1H), 7.68–7.59 (m, 4H), 7.48 (d, J = 5.0 Hz, 1H), 7.38–7.35 (m, 2H), 7.12 (dd, J = 8.7, 1.7 Hz, 1H), 6.57 (dd, J = 18.0, 11.7 Hz, 1H), 5.58 (dd, J = 11.7, 1.4 Hz, 1H), 5.45–5.37 (m, 1H), 4.18 (s, 3H), 2.53 (d, J = 2.0 Hz, 3H).

[0150] Step 2: Synthesis of 8-(4-chlorophenyl)-3-fluoro-6-(2-methyl-2H-indazol-5-yl)-5-(methylamino)-7-oxo-7,8-dihydro-1,8-naphthyridine-2-carbaldehyde

[0151] 1-(4-Chlorophenyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-7-vinyl-1,8-naphthyridin-2(1H)-one (180 mg, 0.39 mmol, 1.0 eq) and potassium osmate dihydrate (24.3 mg, 0.078 mmol, 0.2 eq) were added to tetrahydrofuran (8 mL) and water (2 mL), and then sodium periodate (252.7 mg, 1.17 mmol, 3.0 eq) was added. The mixture was stirred at room temperature for 5 h. After the reaction was completed, the reaction solution was concentrated, extracted with dichloromethane and water, and then concentrated to obtain 8-(4-chlorophenyl)-3-fluoro-6-(2-methyl-2H-indazol-5-yl)-5-(methylamino)-7-oxo-7,8-dihydro-1,8-naphthyridine-2-carbaldehyde (173 mg, yield 96.0%). LCMS (TOF MS ES+) m / z [M+H]+: 462.1. 1 1H NMR (400 MHz, DMSO) δ 9.68 (s, 1H), 8.44 (s, 1H), 8.20 (d, J = 12.4 Hz, 1H), 7.61–7.54 (m, 5H), 7.42–7.36 (m, 3H), 4.22 (s, 3H), 2.53 (s, 3H).

[0152] Step 3: Synthesis of 1-(4-chlorophenyl)-7-(difluoromethyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one

[0153] 8-(4-Chlorophenyl)-3-fluoro-6-(2-methyl-2H-indazol-5-yl)-5-(methylamino)-7-oxo-7,8-dihydro-1,8-naphthyridine-2-carbaldehyde (170 mg, 0.368 mmol, 1.0 eq) was dissolved in dichloromethane (8 mL), and then diethylaminosulfur trifluoride (207.3 mg, 1.288 mmol, 3.5 eq) was added. The mixture was stirred at room temperature for 3 h. After the reaction was completed, the mixture was filtered, concentrated, extracted with dichloromethane and water, and the organic phase was concentrated. The product was separated by reverse-phase column chromatography to obtain 1-(4-chlorophenyl)-7-(difluoromethyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one as a white powdery solid (4.6 mg, yield 2.6%). LCMS (TOF MS ES+) m / z [M+H]+: 484.1141. 11H NMR (400 MHz, DMSO) δ 8.41 (s, 1H), 7.80 (d, J = 11.7 Hz, 1H), 7.71–7.51 (m, 5H), 7.38 (s, 2H), 7.15 (dd, J = 8.9, 1.6 Hz, 1H), 6.91–6.53 (m, 1H), 4.19 (s, 3H), 2.49 (s, 3H).

[0154] Example 7: Synthesis of 7-Amino-1-(4-chlorophenyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one (Compound 7)

[0155]

[0156] Step 1: Synthesis of 7-Amino-1-(4-chlorophenyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one

[0157] 7-Chloro-1-(4-chlorophenyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one (60.0 mg, 0.128 mmol, 1.0 eq) prepared in Example 1, (4-methoxyphenyl)methanamine (176 mg, 1.28 mmol, 10.0 eq), and sodium tert-butoxide (24.5 mg, 0.257 mmol, 2.0 eq) were added to dioxane solvent (3.0 mL). Finally, (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (12.2 mg, 0.0128 mmol, 0.1 eq) was added, and the temperature was raised to 60 °C and reacted for 3 hours. After the reaction was completed, the reaction solution was concentrated, trifluoroacetic acid (2.5 mL) was added, stirred at room temperature for 1 hour, the reaction solution was directly concentrated, and white solid 7-Amino-1-(4-chlorophenyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one (10.3 mg, yield 17.98%) was obtained by preparative chromatography. LCMS (TOF MS ES+) m / z [M+H]+: 449.1069. 1 1H NMR (400 MHz, DMSO) δ 8.29 (s, 1H), 8.13 (d, J = 12.3 Hz, 1H), 7.60–7.45 (m, 4H), 7.29–7.21 (m, 3H), 7.11 (d, J = 9.0 Hz, 1H), 5.95 (s, 2H), 4.17 (s, 3H), 2.51 (s, 3H).

[0158] Example 8: Synthesis of 1-(4-chlorophenyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-7-[(3-oxocyclobutyl)methoxy]-1,8-naphthyridin-2(1H)-one (Compound 18)

[0159]

[0160] Step 1: Synthesis of 1-(4-chlorophenyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-7-[(3-oxocyclobutyl)methoxy]-1,8-naphthyridin-2(1H)-one

[0161] 7-Chloro-1-(4-chlorophenyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one (60.0 mg, 0.128 mmol, 1.0 eq) prepared in Example 1, oxetan-3-ylmethanamine (111.5 mg, 1.28 mmol, 10.0 eq), sodium tert-butoxide (24.7 mg, 0.257 mmol, 2.0 eq) were added to dioxane solvent (3.0 mL). Finally, (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (12.2 mg, 0.0128 mmol, 0.1 eq) was added. The temperature was raised to 60 °C and the reaction was carried out for 4 hours. After LCMS detection, the product was purified by preparative chromatography to obtain 1-(4-chlorophenyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-7-[(3-oxocyclobutyl)methoxy]-1,8-naphthyridin-2(1H)-one as a white solid (19.5 mg, yield 29.55%).

[0162] LCMS (TOF MS ES+) m / z [M+H]+: 519.1595. 1 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 5.7 Hz, 1H),

[0163] 7.72 (t, J = 9.3 Hz, 1H), 7.67–7.51 (m, 2H), 7.47–7.38 (m, 2H), 7.29–7.19 (m, 2H), 4.95 (d, J = 5.7 Hz, 1H), 4.62 (dd, J = 7.5, 6.4 Hz, 2H), 4.24–4.12 (m, 5H), 3.41 (t, J = 6.0 Hz, 2H), 2.93 (m, J = 13.0,

[0164] 7.5, 5.7 Hz, 1H), 2.71 (d, J = 4.9 Hz, 3H).

[0165] Example 9: Synthesis of 1-(4-chlorophenyl)-7-{[2-(dimethylamino)ethyl]amino}-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one (Compound 21)

[0166]

[0167] Step 1: Synthesis of 1-(4-chlorophenyl)-7-{[2-(dimethylamino)ethyl]amino}-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one

[0168] 7-Chloro-1-(4-chlorophenyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one (50 mg, 0.106 mmol, 1.0 eq) prepared in Example 1, N,N-dimethylethane-1,2-diamine (128.2 mg, 0.534 mmol, 5.0 eq), methanesulfonic acid (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (10.1 mg, 0.01 mmol, 0.1 eq) and sodium tert-butoxide (20.5 mg, 0.212 mmol, 2.0 eq) were added to 1,4-dioxane (2 mL), and the reaction was carried out at 100 °C. After the reaction was completed, the reaction solution was filtered, and chromatography was used to separate and obtain a yellow solid 1-(4-chlorophenyl)-7-{[2-(dimethylamino)ethyl]amino}-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one (12.7 mg, yield 22.9%). LCMS (TOF MS ES+) m / z [M + H] + : 520.1914. 1 1H NMR (400 MHz, DMSO) δ 8.29 (s, 1H), 8.06 (d, J = 12.4 Hz, 1H), 7.58–7.46 (m, 4H), 7.33–7.23 (m, 3H), 7.17 (dd, J = 8.8, 1.6 Hz, 1H), 5.67 (t, J = 5.5 Hz, 1H), 4.18 (s, 3H), 2.78 (q, J = 6.3 Hz, 2H), 2.55–2.50 (m, 3H), 2.19 (t, J = 6.6 Hz, 2H), 1.89 (s, 6H).

[0169] Example 10: Synthesis of 1-(4-chlorophenyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-7-(2-morpholinoethoxy)-1,8-naphthyridin-2(1H)-one (Compound 23)

[0170]

[0171] Step 1: Synthesis of 1-(4-chlorophenyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-7-(2-morpholinoethoxy)-1,8-naphthyridin-2(1H)-one

[0172] Dissolve 7-chloro-1-(4-chlorophenyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one (80 mg, 0.17 mmol, 1.0 eq) prepared in Example 1, methanesulfonic acid (9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.017 mmol), cesium carbonate (168 mg, 0.51 mmol, 3.0 eq) and 2-morpholinoethanol-1-ol (44 mg, 0.34 mmol, 2.0 eq) in 1,4-dioxane (2 mL) in a vial. After purging with nitrogen, heat to 100 °C and stir for 4 hours. After the reaction is complete, perform separation and purification to obtain a white solid 1-(4-chlorophenyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-7-(2-morpholinoethoxy)-1,8-naphthyridin-2(1H)-one (12 mg, yield 21.58%). LCMS (TOF MS ES+) m / z [M+H] + : 563.1862. 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.01 (d, J = 11.4 Hz, 1H), 7.72 (s, 1H), 7.56 (dd, J = 9.4, 7.8 Hz, 3H), 7.48 (d, J = 5.0 Hz, 1H), 7.38–7.29 (m, 2H), 7.26 (dd, J = 8.9, 1.6 Hz, 1H), 4.17 (s, 3H), 3.60 (t, J = 5.2 Hz, 2H), 3.42 (t, J = 4.5 Hz, 4H), 2.49 (s, 3H), 2.41 (t, J = 5.2 Hz, 2H), 2.20 (s, 4H).

[0173] Example 11: Synthesis of 1-(4-chlorophenyl)-4-(cyclopropylamino)-6-fluoro-7-methyl-3-(2-methyl-2H-indazol-5-yl)-1,8-naphthyridin-2(1H)-one (Compound 35)

[0174]

[0175] Step 1: Synthesis of 1-(4-chlorophenyl)-4-(cyclopropylamino)-6-fluoro-7-methyl-3-(2-methyl-2H-indazol-5-yl)-1,8-naphthyridin-2(1H)-one

[0176] 7-Chloro-1-(4-chlorophenyl)-4-(cyclopropylamino)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-1,8-naphthyridin-2(1H)-one (60 mg, 0.121 mmol, 1.0 eq), methylboronic acid (10.9 mg, 0.182 mmol, 1.5 eq), tetrakis(triphenylphosphine)palladium (14.0 mg, 0.012 mmol, 0.1 eq), and potassium carbonate (41.9 mg, 0.303 mmol, 2.5 eq) were added to 1,4-dioxane (2 mL) and water (0.2 mL), and the reaction was carried out at 110 °C. After the reaction was completed, the reaction solution was filtered, and preparative chromatography was used to obtain a white solid, 1-(4-chlorophenyl)-4-(cyclopropylamino)-6-fluoro-7-methyl-3-(2-methyl-2H-indazol-5-yl)-1,8-naphthyridin-2(1H)-one (20.8 mg, yield 36.1%). LCMS (TOF MS ES+) m / z [M+H] + : 474.1496. 1 H NMR (400 MHz, DMSO) δ 8.32 (s, 1H), 7.84 (d, J = 12.0 Hz, 1H), 7.62–7.54 (m, 2H), 7.54 (dd, J = 8.8, 1.8 Hz, 3H), 7.37–7.28 (m, 2H), 7.10 (dd, J = 8.8, 1.6 Hz, 1H), 4.18 (s, 3H), 2.24 (s, 4H), 0.40–0.29 (m, 4H).

[0177] Example 12: Synthesis of 1-(4-chlorophenyl)-4-(ethylamino)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-7-[(2,2,2-trifluoroethyl)amino]-1,8-naphthyridin-2(1H)-one (Compound 9)

[0178]

[0179] Step 1: Synthesis of 7-chloro-1-(4-chlorophenyl)-4-(ethylamino)-6-fluoro-1,8-naphthyridin-2(1H)-one

[0180] Dissolve 4,7-dichloro-1-(4-chlorophenyl)-6-fluoro-1,8-naphthyridin-2(1H)-one (800 mg, 2.32 mmol, 1.0 eq), ethylamine hydrochloride (569 mg, 6.98 mmol, 3.0 eq) and N,N-diisopropylethylamine (2.4 g, 18.6 mmol, 8.0 eq) in acetonitrile (10 mL), and react at 80 °C. After the reaction is completed, concentrate, add ethanol and water for slurrying, dry the filter cake to obtain yellow solid 7-chloro-1-(4-chlorophenyl)-4-(ethylamino)-6-fluoro-1,8-naphthyridin-2(1H)-one (680 mg, yield 82.9%). LCMS (TOF MS ES+) m / z [M+H] + : 352.0. 1 1H NMR (400 MHz, DMSO) δ 7.85 (t, J = 5.8 Hz, 1H), 7.76 (d, J = 11.0 Hz, 1H), 7.60–7.52 (m, 2H), 7.34–7.24 (m, 2H), 6.64 (s, 1H), 3.00–2.89 (m, 2H), 0.82 (t, J = 7.1 Hz, 3H).

[0181] Step 2: Synthesis of 3-bromo-7-chloro-1-(4-chlorophenyl)-4-(ethylamino)-6-fluoro-1,8-naphthyridin-2(1H)-one

[0182] Dissolve 7-chloro-1-(4-chlorophenyl)-4-(ethylamino)-6-fluoro-1,8-naphthyridin-2(1H)-one (670 mg, 1.90 mmol, 1.0 eq) and N-bromosuccinimide (372 mg, 2.09 mmol, 1.1 eq) in acetonitrile (12 mL), and stir at 35 °C for 1 hour. After the reaction is completed, concentrate, add ethanol and water for slurrying, dry the filter cake to obtain yellow solid 3-bromo-7-chloro-1-(4-chlorophenyl)-4-(ethylamino)-6-fluoro-1,8-naphthyridin-2(1H)-one (770 mg, yield 93.9%). LCMS (TOFMS ES+) m / z [M+H]+: 429.9. 1 1H NMR (400 MHz, DMSO) δ 7.94 (t, J = 5.7 Hz, 1H), 7.83 (d, J = 11.1 Hz, 1H), 7.62–7.54 (m, 2H), 7.39–7.31 (m, 2H), 2.99–2.88 (m, 2H), 0.82 (t, J = 7.1 Hz, 3H).

[0183] Step 3: Synthesis of 7-chloro-1-(4-chlorophenyl)-4-(ethylamino)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-1,8-naphthyridin-2(1H)-one

[0184] Dissolve 3-bromo-7-chloro-1-(4-chlorophenyl)-4-(ethylamino)-6-fluoro-1,8-naphthyridin-2(1H)-one (760 mg, 1.76 mmol, 1.0 eq), (2-methyl-2H-indazol-5-yl)boronic acid (621 mg, 3.52 mmol, 2.0 eq), and potassium phosphate (1.12 g, 5.28 mmol, 3.0 eq) in 1,4-dioxane (20 mL) and water (2 mL). Add dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (129 mg, 0.176 mmol, 0.1 eq), protect with nitrogen, and stir at 80 °C for 12 hours. After the reaction is completed, filter, concentrate, extract with dichloromethane and water, concentrate the organic phase, and separate by reverse-phase column chromatography to obtain a white powdery solid, 7-chloro-1-(4-chlorophenyl)-4-(ethylamino)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-1,8-naphthyridin-2(1H)-one (220 mg, yield 25.8%). LCMS (TOF MS ES+) m / z [M+H]+: 482.0. 1 H NMR (400 MHz, DMSO) δ 8.38 (s, 1H), 7.91–7.79 (m, 2H), 7.70 (t, J = 1.2 Hz, 1H), 7.60 (t, J = 9.1 Hz, 3H), 7.41–7.37 (m, 2H), 7.19 (dd, J = 8.9, 1.6 Hz, 1H), 4.20 (s, 3H), 3.05–2.94 (m, 2H), 0.88 (t, J = 7.1 Hz, 3H).

[0185] Step 4: Synthesis of 1-(4-chlorophenyl)-4-(ethylamino)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-7-[(2,2,2-trifluoroethyl)amino]-1,8-naphthyridin-2(1H)-one

[0186] 7-Chloro-1-(4-chlorophenyl)-4-(ethylamino)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-1,8-naphthyridin-2(1H)-one (70 mg, 0.145 mmol, 1.0 eq), 2,2,2-trifluoroethylamine (143.7 mg, 1.45 mmol, 10.0 eq), methanesulfonic acid (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (13.7 mg, 0.014 mmol, 0.1 eq), and sodium tert-butoxide (27.8 mg, 0.29 mmol, 2.0 eq) were added to 1,4-dioxane (2.5 mL), and the reaction was carried out at 60 °C. After the reaction was completed, the reaction solution was filtered, and the yellow solid 1-(4-chlorophenyl)-4-(ethylamino)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-7-[(2,2,2-trifluoroethyl)amino]-1,8-naphthyridin-2(1H)-one (14.3 mg, yield 18.1%) was obtained by preparative chromatography. LCMS (TOF MS ES+) m / z [M+H] + : 545.1398. 1 H NMR (400 MHz, DMSO) δ 8.32 (s, 1H), 8.12 (d, J = 12.5 Hz, 1H), 7.64–7.55 (m, 2H), 7.49 (t, J = 7.5 Hz, 3H), 7.32–7.23 (m, 2H), 7.11 (dd, J = 8.8, 1.6 Hz, 1H), 6.34 (t, J = 7.2 Hz, 1H), 4.17 (s, 3H), 3.28 (dd, J = 9.6, 7.1 Hz, 2H), 2.95 (m, J = 6.9 Hz, 2H), 0.84 (t, J = 7.0 Hz, 3H).

[0187] Example 13: Synthesis of 7-chloro-1-(4-chlorophenyl)-4-(cyclopropylamino)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-1,8-naphthyridin-2(1H)-one (Compound 34)

[0188]

[0189] Step 1: Synthesis of 7-chloro-1-(4-chlorophenyl)-4-(cyclopropylamino)-6-fluoro-1,8-naphthyridin-2(1H)-one

[0190] 4,7-Dichloro-1-(4-chlorophenyl)-6-fluoro-1,8-naphthyridin-2(1H)-one (500 mg, 1.46 mmol, 1.0 eq), cyclopropylamine (125 mg, 2.19 mmol, 1.5 eq) and N,N-diisopropylethylamine (752 mg, 5.83 mmol, 4.0 eq) were dissolved in acetonitrile (20 mL) and reacted at 80 °C. After the reaction was completed, the reaction solution was concentrated and triturated with ethanol and water to obtain the yellow solid 7-chloro-1-(4-chlorophenyl)-4-(cyclopropylamino)-6-fluoro-1,8-naphthyridin-2(1H)-one (410 mg, yield 77.3%). LCMS (TOFMS ES+) m / z [M+H] + : 364.0. 1 H NMR (400 MHz, DMSO) δ 7.97 (d, J = 3.6 Hz, 1H), 7.79 (d, J = 11.1 Hz, 1H), 7.60–7.55 (m, 2H), 7.36–7.31 (m, 2H), 6.70 (s, 1H), 2.26 (m, J = 7.6, 3.9 Hz, 1H), 0.41–0.36 (m, 4H).

[0191] Step 2: Synthesis of 3-bromo-7-chloro-1-(4-chlorophenyl)-4-(cyclopropylamino)-6-fluoro-1,8-naphthyridin-2(1H)-one

[0192] 7-Chloro-1-(4-chlorophenyl)-4-(cyclopropylamino)-6-fluoro-1,8-naphthyridin-2(1H)-one (400 mg, 1.10 mmol, 1.0 eq) and N-bromosuccinimide (205 mg, 1.15 mmol, 1.05 eq) were dissolved in acetonitrile (15 mL) and stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated and triturated with ethanol and water to obtain the yellow solid 3-bromo-7-chloro-1-(4-chlorophenyl)-4-(cyclopropylamino)-6-fluoro-1,8-naphthyridin-2(1H)-one (405 mg, yield 83.1%). LCMS (TOF MSES+) m / z [M+H]+: 441.9. 1 H NMR (400 MHz, DMSO) δ 8.05 (d, J = 3.2 Hz, 1H), 7.86 (d, J = 11.1 Hz, 1H), 7.63–7.55 (m, 2H), 7.43–7.34 (m, 2H), 2.25 (dd, J = 7.6, 4.1 Hz, 1H), 0.42–0.31 (m, 4H).

[0193] Step 3: Synthesis of 7-chloro-1-(4-chlorophenyl)-4-(cyclopropylamino)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-1,8-naphthyridin-2(1H)-one

[0194] 3-Bromo-7-chloro-1-(4-chlorophenyl)-4-(cyclopropylamino)-6-fluoro-1,8-naphthyridin-2(1H)-one (100 mg, 0.22 mmol, 1.0 eq), (2-methyl-2H-indazol-5-yl)boronic acid (79 mg, 0.44 mmol, 2.0 eq) and potassium phosphate (144 mg, 0.66 mmol, 3.0 eq) were dissolved in 1,4-dioxane (2.5 mL) and water (0.25 mL). Then dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (16 mg, 0.022 mmol, 0.1 eq) was added. Under nitrogen protection, the mixture was stirred at 80 °C for 12 hours. After the reaction was completed, it was filtered, and the product was separated by reverse-phase column chromatography to obtain a beige solid, 7-chloro-1-(4-chlorophenyl)-4-(cyclopropylamino)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-1,8-naphthyridin-2(1H)-one (66.2 mg, yield 60.9%). LCMS (TOF MS ES+) m / z [M+H]+: 494.0148. 1 H NMR (400 MHz, DMSO) δ 8.37 (s, 1H), 7.94–7.88 (m, 1H), 7.86 (d, J = 11.2 Hz, 1H), 7.69 (s, 1H), 7.63–7.52 (m, 3H), 7.39 (d, J = 8.6 Hz, 2H), 7.18 (dd, J = 8.9, 1.7 Hz, 1H), 4.18 (s, 3H), 2.26 (d, J = 7.0 Hz, 1H), 0.42–0.32 (m, 4H).

[0195] Example 14: Synthesis of 1-(4-chlorophenyl)-4-(cyclopropylamino)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-7-[(2,2,2-trifluoroethyl)amino]-1,8-naphthyridin-2(1H)-one (Compound 10)

[0196]

[0197] Step 1: Synthesis of 1-(4-chlorophenyl)-4-(cyclopropylamino)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-7-[(2,2,2-trifluoroethyl)amino]-1,8-naphthyridin-2(1H)-one

[0198] 7-Chloro-1-(4-chlorophenyl)-4-(cyclopropylamino)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-1,8-naphthyridin-2(1H)-one (70 mg, 0.14 mmol, 1.0 eq) prepared in Example 13, 2,2,2-trifluoroethylamine (140.3 mg, 1.40 mmol, 10.0 eq), methanesulfonic acid (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (13.4 mg, 0.014 mmol, 0.1 eq) and sodium tert-butoxide (27.2 mg, 0.28 mmol, 2.0 eq) were added to 1,4-dioxane (2 mL), and the reaction was carried out at 60 °C. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated and separated by preparative chromatography to obtain a yellow solid 1-(4-chlorophenyl)-4-(cyclopropylamino)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-7-[(2,2,2-trifluoroethyl)amino]-1,8-naphthyridin-2(1H)-one (22.1 mg, yield 28.3%). LCMS (TOF MS ES+) m / z [M+H] + : 557.1467. 1 H NMR (400 MHz, DMSO) δ 8.33 (s, 1H), 8.13 (d, J = 12.5 Hz, 1H), 7.64–7.54 (m, 3H), 7.53–7.45 (m, 2H), 7.33–7.25 (m, 2H), 7.11 (dd, J = 8.9, 1.6 Hz, 1H), 6.37 (t, J = 7.2 Hz, 1H), 4.18 (s, 3H), 3.31–3.22 (m, 2H), 2.22 (d, J = 8.1 Hz, 1H), 0.38–0.31 (m, 4H).

[0199] Example 15: Synthesis of 7-chloro-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1-(o-tolyl)-1,8-naphthyridin-2(1H)-one (Compound 28)

[0200]

[0201] Step 1: Synthesis of 6-chloro-5-fluoro-2-(o-tolylamino)nicotinic acid

[0202] o-Toluidine (5.1 g, 47.6 mmol, 2.0 eq) was dissolved in ultradry tetrahydrofuran (200 mL), cooled to -78 °C, and lithium bis(trimethylsilyl)amide (71.4 mL, 71.4 mmol, 3.0 eq) was slowly added dropwise. After the addition was complete, the reaction was continued for 1 hour. Subsequently, 2,6-dichloro-5-fluoronicotinic acid (5.0 g, 23.8 mmol, 1.0 eq) was dissolved in ultradry tetrahydrofuran (50 mL) and slowly added dropwise to the reaction system at -78 °C. After the addition was complete, the reaction mixture was transferred to room temperature and reacted for 1 hour. After the reaction was completed, dilute hydrochloric acid was added to adjust the pH to 4, and then extracted three times with water and ethyl acetate. The organic phases were combined, dried, concentrated, and slurried (petroleum ether:ethyl acetate = 5:1). After filtration, yellow solid 6-chloro-5-fluoro-2-(o-tolylamino)nicotinic acid (4.66 g, yield 69.9%) was obtained. LCMS (TOF MS ES+) m / z [M+H]+: 281.0320. 1 H NMR (400 MHz, DMSO) δ 13.77 (s, 1H), 10.26 (s, 1H), 8.21 (m, J = 8.5, 2.7, 1.2 Hz, 1H), 8.07 (dd, J = 8.2, 1.3 Hz, 1H), 7.26–7.17 (m, 2H), 7.07–6.98 (m, 1H), 2.29 (s, 3H).

[0203] Step 2: Synthesis of ethyl 3-[6-chloro-5-fluoro-2-(o-tolylamino)pyridin-3-yl]-3-oxopropionate

[0204] Step 1: Dissolve 6-chloro-5-fluoro-2-(o-tolylamino)nicotinic acid (4.5 g, 16.1 mmol, 1.0 eq) and N,N-dimethylformamide (118 mg, 1.6 mmol, 0.1 eq) in dichloromethane (45 mL), and dropwise add oxalyl chloride (3.0 g, 24.1 mmol, 1.5 eq) until no bubbles are generated. Step 2: Dissolve potassium 3-ethoxy-3-oxopropionate (4.1 g, 24.1 mmol, 1.5 eq), magnesium chloride (4.6 g, 48.2 mmol, 3.0 eq) and triethylamine (7.3 g, 72.45 mmol, 4.5 eq) in tetrahydrofuran (60 mL) solution, and stir under an ice bath. Concentrate the mixture from Step 1, dissolve it in tetrahydrofuran (60 mL), and then slowly add it dropwise to the reaction solution from Step 2 at 0 °C. After addition, react at room temperature for 1.5 hours. After the reaction is completed, quench the mixture with dilute hydrochloric acid, and then extract it three times with ethyl acetate and water. Concentrate the organic phase, mix the sample, and purify it by normal-phase column chromatography. In a petroleum ether and ethyl acetate system, when the ethyl acetate content is 36%, yellow solid ethyl 3-[6-chloro-5-fluoro-2-(o-tolylamino)pyridin-3-yl]-3-oxopropionate (4.8 g, yield 85.7%) is obtained. 1 H NMR (400 MHz, DMSO) δ 10.63 (s, 1H), 8.55 (d, J = 9.3 Hz, 1H), 7.96 (dd, J = 8.0, 1.3 Hz, 1H), 7.30 (dd, J = 7.5, 1.6 Hz, 1H), 7.26 (m, J = 7.8, 1.6 Hz, 1H), 7.10 (m, J = 7.4, 1.3 Hz, 1H), 4.32 (s, 2H), 4.17 (m, J = 7.1 Hz, 2H), 3.30 (s, 3H) 1.23 (m, J = 7.1 Hz, 3H).

[0205] Step 3: Synthesis of 7-chloro-6-fluoro-4-hydroxy-1-(o-tolyl)-1,8-naphthyridin-2(1H)-one

[0206] Dissolve ethyl 3-[6-chloro-5-fluoro-2-(o-tolylamino)pyridin-3-yl]-3-oxopropionate (4.8 g, 13.7 mmol, 1.0 eq) and potassium carbonate (3.78 g, 27.4 mmol, 2.0 eq) in ethanol (100 mL), and then react at 70 °C for 1 hour. After the reaction is complete, filter, concentrate the filtrate, and purify it by normal-phase column chromatography to obtain yellow solid 7-chloro-6-fluoro-4-hydroxy-1-(o-tolyl)-1,8-naphthyridin-2(1H)-one (2.1 g, yield 50%). 11H NMR (400 MHz, DMSO) δ 12.25 (s, 1H), 8.29 (d, J = 8.0 Hz, 1H), 7.43–7.31 (m, 3H), 7.15 (dd, J = 7.5, 1.5 Hz, 1H), 6.03 (s, 1H), 1.91 (s, 3H).

[0207] Step 4: Synthesis of 4,7-dichloro-6-fluoro-1-(o-tolyl)-1,8-naphthyridin-2(1H)-one

[0208] 7-Chloro-6-fluoro-4-hydroxy-1-(o-tolyl)-1,8-naphthyridin-2(1H)-one (2.1 g, 6.9 mmol, 1.0 eq) was dissolved in phosphorus oxychloride (20 mL), and the reaction was carried out at 70 °C for 16 h. After the reaction was complete, the mixture was concentrated, and then sodium bicarbonate solution was added to quench phosphorus oxychloride. Then, it was extracted with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate to remove excess water, concentrated, and triturated (with ethyl acetate). The filter cake was retained to obtain yellow solid 4,7-dichloro-6-fluoro-1-(o-tolyl)-1,8-naphthyridin-2(1H)-one (850 mg, 2.63 mmol, yield 38%). 1 1H NMR (400 MHz, DMSO) δ 8.53 (d, J = 8.2 Hz, 1H), 7.44–7.34 (m, 3H), 7.30 (s, 1H), 7.23 (dd, J = 7.3, 1.5 Hz, 1H), 1.95 (s, 3H).

[0209] Step 5: Synthesis of 7-chloro-6-fluoro-4-(methylamino)-1-(o-tolyl)-1,8-naphthyridin-2(1H)-one

[0210] 4,7-Dichloro-6-fluoro-1-(o-tolyl)-1,8-naphthyridin-2(1H)-one (850 mg, 2.63 mmol, 1.0 eq), methylamine hydrochloride (534 mg, 7.92 mmol, 3.0 eq), and N,N-diisopropylethylamine (2.72 g, 21.11 mmol, 8.0 eq) were dissolved in anhydrous acetonitrile (10 mL), and the reaction was carried out at 80 °C for 2 h. After the reaction was complete, the reaction solution was concentrated and triturated (with water and ethanol). The filter cake was retained and dried to obtain crude yellow solid 7-chloro-6-fluoro-4-(methylamino)-1-(o-tolyl)-1,8-naphthyridin-2(1H)-one (922 mg). 1 1H NMR (400 MHz, DMSO) δ 7.82–7.70 (m, 2H), 7.43–7.28 (m, 3H), 7.14 (dd, J = 7.3, 1.7 Hz, 1H), 6.67 (s, 1H), 2.43 (d, J = 4.6 Hz, 3H), 1.93 (s, 3H).

[0211] Step 6: Synthesis of 3-bromo-7-chloro-6-fluoro-4-(methylamino)-1-(o-tolyl)-1,8-naphthyridin-2(1H)-one

[0212] Dissolve 7-chloro-6-fluoro-4-(methylamino)-1-(o-tolyl)-1,8-naphthyridin-2(1H)-one (900 mg, 2.83 mmol, 1.0 eq), N-bromosuccinimide (522 mg, 3.12 mmol, 1.1 eq) in acetonitrile (10 mL), and react at 35 °C for 2 hours. After the reaction is complete, concentrate the reaction solution, perform trituration (ethanol and water), filter, retain the filter cake, and dry to obtain the yellow solid 3-bromo-7-chloro-6-fluoro-4-(methylamino)-1-(o-tolyl)-1,8-naphthyridin-2(1H)-one (980 mg, 2.48 mmol, yield 87.7%). 1 H NMR (400 MHz, DMSO) δ 7.85 (d, J = 11.1 Hz, 2H), 7.45–7.31 (m, 3H), 7.18 (dd, J = 7.5, 1.6 Hz, 1H), 2.43 (d, J = 3.8 Hz, 3H), 1.93 (s, 3H).

[0213] Step 7: Synthesis of 7-chloro-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1-(o-tolyl)-1,8-naphthyridin-2(1H)-one

[0214] Dissolve 3-bromo-7-chloro-6-fluoro-4-(methylamino)-1-(o-tolyl)-1,8-naphthyridin-2(1H)-one (100 mg, 0.25 mmol, 1.0 eq), (2-methyl-2H-indazol-5-yl)boronic acid (ninety mg, 0.51 mmol, 2.0 eq), potassium phosphate (130 mg, 0.64 mmol, 2.5 eq) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (18 mg, 0.03 mmol, 0.1 eq) in water (0.5 mL) and 1,4-dioxane (2 mL), and react at 80 °C for 2 hours. After the reaction is complete, perform preparative separation and purification to obtain the light yellow solid 7-chloro-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1-(o-tolyl)-1,8-naphthyridin-2(1H)-one (33 mg, yield 30%). LCMS (TOF MS ES+) m / z [M+H] + : 448.1327 / 450.1300. 11H NMR (400 MHz, DMSO) δ 8.36 (s, 1H), 7.85 (d, J = 11.2 Hz, 1H), 7.72–7.64 (m, 2H), 7.59 (d, J = 8.9 Hz, 1H), 7.42–7.26 (m, 3H), 7.22–7.14 (m, 2H), 4.18 (s, 3H), 2.44 0 (d, J = 4.6 Hz, 3H), 1.98 (s, 3H).

[0215] Example 16: Synthesis of 7-chloro-6-fluoro-1-(4-methoxyphenyl)-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one (Compound 29)

[0216]

[0217] Step 1: Synthesis of 6-chloro-5-fluoro-2-((4-methoxyphenyl)amino)nicotinic acid

[0218] Dissolve 4-chloroaniline (5.86 g, 47.6 mmol, 2.0 eq) in ultradry tetrahydrofuran (100 mL), cool to -78 °C, slowly add lithium bis(trimethylsilyl)amide (71.4 mL, 71.4 mmol, 3.0 eq) dropwise. After the addition, continue the reaction for 1 hour. Then dissolve 4-methoxyaniline (5 g, 23.8 mmol, 1.0 eq) in ultradry tetrahydrofuran (40 mL) and slowly add it dropwise to the reaction system at -78 °C. After the addition, transfer the reaction mixture to room temperature and react for 1 hour. After the reaction is completed, quench with dilute hydrochloric acid solution, extract with ethyl acetate and water, then wash with saturated brine, concentrate to remove the solvent to obtain a light brown solid, and add methanol for slurrying to obtain a light green solid 6-chloro-5-fluoro-2-((4-methoxyphenyl)amino)nicotinic acid (6.0 g, yield 85.2%). LCMS (TOF MS ES+) m / z [M+H]+: 297.02. 1 1H NMR (400 MHz, DMSO) δ 10.16 (s, 1H), 8.18 (d, J = 8.3 Hz, 1H), 7.53–7.45 (m, 2H), 6.98–6.89 (m, 2H), 3.75 (s, 3H).

[0219] Step 2: Synthesis of ethyl 3-{6-chloro-5-fluoro-2-[(4-methoxyphenyl)amino]pyridin-3-yl}-3-oxopropanoate

[0220] Ethyl malonate potassium salt (4.87 g, 28.6 mmol, 1.5 eq), magnesium chloride (5.45 g, 57.3 mmol, 3.0 eq) and triethylamine (8.69 g, 85.9 mmol, 4.5 eq) were dissolved in acetonitrile solution (80 mL), and the reaction system 1 was obtained by stirring at room temperature. 6-Chloro-5-fluoro-2-((4-methoxyphenyl)amino)nicotinic acid (5.65 g, 19.1 mmol, 1.0 eq) was dissolved in ultradry dichloromethane (80 mL), a small amount of N,N-dimethylformamide was added as a catalyst, and oxalyl chloride (3.64 g, 28.6 mmol, 1.5 eq) was added dropwise at room temperature. After the raw materials were completely reacted detected by TLC, the reaction solution was concentrated to obtain a yellow solid. The yellow solid was dissolved in tetrahydrofuran solution (100 mL) and slowly added dropwise to the reaction system 1 at 0 °C, and the reaction continued at room temperature for 2 hours. After the reaction was completed, it was adjusted to acidic with dilute hydrochloric acid, extracted with ethyl acetate and water, dried and concentrated, and purified by normal phase to obtain the target product ethyl 3-{6-chloro-5-fluoro-2-[(4-methoxyphenyl)amino]pyridin-3-yl}-3-oxopropionate (4.1 g, 58.57%). LCMS (TOF MS ES+) m / z [M+H]+: 367.06. 1 H NMR (400 MHz, DMSO) δ 10.62 (s, 1H), 8.48 (d, J = 9.2 Hz, 1H), 7.55–7.46 (m, 2H), 6.98–6.90 (m, 2H), 4.27 (s, 2H), 4.18–3.96 (m, 2H), 3.75 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H).

[0221] Step 3: Synthesis of 7-chloro-6-fluoro-4-hydroxy-1-(4-methoxyphenyl)-1,8-naphthyridin-2(1H)-one

[0222] Ethyl 3-{6-chloro-5-fluoro-2-[(4-methoxyphenyl)amino]pyridin-3-yl}-3-oxopropionate (4.0 g, 10.9 mmol, 1.0 eq) was dissolved in absolute ethanol (10 mL), potassium carbonate (3.02 g, 21.9 mmol, 2.0 eq) was added, and the reaction was carried out at 70 °C for 3 hours. After the reaction was completed, it was filtered through diatomaceous earth and concentrated to obtain the target product 7-chloro-6-fluoro-4-hydroxy-1-(4-methoxyphenyl)-1,8-naphthyridin-2(1H)-one (4.1 g, yield 115%). LCMS (TOF MS ES+) m / z [M+H]+: 321.04. 1 H NMR (400 MHz, DMSO) δ 8.04 (d, J = 8.3 Hz, 1H), 7.15–6.83 (m, 4H), 4.93 (s, 1H), 3.80 (s, 3H).

[0223] Step 4: Synthesis of 4,7-dichloro-6-fluoro-1-(4-methoxyphenyl)-1,8-naphthyridin-2(1H)-one

[0224] Add 7-chloro-6-fluoro-4-hydroxy-1-(4-methoxyphenyl)-1,8-naphthyridin-2(1H)-one (4.0 g, 12.5 mmol, 1.0 eq) to a reaction flask, add phosphorus oxychloride (10 mL), heat up to 70 °C and react overnight. Concentrate under reduced pressure to remove phosphorus oxychloride, add saturated sodium bicarbonate solution, extract with ethyl acetate, dry and concentrate, slurry with ethyl acetate, and filter to obtain the target product 4,7-dichloro-6-fluoro-1-(4-methoxyphenyl)-1,8-naphthyridin-2(1H)-one (2.9 g, yield 69.1%). LCMS (TOF MSES+) m / z [M+H]+: 338.98. 1 1H NMR (400 MHz, DMSO) δ 8.48 (d, J = 8.1 Hz, 1H), 7.26–7.17 (m, 3H), 7.12–7.04 (m, 2H), 3.84 (s, 3H).

[0225] Step 5: Synthesis of 7-chloro-6-fluoro-1-(4-methoxyphenyl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one

[0226] Dissolve 4,7-dichloro-6-fluoro-1-(4-methoxyphenyl)-1,8-naphthyridin-2(1H)-one (900 mg, 2.66 mmol, 1.0 eq), methylamine hydrochloride (450 mg, 6.66 mmol, 2.5 eq) and N,N-diisopropylethylamine (2.06 g, 15.9 mmol, 6.0 eq) in acetonitrile (20 mL), and react at 80 °C for 2 hours. After the reaction is completed, extract and separate with ethyl acetate and water, concentrate the organic phase to obtain a pale yellow solid, slurry with an ethanol aqueous solution and filter to obtain 7-chloro-6-fluoro-1-(4-methoxyphenyl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one (740 mg, yield 83.5%). LCMS (TOF MS ES+) m / z [M+H] + : 334.06. 1 1H NMR (400 MHz, DMSO) δ 7.78–7.66 (m, 2H), 7.15 (d, J = 8.5 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 6.62 (s, 1H), 3.81 (s, 3H), 2.49 (s, 3H).

[0227] Step 6: Synthesis of 3-bromo-7-chloro-6-fluoro-1-(4-methoxyphenyl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one

[0228] 7-Chloro-6-fluoro-1-(4-methoxyphenyl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one (730 mg, 2.19 mmol, 1.0 eq) and N-bromosuccinimide (429 mg, 2.41 mmol, 1.1 eq) were added to acetonitrile solution (8 mL), and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated, and the residue was triturated with aqueous acetonitrile and filtered to obtain pale yellow solid 3-bromo-7-chloro-6-fluoro-1-(4-methoxyphenyl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one (749 mg, yield 83.5%). LCMS (TOF MS ES+) m / z [M+H]+: 413.97. 1 H NMR (400 MHz, DMSO) δ 7.79 (d, J = 7.6 Hz, 2H), 7.25–7.13 (m, 2H), 7.08–6.99 (m, 2H), 3.81 (s, 3H), 2.51 (d, J = 2.1 Hz, 3H).

[0229] Step 7: Synthesis of 7-chloro-6-fluoro-1-(4-methoxyphenyl)-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one

[0230] 3-Bromo-7-chloro-6-fluoro-1-(4-methoxyphenyl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one (60 mg, 0.15 mmol, 1.0 eq), 2-methyl-2H-indazole-5-boronic acid (52.5 mg, 0.30 mmol, 1.5 eq) and potassium phosphate (79.6 mg, 0.375 mmol, 2.5 eq) were added to a mixed solvent of dioxane (5 mL) and water (0.5 mL). Finally, 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (11.0 mg, 0.015 mmol, 0.1 eq) was added, and the reaction was carried out at 80 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated and purified by preparative chromatography to obtain yellow solid 7-chloro-6-fluoro-1-(4-methoxyphenyl)-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one (25 mg, yield 35.2%). LCMS (TOF MS ES+) m / z [M+H]+: 464.1015. 11H NMR (400 MHz, DMSO) δ 8.36 (s, 1H), 7.83 (d, J = 11.2 Hz, 1H), 7.70–7.62 (m, 2H), 7.58 (d, J = 8.9 Hz, 1H), 7.25–7.18 (m, 2H), 7.07–6.99 (m, 2H), 4.18 (s, 3H), 3.80 (s, 3H), 2.52 (d, J = 4.6 Hz, 3H).

[0231] Example 17: Synthesis of 7-chloro-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1-[4-(trifluoromethoxy)phenyl]-1,8-naphthyridin-2(1H)-one (Compound 30)

[0232]

[0233] Step 1: Synthesis of 6-chloro-5-fluoro-2-{[4-(trifluoromethoxy)phenyl]amino}nicotinic acid

[0234] Dissolve 4-(trifluoromethoxy)aniline (8.43 g, 47.6 mmol, 2.0 eq) in ultradry tetrahydrofuran (200 mL), cool to -78 °C, slowly add lithium bis(trimethylsilyl)amide (71.4 mL, 71.4 mmol, 3.0 eq) dropwise. After the addition is complete, continue the reaction for 1 hour. Then dissolve 2,6-dichloro-5-fluoronicotinic acid (5.0 g, 23.8 mmol, 1.0 eq) in ultradry tetrahydrofuran (50 mL) and slowly add it to the reaction system at -78 °C. After the addition is complete, transfer the reaction mixture to room temperature and react for 1 hour. After the reaction is completed, quench the reaction with saturated ammonium chloride solution, extract with ethyl acetate (200 mL). Combine the organic phases, dry and concentrate, then add an appropriate amount of ethyl acetate for washing and slurrying. After filtration, a pale yellow solid, 6-chloro-5-fluoro-2-{[4-(trifluoromethoxy)phenyl]amino}nicotinic acid (4.8 g, yield 60.0%), is obtained. LCMS (TOF MS ES+) m / z [M+H]+: 351.0. 1 1H NMR (400 MHz, DMSO) δ 14.18 (s, 1H), 10.46 (s, 1H), 8.26 (dd, J = 8.6, 1.1 Hz, 1H), 7.79–7.68 (m, 2H), 7.37 (d, J = 8.6 Hz, 2H).

[0235] Step 2: Synthesis of ethyl 3-(6-chloro-5-fluoro-2-{[4-(trifluoromethoxy)phenyl]amino}pyridin-3-yl)-3-oxopropionate

[0236] Step 1: Dissolve 6-chloro-5-fluoro-2-{[4-(trifluoromethoxy)phenyl]amino}nicotinic acid (4.75 g, 13.6 mmol, 1.0 eq) and N,N-dimethylformamide (50 mg, 0.68 mmol, 0.05 eq) in dichloromethane (50 mL), add oxalyl chloride (2.6 g, 20.4 mmol, 1.5 eq) dropwise, and react for 1 hour until no bubbles are generated. Step 2: Dissolve potassium 3-ethoxy-3-oxopropionate (3.46 g, 20.4 mmol, 1.5 eq), magnesium chloride (3.88 g, 40.7 mmol, 3.0 eq) and triethylamine (6.2 g, 61.07 mmol, 4.5 eq) in tetrahydrofuran solution (30 mL), and stir under an ice bath. Concentrate the mixture from Step 1, then add tetrahydrofuran (5 mL), and then slowly add it dropwise to the reaction solution from Step 2 at 0 °C. After the reaction is completed, extract the mixture, concentrate the organic phase, mix the sample and purify it by normal-phase column chromatography to obtain the yellow solid ethyl 3-(6-chloro-5-fluoro-2-{[4-(trifluoromethoxy)phenyl]amino}pyridin-3-yl)-3-oxopropionate (4.07 g, yield 71%). 1 H NMR (400 MHz, DMSO) δ 10.81 (s, 1H), 8.57 (d, J = 9.2 Hz, 1H), 7.81–7.71 (m, 2H), 7.40 (d, J = 8.6 Hz, 2H), 4.32 (s, 2H), 4.17 (q, J = 7.1 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H).

[0237] Step 3: Synthesis of 7-chloro-6-fluoro-4-hydroxy-1-[4-(trifluoromethoxy)phenyl]-1,8-naphthyridin-2(1H)-one

[0238] Dissolve ethyl 3-(6-chloro-5-fluoro-2-{[4-(trifluoromethoxy)phenyl]amino}pyridin-3-yl)-3-oxopropionate (4.0 g, 9.5 mmol, 1.0 eq) and potassium carbonate (2.63 g, 19 mmol, 2.0 eq) in ethanol (40 mL), and then react at 70 °C for 1 hour. After the reaction is complete, cool and filter the mixture, concentrate the filtrate to obtain the crude yellow solid 7-chloro-6-fluoro-4-hydroxy-1-[4-(trifluoromethoxy)phenyl]-1,8-naphthyridin-2(1H)-one (4.05 g). 1 H NMR (400 MHz, DMSO) δ 8.10 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.36–7.24 (m, 2H), 4.98 (s, 1H).

[0239] Step 4: Synthesis of 4,7-dichloro-6-fluoro-1-[4-(trifluoromethoxy)phenyl]-1,8-naphthyridin-2(1H)-one

[0240] 7-Chloro-6-fluoro-4-hydroxy-1-[4-(trifluoromethoxy)phenyl]-1,8-naphthyridin-2(1H)-one (4.0 g, 10.6 mmol, 1.0 eq) was dissolved in phosphorus oxychloride (35 mL), and the reaction was carried out at 70 °C for 16 h. After the reaction was complete, the mixture was concentrated, then sodium bicarbonate solution was added to quench phosphorus oxychloride, and then extracted with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate to remove excess water, concentrated, and slurried (ethyl acetate), and the filter cake was retained to obtain 4,7-dichloro-6-fluoro-1-[4-(trifluoromethoxy)phenyl]-1,8-naphthyridin-2(1H)-one as a yellow solid (2.9 g, 7.3 mmol, yield 69.8%). 1 1H NMR (400 MHz, DMSO) δ 8.53 (d, J = 8.2 Hz, 1H), 7.62–7.56 (m, 2H), 7.53–7.48 (m, 2H), 7.30 (s, 1H).

[0241] Step 5: Synthesis of 7-chloro-6-fluoro-4-(methylamino)-1-[4-(trifluoromethoxy)phenyl]-1,8-naphthyridin-2(1H)-one

[0242] 4,7-Dichloro-6-fluoro-1-[4-(trifluoromethoxy)phenyl]-1,8-naphthyridin-2(1H)-one (900 mg, 2.3 mmol, 1.0 eq), methylamine hydrochloride (466 mg, 6.8 mmol, 3.0 eq), and N,N-diisopropylethylamine (2.36 mg, 18.4 mmol, 8.0 eq) were dissolved in anhydrous acetonitrile (10 mL), and the reaction was carried out at 80 °C overnight. After the reaction was complete, the reaction solution was concentrated and slurried (water and ethanol), and the filter cake was retained and dried to obtain 7-chloro-6-fluoro-4-(methylamino)-1-[4-(trifluoromethoxy)phenyl]-1,8-naphthyridin-2(1H)-one as a yellow solid (833 mg, 2.15 mmol, yield 93.5%). 1 1H NMR (400 MHz, DMSO) δ 7.82–7.75 (m, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.5 Hz, 2H), 6.68 (s, 1H), 2.48 (d, J = 4.5 Hz, 3H).

[0243] Step 6: Synthesis of 3-bromo-7-chloro-6-fluoro-4-(methylamino)-1-[4-(trifluoromethoxy)phenyl]-1,8-naphthyridin-2(1H)-one

[0244] Dissolve 7-chloro-6-fluoro-4-(methylamino)-1-[4-(trifluoromethoxy)phenyl]-1,8-naphthyridin-2(1H)-one (800 mg, 2.06 mmol, 1.0 eq) and N-bromosuccinimide (403 mg, 2.27 mmol, 1.1 eq) in acetonitrile (8 mL), and react at 35 °C for 3 hours. After the reaction is complete, concentrate the reaction solution, perform trituration (ethanol and water), filter, retain the filter cake, and dry it to obtain the yellow solid 3-bromo-7-chloro-6-fluoro-4-(methylamino)-1-[4-(trifluoromethoxy)phenyl]-1,8-naphthyridin-2(1H)-one (830 mg, 1.78 mmol, yield 86.6%), namely ALKZJ001-S131-6. 1 H NMR (400 MHz, DMSO) δ 7.89–7.82 (m, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 9.0 Hz, 2H), 2.47 (d, J = 4.6 Hz, 3H).

[0245] Step 7: Synthesis of 7-chloro-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1-[4-(trifluoromethoxy)phenyl]-1,8-naphthyridin-2(1H)-one

[0246] Dissolve 3-bromo-7-chloro-6-fluoro-4-(methylamino)-1-[4-(trifluoromethoxy)phenyl]-1,8-naphthyridin-2(1H)-one (60 mg, 0.13 mmol, 1.0 eq), (2-methyl-2H-indazol-5-yl)boronic acid (45 mg, 0.26 mmol, 2.0 eq), potassium phosphate (690 mg, 0.325 mmol, 2.5 eq), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (9.5 mg, 0.013 mmol, 0.1 eq) in water (0.2 mL) and 1,4-dioxane (2 mL), and react at 80 °C for 16 hours. After the reaction is complete, filter and send it for preparation. Obtain the yellow solid 7-chloro-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1-[4-(trifluoromethoxy)phenyl]-1,8-naphthyridin-2(1H)-one (40.2 mg, 0.077 mmol, yield 30%). LCMS (TOF MS ES+) m / z [M+H] + : 518.0528 / 520.0504. 11H NMR (400 MHz, DMSO) δ 8.37 (s, 1H), 7.86 (d, J = 11.2 Hz, 1H), 7.72 (d, J = 5.1 Hz, 1H), 7.69 (s, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.54–7.47 (m, 4H), 7.18 (dd, J = 9.0, 1.6 Hz, 1H), 4.18 (s, 3H), 2.49 (d, J = 1.7 Hz, 3H).

[0247] Example 18: Synthesis of 3-(7-chloro-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-2-oxo-1,8-naphthyridin-1(2H)-yl)benzonitrile (Compound 31)

[0248]

[0249] Step 1: Synthesis of 6-chloro-2-[(3-cyanophenyl)amino]-5-fluoronicotinic acid

[0250] Dissolve 3-aminobenzonitrile (6.5 g, 55.26 mmol, 2.0 eq) in ultradry tetrahydrofuran (200 mL), cool to -78 °C, slowly add lithium bis(trimethylsilyl)amide (83 mL, 82.9 mmol, 3.0 eq) dropwise. After the addition, continue the reaction for 1 hour. Then dissolve 2,6-dichloro-5-fluoronicotinic acid (5.8 g, 27.63 mmol, 1.0 eq) in ultradry tetrahydrofuran (50 mL) and slowly add it dropwise to the reaction system at -78 °C. After the addition, transfer the reaction mixture to room temperature and react for 1 hour. After the reaction is completed, quench the reaction with dilute hydrochloric acid solution, extract with ethyl acetate (400 mL). Combine the organic phases, dry and concentrate, then add an appropriate amount of ethyl acetate for washing and slurrying, and filter to obtain a pale yellow solid 6-chloro-2-[(3-cyanophenyl)amino]-5-fluoronicotinic acid (5.4 g, yield 67.16%). LCMS (TOFMS ES+) m / z [M+H]+: 292. 1 1H NMR (400 MHz, DMSO-d6) δ 14.23 (s, 1H), 10.53 (s, 1H), 8.29 (m, J = 8.5, 2.3 Hz, 1H), 8.22–8.17 (m, 1H), 7.91 (m, J = 8.2, 1.9 Hz, 1H), 7.61–7.48 (m, 2H).

[0251] Step 2: Synthesis of ethyl 3-{6-chloro-2-[(3-cyanophenyl)amino]-5-fluoropyridin-3-yl}-3-oxopropionate

[0252] Step 1: 6-Chloro-2-[(3-cyanophenyl)amino]-5-fluoronicotinic acid (5.35 g, 18.4 mmol, 1.0 eq) and N,N-dimethylformamide (1 mL) were dissolved in dichloromethane (50 mL), and oxalyl chloride (3.5 g, 27.58 mmol, 1.5 eq) was added dropwise. The reaction was carried out for 1 hour until no bubbles were generated. Step 2: Potassium 3-ethoxy-3-oxopropionate (4.7 g, 27.58 mmol, 1.5 eq), magnesium chloride (5.2 g, 55.2 mmol, 3.0 eq) and triethylamine (8.36 g, 82.8 mmol, 4.5 eq) were dissolved in tetrahydrofuran solution (30 mL) and stirred under an ice bath. The mixture obtained in Step 1 was concentrated, then tetrahydrofuran (5 mL) was added, and subsequently, it was slowly added dropwise to the reaction solution in Step 2 at 0 °C. After the reaction was completed, the mixture was extracted, and the organic phase was concentrated, loaded onto a sample and purified by normal-phase column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain the yellow solid ethyl 3-{6-chloro-2-[(3-cyanophenyl)amino]-5-fluoropyridin-3-yl}-3-oxopropionate (2.1 g, yield 31.82%). LCMS (TOF MS ES+) m / z [M+H]+: 362.

[0253] Step 3: Synthesis of 3-[7-chloro-6-fluoro-4-hydroxy-2-oxo-1,8-naphthyridin-1(2H)-yl]benzonitrile

[0254] Ethyl 3-{6-chloro-2-[(3-cyanophenyl)amino]-5-fluoropyridin-3-yl}-3-oxopropionate (2.1 g, 5.85 mmol, 1.0 eq) and potassium carbonate (1.6 g, 11.63 mmol, 2.0 eq) were dissolved in ethanol (40 mL), and then the reaction was carried out at 70 °C for 1 hour. After the reaction was complete, the mixture was cooled, filtered, the filtrate was concentrated, and purified by normal-phase separation (dichloromethane:methanol = 10:1) to obtain the yellow solid 3-[7-chloro-6-fluoro-4-hydroxy-2-oxo-1,8-naphthyridin-1(2H)-yl]benzonitrile (1.34 g). LCMS (TOF MS ES+) m / z [M+H]+: 316. 1 1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 8.0 Hz, 1H), 7.94 (dd, J = 7.6, 1.5 Hz, 1H), 7.87 (d, J = 1.8 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.68 (dd, J = 8.2, 1.6 Hz, 1H), 5.96 (s, 1H).

[0255] Step 4: Synthesis of 3-[4,7-dichloro-6-fluoro-2-oxo-1,8-naphthyridin-1(2H)-yl]benzonitrile

[0256] [7-Chloro-6-fluoro-4-hydroxy-2-oxo-1,8-naphthyridin-1(2H)-yl]benzonitrile (1.34 g, 4.25 mmol, 1.0 eq) was dissolved in phosphorus oxychloride (30 mL), and the reaction was carried out at 70 °C for 5 h. After the reaction was complete, the mixture was concentrated, and then sodium bicarbonate solution was added to quench phosphorus oxychloride. Then, it was extracted with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate to remove excess water, and purified by normal-phase separation. The pure dichloromethane was passed through a column to obtain yellow solid 3-[4,7-dichloro-6-fluoro-2-oxo-1,8-naphthyridin-1(2H)-yl]benzonitrile (650 mg, yield 46.43%). LCMS (TOF MS ES+) m / z [M+H]+: 334. 1 1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 8.2 Hz, 1H), 8.00 (m, J = 7.6, 1.5 Hz, 1H), 7.93 (t, J = 1.8 Hz, 1H), 7.83–7.71 (m, 2H), 7.31 (s, 1H).

[0257] Step 5: Synthesis of 3-[7-chloro-6-fluoro-4-(methylamino)-2-oxo-1,8-naphthyridin-1(2H)-yl]benzonitrile

[0258] 3-[4,7-Dichloro-6-fluoro-2-oxo-1,8-naphthyridin-1(2H)-yl]benzonitrile (630 mg, 1.89 mmol, 1.0 eq), methylamine hydrochloride (319 mg, 4.73 mmol, 2.5 eq), and N,N-diisopropylethylamine (1.46 g, 11.34 mmol, 6.0 eq) were dissolved in anhydrous acetonitrile (10 mL), and the reaction was carried out at 80 °C for 2 h. After the reaction was complete, the reaction solution was concentrated and slurried (with water and ethanol), and the filter cake was retained. After drying, yellow solid 3-[7-chloro-6-fluoro-4-(methylamino)-2-oxo-1,8-naphthyridin-1(2H)-yl]benzonitrile (523 mg, yield 84.22%) was obtained. LCMS (TOF MS ES+) m / z [M+H]+: 329. 1 1H NMR (400 MHz, DMSO-d6) δ 7.93 (m, J = 7.4, 1.6 Hz, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.84–7.74 (m, 2H), 7.74–7.67 (m, 2H), 6.68 (s, 1H), 2.46 (d, J = 4.5 Hz, 3H).

[0259] Step 6: Synthesis of 3-[3-bromo-7-chloro-6-fluoro-4-(methylamino)-2-oxo-1,8-naphthyridin-1(2H)-yl]benzonitrile

[0260] 7-Chloro-6-fluoro-4-(methylamino)-1-[4-(trifluoromethoxy)phenyl]-1,8-naphthyridin-2(1H)-one (503 mg, 1.53 mmol, 1.0 eq), N-bromosuccinimide (300 mg, 1.68 mmol, 1.1 eq) were dissolved in acetonitrile (10 mL), and the reaction was carried out at 35 °C for 3 h. After the reaction was complete, the reaction solution was concentrated, triturated (ethanol and water), filtered, and the filter cake was retained. After drying, yellow solid 3-[3-bromo-7-chloro-6-fluoro-4-(methylamino)-2-oxo-1,8-naphthyridin-1(2H)-yl]benzonitrile (574 mg, yield 92.28%) was obtained. LCMS (TOF MS ES+) m / z [M+H]+: 407. 1 1H NMR (400 MHz, DMSO-d6) δ 7.97–7.92 (m, 2H), 7.88 (d, J = 5.3 Hz, 1H), 7.85 (d, J = 11.1 Hz, 1H), 7.78–7.70 (m, 2H), 2.44 (d, J = 4.6 Hz, 3H).

[0261] Step 7: Synthesis of 3-(7-chloro-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-2-oxo-1,8-naphthyridin-1(2H)-yl)benzonitrile

[0262] 3-[3-Bromo-7-chloro-6-fluoro-4-(methylamino)-2-oxo-1,8-naphthyridin-1(2H)-yl]benzonitrile (88 mg, 0.216 mmol, 1.0 eq), (2-methyl-2H-indazol-5-yl)boronic acid (76 mg, 0.43 mmol, 2.0 eq), potassium phosphate (137 mg, 0.65 mmol, 3.0 eq), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (15.7 mg, 0.021 mmol, 0.1 eq) were dissolved in water (0.2 mL) and 1,4-dioxane (2 mL), and the reaction was carried out at 80 °C for 16 h. After the reaction was complete, purification by preparation gave yellow solid 3-(7-chloro-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-2-oxo-1,8-naphthyridin-1(2H)-yl)benzonitrile (30 mg, yield 30.30%). LCMS (TOF MS ES+) m / z [M+H]+: 459.1124. 11H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.96 (d, J = 1.9 Hz, 1H), 7.96–7.89 (m, 1H), 7.88 (d, J = 11.2 Hz, 1H), 7.78–7.67 (m, 4H), 7.60 (d, J = 8.9 Hz, 1H), 7.18 (dd, J = 8.9, 1.6 Hz, 1H), 4.18 (s, 3H), 2.51 (d, J = 1.9 Hz, 3H).

[0263] Example 19: Synthesis of 7-chloro-1-(4-chlorophenyl)-6-fluoro-4-(isopropylamino)-3-(2-methyl-2H-indazol-5-yl)-1,8-naphthyridin-2(1H)-one (Compound 33)

[0264]

[0265] Step 1: Synthesis of 7-chloro-1-(4-chloromethyl)-6-fluoro-4-(isopropylamino)-1,8-naphthyridin-2(1H)-one

[0266] Dissolve 4,7-dichloro-1-(4-chlorophenyl)-6-fluoro-1,8-naphthyridin-2(1H)-one (500.00 mg, 1.45 mmol, 1.00 eq), isopropylamine (860.40 mg, 14.55 mmol, 10.0 eq) and N,N-diisopropylethylamine (751.0 mg, 5.82 mmol, 4.0 eq) in acetonitrile (7.5 mL), react at 80 °C for 2 hours, concentrate the acetonitrile to obtain a yellow solid, and slurry-filter (ethanol:water = 1:1) to obtain the crude yellow solid 7-chloro-1-(4-chloromethyl)-6-fluoro-4-(isopropylamino)-1,8-naphthyridin-2(1H)-one (440 mg, yield 81.36%), without further purification, and directly use it for the next reaction. LCMS (TOF MS ES+) m / z [M+H] + : 366.

[0267] Step 2: Synthesis of 3-bromo-7-chloro-1-(4-chloromethyl)-6-fluoro-4-(isopropylamino)-1,8-naphthyridin-2(1H)-one

[0268] 7-Chloro-1-(4-chloromethyl)-6-fluoro-4-(isopropylamino)-1,8-naphthyridin-2(1H)-one (440.00 mg, 1.15 mmol, 1.0 eq) and N-bromosuccinimide (225.30 mg, 1.26 mmol, 1.1 eq) were added to acetonitrile solution (9 mL). The reaction was carried out at room temperature for 2 hours, and then slurried (ethanol:water = 1:1) and filtered to obtain the yellow solid 3-bromo-7-chloro-1-(4-chloromethyl)-6-fluoro-4-(isopropylamino)-1,8-naphthyridin-2(1H)-one (320 mg, yield 62.86%). LCMS (TOF MS ES+) m / z [M+H]+: 444.

[0269] Step 3: Synthesis of 7-chloro-1-(4-chlorophenyl)-6-fluoro-4-(isopropylamino)-3-(2-methyl-2H-indazol-5-yl)-1,8-naphthyridin-2(1H)-one

[0270] 3-Bromo-7-chloro-1-(4-chloromethyl)-6-fluoro-4-(isopropylamino)-1,8-naphthyridin-2(1H)-one (320.0 mg, 0.72 mmol, 1.0 eq), 2-methyl-2H-indazole-5-boronic acid (252.95 mg, 1.44 mmol, 2.0 eq), and potassium phosphate (383.3 mg, 1.80 mmol, 2.5 eq) were added to a mixed solvent of dioxane (6 mL) and water (0.6 mL). Finally, 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (52.3 mg, 0.07 mmol, 0.1 eq) was added, and the temperature was raised to 80 °C for reaction for 4 hours. Purification by reverse column chromatography was carried out. When the acetonitrile content was 50%, the white solid 7-chloro-1-(4-chlorophenyl)-6-fluoro-4-(isopropylamino)-3-(2-methyl-2H-indazol-5-yl)-1,8-naphthyridin-2(1H)-one (170 mg, yield 47.55%) was obtained. LCMS (TOF MS ES+) m / z [M+H]+: 496.1092 / 498.1067. 1 H NMR (400 MHz, DMSO) δ 8.36 (s, 1H), 7.85 (d, J = 11.2 Hz, 1H), 7.68 (s, 1H), 7.57 (q, J = 9.7 Hz, 4H), 7.37 (d, J = 8.5 Hz, 2H), 7.17 (dd, J = 9.0, 1.6 Hz, 1H), 4.18 (s, 3H), 3.50 (h, J = 6.5 Hz, 1H), 0.97 (d, J = 6.5 Hz, 6H).

[0271] Example 20: Synthesis of 1-(4-chlorophenyl)-6-fluoro-4-(isopropylamino)-3-(2-methyl-2H-indazol-5-yl)-7-[(2,2,2-trifluoroethyl)amino]-1,8-naphthyridin-2(1H)-one (Compound 11)

[0272]

[0273] Step 1: Synthesis of 1-(4-chlorophenyl)-6-fluoro-4-(isopropylamino)-3-(2-methyl-2H-indazol-5-yl)-7-[(2,2,2-trifluoroethyl)amino]-1,8-naphthyridin-2(1H)-one

[0274] Dissolve 7-chloro-1-(4-chlorophenyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1,8-naphthyridin-2(1H)-one (70 mg, 0.14 mmol, 1.0 eq) prepared in Example 19, methanesulfonic acid (9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (13 mg, 0.014 mmol, 0.1 eq), sodium tert-butoxide (27 mg, 0.28 mmol, 2.0 eq) and 2,2,2-trifluoroethan-1-amine (138 mg, 1.4 mmol, 10.0 eq) in 1,4-dioxane (2 mL). After replacing nitrogen, heat to 60 °C and stir for 3.5 hours. After the reaction is completed, purify by preparative separation using high performance liquid chromatography to obtain a white solid 1-(4-chlorophenyl)-6-fluoro-4-(isopropylamino)-3-(2-methyl-2H-indazol-5-yl)-7-[(2,2,2-trifluoroethyl)amino]-1,8-naphthyridin-2(1H)-one (36 mg, yield 45.57%). LCMS (TOF MS ES+) m / z [M+H] + : 559.1569. 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.11 (d, J = 12.5 Hz, 1H), 7.60 (m, J = 8.8, 1.0 Hz, 1H), 7.57 (d, J = 1.2 Hz, 1H), 7.52–7.47 (m, 2H), 7.30–7.25 (m, 2H), 7.16 (d, J = 7.1 Hz, 1H), 7.11 (dd, J = 8.9, 1.5 Hz, 1H), 6.33 (t, J = 7.2 Hz, 1H), 4.17 (s, 3H), 3.48 (h, J = 6.6 Hz, 1H), 3.31–3.23 (m, 2H), 0.96 (d, J = 6.5 Hz, 6H).

[0275] Example 21: Synthesis of 7-amino-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1-(2-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one (Compound 51)

[0276]

[0277] Step 1: Synthesis of 6-chloro-5-fluoro-2-((2-methylpyridin-3-yl)amino)nicotinic acid

[0278] Dissolve 3-amino-2-methylpyridine (10.28 g, 95.23 mmol, 2.0 eq) in ultradry tetrahydrofuran (60 mL), cool to -78 °C, slowly add lithium bis(trimethylsilyl)amide (142.83 mL, 142.83 mmol, 3.0 eq), continue the reaction for 1 hour after the addition is complete. Then dissolve 2,6-dichloro-5-fluoronicotinic acid (10.00 g, 47.61 mmol, 1.0 eq) in ultradry tetrahydrofuran (30 mL), slowly add it to the reaction system at -78 °C. After the addition is complete, transfer to room temperature and react for 1 hour. After the reaction is completed, quench the reaction with saturated ammonium chloride solution, extract with ethyl acetate (200 mL), combine the organic phases, dry and concentrate, then add an appropriate amount of ethyl acetate for washing and slurrying, and filter to obtain a pale yellow solid 6-chloro-5-fluoro-2-((2-methylpyridin-3-yl)amino)nicotinic acid (11.9 g, yield 89.0%). LCMS (TOF MS ES+) m / z [M+H]+: 282.

[0279] Step 2: Synthesis of ethyl 3-(6-chloro-5-fluoro-2-((2-methylpyridin-3-yl)amino)pyridin-3-yl)-3-oxopropionate

[0280] Potassium 3-ethoxy-3-oxopropionate (8.28 g, 48.66 mmol, 2.0 eq), magnesium chloride (6.73 g, 72.99 mmol, 3.0 eq) and triethylamine (9.85 g, 97.32 mmol, 4.0 eq) were dissolved in tetrahydrofuran solution (100 mL), and stirred at room temperature for 4 hours. 6-Chloro-5-fluoro-2-((2-methylpyridin-3-yl)amino)nicotinic acid (6.8 g, 24.33 mmol, 1.0 eq) and super dry dichloromethane (60 mL) were added to another reaction flask, and a small amount of N,N-dimethylformamide was added as a catalyst. Then, at 0 °C, oxalyl chloride (5.07 g, 39.99 mmol, 1.5 eq) was slowly added dropwise. After the addition was complete, the reaction was transferred to room temperature and reacted for 2 hours. After monitoring the reaction to completion by TLC, the reaction solution was directly concentrated to obtain a yellow solid, which was then dissolved in tetrahydrofuran solution (60 mL). At 0 °C, it was slowly added dropwise to the potassium 3-ethoxy-3-oxopropionate reaction system, and the reaction continued at room temperature for 2 hours. After the reaction was completed, the reaction solution was directly concentrated, and purified by normal-phase column chromatography to obtain yellow solid ethyl 3-(6-chloro-5-fluoro-2-((2-methylpyridin-3-yl)amino)pyridin-3-yl)-3-oxopropionate (4.4 g, yield 52.0%). LCMS (TOF MS ES+) m / z [M+H]+: 352.

[0281] Step 3: Synthesis of 7-chloro-6-fluoro-4-hydroxy-1-(2-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one

[0282] Ethyl 3-(6-chloro-5-fluoro-2-((2-methylpyridin-3-yl)amino)pyridin-3-yl)-3-oxopropionate (4.40 g, 12.53 mmol, 1.0 eq) and potassium carbonate (3.46 g, 25.07 mmol, 2.0 eq) were dissolved in anhydrous ethanol (50 mL), and reacted at 70 °C for 3 hours. After the reaction was completed, it was filtered through diatomaceous earth, and the filtrate was purified by normal-phase column chromatography to obtain solid 7-chloro-6-fluoro-4-hydroxy-1-(2-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one (3.6 g, yield 93.9%). LCMS (TOF MS ES+) m / z [M+H]+: 306.

[0283] Step 4: Synthesis of 4,7-dichloro-6-fluoro-1-(2-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one

[0284] 7-Chloro-6-fluoro-4-hydroxy-1-(2-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one (3.6 g, 11.80 mmol, 1.0 eq) and phosphorus oxychloride (20 mL) were added to a reaction flask, and the reaction was carried out at 80 °C for 16 hours. After the reaction was completed, phosphorus oxychloride was removed by concentration under reduced pressure, ethyl acetate was added for pulping, and the yellow solid 4,7-dichloro-6-fluoro-1-(2-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one (3.3 g, yield 86.8%) was obtained by filtration. LCMS (TOF MS ES+) m / z [M+H]+: 324.

[0285] Step 5: Synthesis of 7-chloro-6-fluoro-4-(methylamino)-1-(2-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one

[0286] 4,7-Dichloro-6-fluoro-1-(2-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one (1.0 g, 3.09 mmol, 1.0 eq), methylamine hydrochloride (313 mg, 4.64 mmol, 1.5 eq) and N,N-diisopropylethylamine (1.6 g, 12.36 mmol, 4.0 eq) were dissolved in acetonitrile (20 mL), and the reaction was carried out at 80 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain a pale yellow solid, and the yellow solid 7-chloro-6-fluoro-4-(methylamino)-1-(2-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one (792 mg, yield 80.7%) was obtained by pulping and filtering with ethanol and water, and directly used for the next reaction. LCMS (TOF MS ES+) m / z [M+H]+: 319.

[0287] Step 6: Synthesis of 3-bromo-7-chloro-6-fluoro-4-(methylamino)-1-(2-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one

[0288] 7-Chloro-6-fluoro-4-(methylamino)-1-(2-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one (500 mg, 1.57 mmol, 1.0 eq) and N-bromosuccinimide (307.8 mg, 1.73 mmol, 1.1 eq) were added to an acetonitrile solution (10 mL), and the reaction was carried out at room temperature for 4 hours. After the reaction was completed, the reaction solution was directly concentrated, and the pale yellow solid 3-bromo-7-chloro-6-fluoro-4-(methylamino)-1-(2-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one (573 mg, yield 92.4%) was obtained by pulping with ethanol and water. LCMS (TOF MS ES+) m / z [M+H]+: 396.

[0289] Step 7: Synthesis of 7-chloro-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1-(2-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one

[0290] 3-Bromo-7-chloro-6-fluoro-4-(methylamino)-1-(2-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one (200.0 mg, 0.50 mmol, 1.0 eq), 2-methyl-2H-indazole-5-boronic acid (132.0 mg, 0.75 mmol, 1.5 eq), and potassium phosphate (265 mg, 1.25 mmol, 2.5 eq) were added to a mixed solvent of dioxane (6 mL) and water (0.6 mL). Finally, 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (36.5 mg, 0.05 mmol, 0.1 eq) was added. The reaction was carried out at 80 °C for 16 h under nitrogen protection. After the reaction was completed, the reaction solution was directly concentrated, and purified by reverse-phase chromatography to obtain the yellow solid 7-chloro-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1-(2-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one (110.8 mg, yield 48.9%). LCMS (TOF MS ES+) m / z [M+H]+: 449.

[0291] Step 8: Synthesis of 7-amino-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1-(2-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one

[0292] 7-Chloro-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1-(2-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one (110.8 mg, 0.24 mmol, 1.0 eq), 4-methoxybenzylamine (65.7 mg, 0.48 mmol, 2.0 eq), methanesulfonic acid (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (22.7 mg, 0.024 mmol, 0.1 eq) and sodium tert-butoxide (46.0 mg, 0.48 mmol, 2.0 eq) were added to 1,4-dioxane (3.0 mL), and the reaction was carried out at 100 °C. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to obtain a crude intermediate. The above crude intermediate was dissolved in dichloromethane (2.0 mL) and trifluoroacetic acid (2.0 mL), and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated, neutralized with sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was concentrated. After preparation, separation and purification, white solid 7-amino-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-4-(methylamino)-1-(2-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one (31 mg, yield 30.1%) was obtained. LCMS (TOF MS ES+) m / z [M+H] + : 430. 1 H NMR (400 MHz, DMSO) δ 8.39 (dd, J = 8.8, 1.6 Hz, 1H), 8.29 (s, 1H), 8.15 (d, J = 12.3 Hz, 1H), 7.62–7.54 (m, 3H), 7.47–7.31 (m, 2H), 7.22 (d, J = 5.1 Hz, 1H), 6.01 (s, 2H), 4.17 (s, 3H), 2.42 (d, J = 4.6 Hz, 3H), 2.01 (s, 3H).

[0293] The compounds listed in Table 1 below were prepared by a method similar to that described in the examples, with appropriate changes in the amounts of reactants, reagents, protection and deprotection, solvents and reaction conditions. The characterization data of the compounds are summarized in Table 1 below.

[0294] Table 1: Structures and characterizations of some compounds

[0295]

[0296]

[0297]

[0298] Experimental Example 1: The compounds of the present invention against HCT116 MTAP - / -Measurement of cell proliferation

[0299] Experimental purpose: The purpose of this test example is to test the effect of the compound on the proliferation of HCT116 MTAP - / - cells

[0300] Background principle: Methionine adenosyltransferase 2A (MAT2A) is considered a synthetic lethal target for cancers lacking the methylthioadenosine phosphorylase (MTAP) gene. The MTAP gene is adjacent to the CDKN2A tumor suppressor gene and is co-deleted with CDKN2A in approximately 15% of cancers. Therefore, by detecting the inhibitory rate of the compound on the proliferation of HCT116 MTAP - / - cells, it is used for the screening of MAT2A protein inhibitors

[0301] Specific experimental procedure:

[0302] Construct HCT116 MTAP knockout cells and screen monoclonal cells. Seed the exponentially growing HCT116 MTAP - / - and WT cells into 96-well plates, 90 μL per well, 1000 cells per well, and incubate overnight in a 37 °C incubator. The next day, add 10 μL of compounds at different concentrations (final DMSO concentration is 1%), and incubate in a 37 °C incubator for 10 days. On the 10th day, aspirate the old medium, add 110 μL of medium (the ratio of medium to CCK8 is 100:10), and incubate at 37 °C for 1 - 4 h. Measure the absorbance at 450 nM, calculate the IC50 through GraphPad software, and screen the compounds by comparing with the positive drug

[0303] IC50 (half maximal inhibitory concentration) refers to the half-inhibitory concentration of the measured antagonist. It can indicate the half amount of a certain drug or substance (inhibitor) in inhibiting certain biological processes (or certain substances included in this process, such as enzymes, cell receptors, or microorganisms). Use AG270 from Angios Pharmaceuticals Co., Ltd. and Compound A (Compound 167 in WO2020123395) as positive reference compounds. Their structural formulas are as follows respectively, and the experimental results are shown in Table 2

[0304]

[0305] Table 2: Test results of the inhibitory effect on HCT116 MTAP- / - cells

[0306]

[0307]

[0308] The results showed that the representative compounds of the present invention had good inhibitory effects on HCT116 MTAP - / - cells, which were superior to the positive control.

[0309] Experimental Example 2: Determination of the functional effect of the compounds of the present invention on MAT2A protease

[0310] Experimental purpose: The purpose of this test example was to test the inhibitory ability of the compounds on the function of MAT2A protease.

[0311] Background principle: The metabolic enzyme methionine adenosyltransferase 2A (MAT2A) plays an important role in metabolism and epigenetics because it is the main producer of the universal methyl donor S-adenosylmethionine (SAM). SAM and phosphate groups are produced from ATP and L-Met under the action of MAT2A. Therefore, after incubation with the compounds, the inhibitory ability of the compounds on the function of MAT2A enzyme was evaluated by detecting the amount of SAM produced, which was used for the screening of MAT2A protein inhibitors.

[0312] Specific experimental procedure:

[0313] MAT2A protein expression: The full-length MAT2A was cloned into the pET24N vector with an N-terminal (His)6x tag and a tobacco etch virus (TEV) protease cleavage site. The constructed vector was transformed into Escherichia coli BL21(DE3). When the OD reached 0.6 during shaking culture, 1 mM IPTG was added and cultured at 18 °C for 16 h. The bacterial cells were collected, sonicated, centrifuged, and the supernatant was taken. The protein was purified by Ni-NTA and the protein concentration and purity were measured after dialysis. SAM determination: Reaction system: 91 - x μL of 50 mM TrisHCl pH 7.5, 1.5 μL (10 / 3 M) of KCl, 1.5 μL (1 M) of MgCl2, 1 μL (100 mM) of ATP, 1 μL (80 mM) of L-Met, 1 μL (30 mM pH 7.67) of EDTA, 1 μL of 5% BSA, 2 μL of the drug dissolved in DMSO above, and x μL of MAT2A protein were added in sequence. In the experimental groups, different drug concentrations were prepared respectively. 2 μL (100x) was taken out and added to the reaction system, and the reaction was carried out at 37 °C for 18 h. A solvent control group and a blank control group were set respectively. After the reaction was terminated, 40 μL of the system was taken out and 4 μL of 10% SDS was added to quench the reaction. The IC50 was calculated by processing with GraphPad software. By comparing with the positive drug, the compounds were screened, and the experimental results are shown in Table 3.

[0314] Table 3: Determination results of the functional effect of MAT2A protease

[0315]

[0316] The results showed that the compounds of the present invention had a very strong inhibitory effect on the function of MAT2A protease, and the IC50 values all reached the nM level, equivalent to or less than the positive drug. This strong inhibitory effect has important therapeutic significance for the treatment of diseases or disorders related to MAT2A inhibition.

[0317] Experimental Example 3: Pharmacokinetic testing of the compounds of the present invention in rats

[0318] Experimental purpose: To investigate the pharmacokinetic characteristics by orally administering (PO) the compounds of the present invention to SD female rats

[0319] Specific experimental procedure:

[0320] The compounds of the present invention and control compound A (the preparation method refers to compound 167 in patent application WO2020123395) were administered by gavage (10 mg / kg). PO solvent: 30% PEG300 + 10% Tween 80 + 60% water, prepared on the day of administration. Blood samples were collected from the jugular vein at 0 h before administration and 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h (after gavage). Approximately 0.02 mL of each sample was collected, anticoagulated with K2-EDTA, and placed on ice after collection. Plasma sample treatment: The blood samples were placed on ice after collection and centrifuged to separate plasma within 1 hour (centrifugation conditions: 6800 g, 6 minutes, 2 - 8 °C). The plasma samples were stored in a -80 °C refrigerator before analysis. Pharmacokinetic parameters were calculated using Phoenix WinNonlin 7.0 based on the plasma concentration data at different time points. The experimental results are shown in Table 4 below:

[0321] Table 4: Results of in vivo pharmacokinetic testing in female rats

[0322]

[0323] The pharmacokinetic data of the compounds of the present invention in rats showed that, compared with control compound A, the oral absorption in rats was better than that of control compound A.

[0324] The above examples are only representative. From the above examples, it can be seen that the compounds of the present invention are ideal highly efficient MAT2A inhibitors and can be expected to be used for the treatment or prevention of diseases or disorders related to MAT2A inhibition.

Claims

1. A compound represented by formula (I), its stereoisomers, or its pharmaceutically acceptable salts, wherein, R1 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; R2 and R3 are each independently selected from 5- to 12-membered monocyclic or bicyclic aromatic or heteroaromatic rings, said aromatic or heteroaromatic being optionally substituted with one or more identical or different substituents R a substituted; The heteroaryl contains 1-3 heteroatoms selected from N, O, S, and the ring system includes saturated or partially unsaturated ring systems such as spiro rings, bridged rings, fused rings, and annelated rings; R a selected from hydrogen, deuterium, halogen, cyano, -C(O)NH2, hydroxy, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 monoalkylamino, C1-C6 dialkylamino, alkenyl, alkynyl, 3- to 8-membered cycloalkyl or heterocycloalkyl; R4 and R5 are each independently selected from hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxy, C1-C 12 alkyl, 3- to 12-membered cycloalkyl or heterocycloalkyl, 3- to 12-membered halocycloalkyl or halocycloheteroalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 monoalkylamino, C1-C6 dialkylamino, -NH-(CH2) n -C1-C6 haloalkyl, -NH-(CH2) n -C3-C8 heterocycloalkyl, -NH-(CH2) n -NR b R c 、-NH-(CH2) n -O-C1-C6 alkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -O-(CH2) n -heterocyclic group, -O-(CH2) n -cycloalkyl, -O-(CH2) n -C3-C6 heterocycloalkyl, -O-(CH2) n -O-C1-C6 alkyl; The C1-C6 monoalkylamino, C1-C6 dialkylamino, -N(H)-(CH2) n -C1-C6 haloalkyl, -NH-(CH2) n -C3-C8 heterocycloalkyl, -N(H)-(CH2) n -NR b R c 、-NH-(CH2) n -C3-C8 heterocycloalkyl, -NH-(CH2) n -O-C1-C6 alkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -O-(CH2) n -heterocyclic group, -O-(CH2) n -cycloalkyl, -O-(CH2) n -C3-C6 heterocycloalkyl, -O-(CH2) n -O-C1-C6 alkyl is optionally substituted by one or more substituents of the following group: halogen, hydroxy, amino, oxo, C1-C6 alkylamino, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl; R b and R c are each independently selected from H, C1-C6 alkyl; n is 0, 1, 2, 3.

2. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, R1 is selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl.

3. The compound according to claim 1, its stereoisomers, or its pharmaceutically acceptable salts, characterized in that, R2 is selected from 5- to 12-membered bicyclic heteroaryl rings optionally substituted with one or more identical or different R a groups, preferably 4. The compound according to claim 1, its stereoisomers, or its pharmaceutically acceptable salts, characterized in that, R3 is selected from optionally 5- to 12-membered monocyclic aromatic or heteroaromatic rings which are substituted by one or more identical or different Rs a and is preferably 5. The compound according to claim 1, its stereoisomers, or its pharmaceutically acceptable salts, characterized in that, R4 is selected from Cl, methyl, methoxy, trifluoroethylamino, difluoromethyl, amino, trifluoroethoxy, trifluoromethyl, 6. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, R5 is selected from F, hydrogen, methoxy.

7. The compound according to any one of claims 1-6, its stereoisomers, or its pharmaceutically acceptable salts, characterized in that, It has the structures shown in the following formulas (Ia), (Ib), (Ic), (Id), (Ie), wherein, R6 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, preferably methyl; R7 and R8 are each independently selected from hydrogen, deuterium, halogen, cyano, -C(O)NH2, hydroxy, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 monoalkylamino, C1-C6 dialkylamino, alkenyl, alkynyl, 3-8 membered cycloalkyl or heterocycloalkyl.

8. The compound according to claim 7, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, R7 and R8 are each independently selected from hydrogen, chlorine, fluorine, methoxy, trifluoromethoxy, cyano, trifluoromethyl, methyl.

9. A compound, its stereoisomers, or its pharmaceutically acceptable salts, the compound being:

10. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9, its stereoisomers or its pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers, diluents or excipients.

11. Use of the compound according to any one of claims 1 to 10, its stereoisomers, or its pharmaceutically acceptable salts and the pharmaceutical composition according to claim 10 in the preparation of a medicament for a subject suffering from a disease or disorder associated with MAT2A or MTAP protein activity or expression, wherein the disease or disorder is preferably cancer or an autoimmune disease, the cancer is preferably selected from lung cancer, pancreatic cancer, liver cancer, colorectal cancer, cholangiocarcinoma, gallbladder cancer, brain cancer, gastric cancer, leukemia, lymphoma, melanoma, thyroid cancer, nasopharyngeal cancer, glioma, bladder cancer, astrocytoma, basal cell carcinoma, osteosarcoma, head and neck cancer, chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma and mesothelioma; the autoimmune disease is preferably selected from thyroiditis, inflammatory bowel disease, lupus erythematosus, fibrosis, myasthenia gravis, vasculitis, psoriasis, arthritis, scleroderma, dermatitis.

12. Intermediate compounds shown below, their stereoisomers, or their pharmaceutically acceptable salts, 13. A method for preparing a compound represented by formula (1), characterized in that, including the following steps: (1) The starting material (i-1) is prepared into the intermediate compound (i-2) by a substitution reaction; (2) The intermediate compound (i-2) is prepared into the intermediate compound (i-3) by a condensation and decarboxylation reaction; (3) The intermediate compound (i-3) is prepared into the intermediate compound (i-4) by an ammonolysis cyclization reaction; (4) The intermediate compound (i-4) is prepared into the intermediate compound (i-5) by a halogenation reaction; (5) The intermediate compound (i-5) is prepared into the intermediate compound (i-6) through an amine substitution reaction; (6) The intermediate compound (i-6) is prepared into the intermediate compound (i-7) through an aromatic ring halogenation reaction; (7) The intermediate compound (i-7) is prepared into the compound (1) through a coupling reaction.

14. A method for preparing a compound represented by formula (II), the method comprising the following steps: The general formula compound (IIA) undergoes a substitution reaction to obtain the general formula (II) compound; Wherein, R6 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, preferably methyl; R7 and R8 are each independently selected from hydrogen, deuterium, halogen, cyano, -C(O)NH2, hydroxy, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 monoalkylamino, C1-C6 dialkylamino, alkenyl, alkynyl, 3-8 membered cycloalkyl or heterocycloalkyl; The definitions of R1, R4 and R5 are as described in claims 1 to 6.

15. The preparation method according to claim 14, wherein R1 is selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl.

16. The preparation method according to claim 14, wherein R4 is selected from Cl, methyl, methoxy, trifluoroethylamino, difluoromethyl, amino, trifluoroethoxy, trifluoromethyl, 17. The preparation method according to claim 14, wherein R5 is selected from F, hydrogen, methoxy.

18. The preparation method according to claim 14, wherein R7 and R8 are each independently selected from hydrogen, chlorine, fluorine, methoxy, trifluoromethoxy, cyano, trifluoromethyl, methyl.

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