Methionine adenosyltransferase inhibitors, processes for their preparation and use

Abstract

A compound of Formula (I) that can act as a MAT2a inhibitor, a pharmaceutical composition comprising such a compound, the use of such a compound for the manufacture of a medicament for the treatment of, e.g., cancer, and a method of preparing such a compound.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemistry, specifically to a methionine adenosine transferase inhibitor, its preparation method, and its application in the pharmaceutical field. Background Technology

[0002] Loss-of-function mutations in tumor suppressor genes are very common, but there are very few therapies that selectively target these mutations. This is easily understood, as the missing proteins are difficult to inhibit directly to achieve therapeutic effects. Targeted therapy for tumor suppressor genes that are inactivated due to homozygous deletion is particularly challenging because the lack of residual proteins renders treatment strategies that directly activate, stabilize, or repair the tumor suppressor genes ineffective.

[0003] Methionine adenosine transferase (MAT), also known as S-adenosylmethionine synthase, is a cellular enzyme that catalyzes the synthesis of S-adenosylmethionine (SAM or AdoMet) from methionine and ATP, and is considered the rate-limiting step in the methionine cycle. SAM is the alanine donor in polyamine biosynthesis and a major methyl donor for DNA methylation, participating in gene transcription, cell proliferation, and the generation of secondary metabolites. The MAT gene can be divided into the MAT1A and MAT2a genes, encoding the only enzyme capable of catalyzing the synthesis of SAM—MAT. There are three isoenzymes of MAT: MAT I, MAT III, and MAT II. The first two are products encoded by the MAT1a gene, and the last is a product encoded by the MAT2a gene. The MAT1a gene is mainly expressed in the adult liver, while the MAT2a gene is widely expressed in human tissues other than the liver. More and more studies have found that the MAT2a protein is also highly expressed in other cancer tissues or cells, such as breast cancer, colorectal cancer, leukemia and lymphoma. Silencing the MAT2a gene leads to the death of the corresponding cancer cells, indicating that the MAT2a protein has the potential to be a therapeutic target.

[0004] Methylthioadenosine phosphorylase (MTAP) is an enzyme expressed in all normal tissues that catalyzes the conversion of methylthioadenosine (MTA) to adenine and 5-methylthio glucose-1-phosphate. Many malignant cell lines lack MTAP activity, and loss of MTAP activity has been detected in a large number of primary lesions, including gliomas, melanomas, pancreatic cancers, non-small cell lung cancers, bladder cancers, astrocytomas, osteosarcomas, head and neck cancers, myxoid chondrosarcomas, ovarian cancers, endometrial cancers, breast cancers, soft tissue sarcomas, and non-Hodgkin's lymphomas. When MTAP is absent, MTA accumulates to about 100 μM in the cell, and the cell begins to export MTA. The abnormal accumulation of MTA leads to the vulnerability of Protein Arginine Methyltransferase 5 (PRMT5). Since PRMT5 utilizes SAM as a methyl donor substrate, inhibiting MAT2a activity decreases the concentration of SAM in the cell, thereby selectively reducing PRMT5 methylation activity in MTAP-deleted cells below the threshold level required for growth. Thus, inhibiting MAT2a activity can produce a combined lethality in MTAP-deleted cells by inhibiting PRMT5 activity, and can provide therapeutic benefits for a variety of cancers. SUMMARY

[0005] It is an object of the present application to provide a compound having MAT2a inhibitory activity.

[0006] In particular, the present application provides a compound represented by the following formula I:

[0007]

[0008] wherein Y represents N or CR4, X represents N or CR5, W represents N or CR6, and Z represents N or CR7;

[0009] R1is selected from a 5-10 membered aryl or heteroaryl group;

[0010] said R1group is optionally substituted with q Ra groups, each said Ra group is independently selected from C1-C4 alkyl-, halogen, -CN, -CHF2, -CF3, -OCH3, -OCF3, -OCHF2, -OH, -(CH2) m OH, -NHSO2CH3, -COOH, -CONH2, -CONHCH3, -CH2COCH3, cyclopropyl, , , q = 0, 1, 2;

[0011] R2is -NRcRd, -OH, -OCH3, -CH3, ethyl, isopropyl, or -O-cyclopropyl;

[0012] wherein Rc is selected from H or -CH3,

[0013] Rd is selected from

[0014] 1) H;

[0015] 2) -COCH3 or -SO2CH3;

[0016] 3) alkyl optionally substituted with one or more groups selected from methyl, hydroxyl, amino, cyano, methoxy, halogen, deuterium, -CH2OH, -NHCH3, -N(CH3)2, -SO2CH3, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, -CONHCH3, -CONH2, -SO2-morpholinyl, -SO2NH-cyclopropyl, -NHSO2NH2;

[0017] 4) -(CH2) n R3, wherein R3 is selected from C3-C6 cycloalkyl, 3-6 membered aliphatic heterocyclyl, 5-6 membered aromatic heterocyclyl, or phenyl, 4-10 membered bridged ring, said R3 is optionally substituted with one or more groups selected from halogen, alkyl, alkoxy, deuterated alkoxy, substituted or unsubstituted cycloalkyl, haloalkyl, hydroxyl, hydroxyC1-C4alkyl-, hydroxyC1-C4alkoxy-, =0, -CN, sulfone, -NR8R9, amido, -P=O(C1-C4alkyl)2, aliphatic heterocyclyl-C1-C4alkyl-, aliphatic heterocyclyl-CO-, haloalkoxy, substituted or unsubstituted aliphatic heterocyclyl, spirocyclyl, annulated cyclyl;

[0018] 5) spirocyclic;

[0019] alternatively, Rc and Rd, together with the N atom to which they are both attached, form a ring A, and said ring A has only one heteroatom; said ring A is optionally substituted with one or more groups selected from methyl, halogen, -OCH3, -NH2, -NHCH3, -COOH, -(CH2) m OH, -CH2OCH3, -CN, -CONH2, -CON(CH3)2, -COOCH3, -CONHCH3;

[0020] m = 0, 1, 2, or 3;

[0021] n = 0, 1, 2, or 3;

[0022] R4is selected from hydrogen, halogen, -CN, halogen substituted C1-C4alkyl, -C1-C4alkyl, -C2-C4alkenyl, -C2-C4alkynyl, -CH2OH, C1-C4alkoxy-, halogen substituted C1-C4alkoxy, substituted or unsubstituted C3-C5cycloalkyl or heterocyclyl, -COOCH2CH3, -N(CH3)2;

[0023] R5is selected from hydrogen, halogen, -CH3, -OCH3, -SCH3, -CHF2, -CF3, -CN;

[0024] R6is selected from hydrogen, halogen, -OC1-C6alkyl, -OCH2CH2NH2, -OCHF2, -CH2OH;

[0025] R7is selected from hydrogen, -CH3, halogen;

[0026] R8, R9are each independently selected from H, C1-C4alkyl, halogen, hydroxyl substituted C1-C4alkyl, halogen substituted C1-C4alkyl, C1-C4alkyl-CO-, or, R8and R9together with the N atom to which they are both attached form a ring B, said ring B is optionally substituted with one or more groups selected from methyl, halogen, -OCH3, -NH2, -NHCH3, -COOH, -(CH2) t OH, -CH2OCH3, -CN, -CONH2, -CON(CH3)2, -COOCH3, -CONHCH3;

[0027] t = 0, 1, 2 or 3.

[0028] In certain specific embodiments, Y represents N or CR4, X represents N or CR5, W represents N or CR6, Z represents N or CR7;

[0029] R1is selected from a 5-10 membered aryl or heteroaryl group;

[0030] said R1group is optionally substituted with q Ra groups, each said Ra group is independently selected from -CH3, halogen, -CN, -CHF2, -CF3, -OCH3, -OCF3, -OCHF2, -OH, -(CH2) m OH, -NHSO2CH3, -COOH, -CONH2, -CONHCH3, -CH2COCH3, cyclopropyl, , , ; q = 0, 1, 2;

[0031] R2is -NRcRd, -OH, -OCH3, -CH3, ethyl, isopropyl, -O-cyclopropyl;

[0032] Rc is selected from H or -CH3.

[0033] Rd is selected from

[0034] 1) H;

[0035] 2)-COCH3;

[0036] 3) An alkyl group, wherein the alkyl group is substituted by one or more groups selected from methyl, hydroxy, amino, cyano, methoxy, halogen, deuterium, -CH2OH, -NHCH3, -N(CH3)2, -SO2CH3, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, -CONHCH3, -CONH2, -SO2-morpholinyl, -SO2NH-cyclopropyl, -NHSO2NH2;

[0037] 4)-(CH2) n R3, wherein R3 is selected from C3-C6 cycloalkyl, 3-6-membered alicyclic, 5-6-membered aromatic heterocyclic or phenyl, 4-10-membered bridged cycloalkyl, and R3 may be selectively substituted by one or more groups selected from halogen, alkyl, alkoxy, substituted or unsubstituted cycloalkyl, haloalkyl, hydroxyl, O, -CN, sulfone, -NR8R9, amide, haloalkoxy, substituted or unsubstituted alicyclic;

[0038] 5) Spiral ring;

[0039] Alternatively, Rc and Rd, together with the N atom they are bonded to, form a ring A, wherein ring A has only one heteroatom; ring A may be selectively bonded by one or more atoms selected from methyl, halogen, -OCH3, -NH2, -NHCH3, -COOH, -(CH2). m Substitution of groups such as OH, -CH2OCH3, -CN, -CONH2, -CON(CH3)2, -COOCH3, and -CONHCH3;

[0040] m = 0, 1, 2, 3;

[0041] n = 0, 1, 2, 3;

[0042] R4 is selected from hydrogen, halogen, -CN, -CF3, -CHF2, -CF2CH3, -C1-C4 alkyl, -C2-C4 alkenyl, -C2-C4 alkynyl, -CH2OH, -OCF3, substituted or unsubstituted C3-C5 cycloalkyl or heterocyclic groups, -COOCH2CH3, -N(CH3)2;

[0043] R5 is selected from hydrogen, halogen, -CH3, -OCH3, -SCH3, -CHF2, -CF3, -CN;

[0044] R6is selected from hydrogen, halogen, -OCi-C6alkyl, -OCH2CH2NH2, -OCHF2, -CH2OH;

[0045] R7is selected from hydrogen, -CH3, halogen;

[0046] R8, R9are each independently selected from H, Ci-C4alkyl, halogen, hydroxyl substituted Ci-C4alkyl, halogen substituted Ci-C4alkyl, or, R8and R9together with the N atom to which they are both attached form a ring B, said ring B is optionally substituted with one or more groups selected from methyl, halogen, -OCH3, -NH2, -NHCH3, -COOH, -(CH2) t OH, -CH2OCH3, -CN, -CONH2, -CON(CH3)2, -COOCH3, -CONHCH3;

[0047] t = 0, 1, 2, 3.

[0048] In certain embodiments, Y represents N or CR4, X represents N or CR5, W represents N or CR6, and Z represents N or CR7;

[0049] R1is selected from a 5-10 membered aryl or heteroaryl group;

[0050] said R1group is optionally substituted with q Ra groups, each said Ra group is independently selected from -CH3, halogen, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -OH, -(CH2) m OH, -NHSO2CH3, -COOH, -CONH2, -CONHCH3, -CH2COCH3, cyclopropyl, , , ; q = 0, 1, 2.

[0051] R2is -NRcRd, -OH, -OCH3, -CH3, ethyl, isopropyl, -O-cyclopropyl;

[0052] wherein Rc is selected from H or -CH3,

[0053] Rd is selected from

[0054] 1) H;

[0055] 2) -COCH3;

[0056] 3) alkyl, said alkyl being substituted with one or more groups selected from methyl, hydroxyl, amino, cyano, methoxy, halogen, deuterium, -CH2OH, -NHCH3, -N(CH3)2, -SO2CH3, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, -CONHCH3, -CONH2, -SO2-morpholinyl, -SO2NH-cyclopropyl, -NHSO2NH2;

[0057] 4) -(CH2)n- R3, wherein R3 is selected from C3-C6 cycloalkyl, 3-6 membered aliphatic heterocyclyl, 5-6 membered aromatic heterocyclyl, or phenyl, said R3 being optionally substituted with one or more groups selected from halogen, methyl, methoxy, hydroxyl, -CH2OH, -CF3, -CHF2, -CN, -OCHF2, cyclopropyl, morpholinyl; n R3, wherein R3 is selected from C3-C6 cycloalkyl, 3-6 membered aliphatic heterocyclyl, 5-6 membered aromatic heterocyclyl, or phenyl, said R3 being optionally substituted with one or more groups selected from halogen, methyl, methoxy, hydroxyl, -CH2OH, -CF3, -CHF2, -CN, -OCHF2, cyclopropyl, morpholinyl;

[0058] 5) spirocyclic;

[0059] or Rc and Rd, together with the N atom to which they are both attached, form a ring A, and said ring A has only one heteroatom; said ring A being optionally substituted with one or more groups selected from methyl, halogen, -OCH3, -NH2, -NHCH3, -COOH, -(CH2)n-R3, wherein R3 is selected from C3-C6 cycloalkyl, 3-6 membered aliphatic heterocyclyl, 5-6 membered aromatic heterocyclyl, or phenyl, said R3 being optionally substituted with one or more groups selected from halogen, methyl, methoxy, hydroxyl, -CH2OH, -CF3, -CHF2, -CN, -OCHF2, cyclopropyl, morpholinyl; m OH, -CH2OCH3, -CN, -CONH2, -CON(CH3)2, -COOCH3, -CONHCH3;

[0060] m = 0, 1, 2, 3;

[0061] n = 0, 1, 2, 3;

[0062] R4 is selected from hydrogen, halogen, -CN, -CF3, -CHF2, -CF2CH3, -C1-C4 alkyl, -C2-C4 alkenyl, -C2-C4 alkynyl, -CH2OH, -OCF3, C3-C5 cycloalkyl or heterocyclyl, -COOCH2CH3, -N(CH3)2;

[0063] R5 is selected from hydrogen, halogen, -CH3, -OCH3, -SCH3, -CHF2, -CF3, -CN;

[0064] R6 is selected from hydrogen, halogen, -OC1-C6 alkyl, -OCH2CH2NH2, -OCHF2, -CH2OH;

[0065] R7 is selected from hydrogen, -CH3, halogen.

[0066] In certain specific embodiments, R1 of the present application is selected from imidazolyl, thiazolyl, pyrazolyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and

[0067] 、 、 、 、 、 、 、 、 ;

[0068] In certain embodiments, R1of the present application is selected from the group consisting of imidazolyl, thiazolyl, pyrazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and

[0069] 、 、 、 、 、 、 、 、 ;

[0070] In certain embodiments, R1of the present application is selected from the group consisting of:

[0071] 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ;

[0072] In certain embodiments, R1of the present application is selected from the group consisting of phenyl, naphthyl, pyridyl, and .

[0073] In certain embodiments, the R1group is optionally substituted with q Ra groups, each Ra group is independently selected from -CH3, -F, -CI, -Br, -I, -CN, -CHF2, -CF3, -OCF3, -OCH3, -OCHF2, -OH, -(CH2) m OH, -NHSO2CH3, -COOH, -CONH2, -CONHCH3, -CH2COCH3, cyclopropyl, 、 、 wherein q = 0, 1, 2, m = 0, 1, 2, 3.

[0074] In certain embodiments, the R1group is optionally substituted with q Ra groups, each Ra group is independently selected from C1-C4 alkyl-, -F, -CI, -Br, -I, -CHF2, -CF3, -OCF3, -OCH3, -OCHF2, and -OH, wherein q = 0, 1, 2.

[0075] In certain embodiments, the R2of the present application is -NRcRd;

[0076] In certain embodiments, the R2of the present application is -NRcRd;

[0077] In certain embodiments, the R2of the present application is -NRcRd; n R3, selected from C3-C6 cycloalkyl, 3-6 membered aliphatic heterocyclyl, 5-6 membered aromatic heterocyclyl, phenyl, and 4-10 membered bridged cyclyl;

[0078] In certain embodiments, the R3is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thianyl, piperidinyl, pyrrolidinyl, phenyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, pyrrolyl, pyridazinyl, morpholinyl, and spirocyclyl;

[0079] In certain embodiments, R3is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thianyl, piperidinyl, pyrrolidinyl, phenyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl;

[0080] In certain embodiments, the present application, Rdis -(CH2) n R3, selected from:

[0081] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

[0082] In certain embodiments, the present application, Rdis -(CH2) n R3, selected from:

[0083] , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ;

[0084] In certain embodiments, R3is optionally substituted with one or more groups selected from halogen, C1-C4alkyl, C1-C4alkoxy, substituted or unsubstituted C3-C6cycloalkyl, haloC1-C4alkyl, hydroxyl, =0, -CN, sulfone, -NR8R9, amido, C1-C4haloalkoxy, substituted or unsubstituted five- to six-membered aliphatic heterocyclyl, wherein the C3-C6cycloalkyl, five- to six-membered aliphatic heterocyclyl is optionally substituted with one or more groups selected from C1-C4alkyl-, halogen, hydroxyl, or C3-C6cycloalkyl-. 1-4 In certain embodiments, R3is optionally substituted with one or more groups selected from halogen, C1-C4alkyl, C1-C4alkoxy, substituted or unsubstituted C3-C6cycloalkyl, haloC1-C4alkyl, hydroxyl, =0, -CN, sulfone, -NR8R9, amido, C1-C4haloalkoxy, substituted or unsubstituted five- to six-membered aliphatic heterocyclyl, wherein the C3-C6cycloalkyl, five- to six-membered aliphatic heterocyclyl is optionally substituted with one or more groups selected from C1-C4alkyl-, halogen, hydroxyl, or C3-C6cycloalkyl-. 3-6 In certain embodiments, R3is optionally substituted with one or more groups selected from halogen, C1-C4alkyl, C1-C4alkoxy, substituted or unsubstituted C3-C6cycloalkyl, haloC1-C4alkyl, hydroxyl, =0, -CN, sulfone, -NR8R9, amido, C1-C4haloalkoxy, substituted or unsubstituted five- to six-membered aliphatic heterocyclyl, wherein the C3-C6cycloalkyl, five- to six-membered aliphatic heterocyclyl is optionally substituted with one or more groups selected from C1-C4alkyl-, halogen, hydroxyl, or C3-C6cycloalkyl-.

[0085] In certain embodiments, R3is optionally substituted with one or more groups selected from halogen, C1-C4alkyl, C1-C4alkoxy, substituted or unsubstituted C3-C6cycloalkyl, haloC1-C4alkyl, hydroxyl, =0, -CN, sulfone, -NR8R9, amido, C1-C4haloalkoxy, substituted or unsubstituted five- to six-membered aliphatic heterocyclyl, wherein the C3-C6cycloalkyl, five- to six-membered aliphatic heterocyclyl is optionally substituted with one or more groups selected from C1-C4alkyl-, halogen, hydroxyl, or C3-C6cycloalkyl-.

[0086] In certain embodiments, R3is optionally substituted with one or more groups selected from =0, F, Cl, Br, methyl, methoxy, hydroxyl, -CH2OH, -CF3, -NH2, -CHF2, -CN, -OCHF2, sulfone, amido, cyclopropyl, morpholinyl, piperazinyl, thiomorpholinyl, n = 0, 1, 2, or 3.

[0087] In certain embodiments, Rdis selected from: 、 ;

[0088] In certain embodiments, the ring A of the present application has 4-10 ring members.

[0089] In certain embodiments, the ring A of the present application is selected from: , , , ; the ring A is optionally substituted with one or more groups selected from methyl, halogen, -OCH3, -NH2, -NHCH3, -COOH, -(CH2) m OH, -CH2OCH3, -CN, -CONH2, -CON(CH3)2, -COOCH3, -CONHCH3; m = 0, 1, 2, 3; preferably, the ring A is optionally substituted with one or more groups selected from methyl, halogen, -OCH3, -(CH2) m OH; m = 0, 1, 2, 3.

[0090] In certain embodiments, the ring A of the present application is selected from: , , , ; the ring A is optionally substituted with one or more groups selected from methyl, halogen, -OCH3, -NH2, -NHCH3, -COOH, -(CH2) m OH, -CH2OCH3, -CN, -CONH2, -CON(CH3)2, -COOCH3, -CONHCH3; m = 0, 1, 2, 3; preferably, the ring A is optionally substituted with one or more groups selected from methyl, halogen, -OCH3, -(CH2) m OH; m = 0, 1, 2, 3. More preferably, the ring A is optionally substituted with one -(CH2) m OH group; m = 0, 1, 2, 3.

[0091] In certain embodiments, the ring B of the present application is selected from 4-6 membered aliphatic heterocycle, preferably morpholine, piperazine, thiomorpholine, azetidine or pyrrolidine group, the ring B is optionally substituted with one or more groups selected from methyl, halogen, -OCH3, -OH.

[0092] In certain embodiments, the R1of the present application is selected from:

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102] In certain embodiments, R1of the present application is selected from:

[0103] and .

[0104] In certain embodiments, R2of the present application is selected from:

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119] .

[0120] In certain embodiments, R2of the present application is selected from:

[0121]

[0122] and .

[0123] In certain embodiments, Y represents CR4, X represents CR5, W represents CR6, and Z represents N or CR7,

[0124] Preferably, when R7 is H, R4 is not H or isopropyl; and when R7 is CH3, R4 is not H.

[0125] In certain embodiments, R4 is selected from the group consisting of H, -F, -Cl, -Br, -CN, -CF3, -CF2CH3, -CHF2, -CH3, ethyl, ethenyl, ethynyl, propyl, isopropyl, butyl, -CH2OH, -COOCH2CH3, -OCF3, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclopentyl, -N(CH3)2, , , , .

[0126] In certain embodiments, R4 is selected from the group consisting of H, -F, -Cl, -Br, -CF3, -CF2CH3, -CHF2, -CH3, ethyl, isopropyl, ethoxy, methoxy, -OCF3, unsubstituted or halogen-substituted cyclopropyl, unsubstituted or halogen-substituted cyclopentyl, preferably from the group consisting of H, -F, -Cl, -Br, -CF3, -CF2CH3, -CHF2, -CH3, ethyl, isopropyl, -OCF3, unsubstituted or halogen-substituted cyclopropyl, unsubstituted or halogen-substituted cyclopentyl.

[0127] In certain embodiments, R5 is selected from the group consisting of H, -F, -Cl, -Br, -CN, -CF3, -CHF2, -CH3, -OCH3, -SCH3, preferably H.

[0128] In certain embodiments, R6 is selected from the group consisting of H, -F, -Cl, -Br, -OCH3, ethyl, -OCHF2, -OCH(CH3)2, -OCH2C(CH3)3, preferably H.

[0129] In certain embodiments, R7 is selected from the group consisting of H, -CH3, -F, -Cl, -Br, preferably H.

[0130] In certain embodiments, the compound of formula I according to the present application has the following structure according to formula II:

[0131]

[0132] wherein R1, R2, R4, R5, R6 are defined as in formula I, and R2 is not OH.

[0133] In some specific embodiments, the compound of formula I of the present invention has the structure shown in formula III:

[0134]

[0135] The definitions of R1, R2, R4, R5, R6, and R7 are the same as those defined in Equation I above, and R1 is not a constant. , , , , .

[0136] In some specific embodiments, the compound of formula I of the present invention has the structure shown in formula IV:

[0137]

[0138] The definitions of R1, R2, R4, R6, and R7 are the same as those defined in Equation I above.

[0139] In some specific embodiments, the compound of formula I of the present invention has the structure shown in formula V:

[0140]

[0141] The definitions of R1, R2, R4, R5, and R7 are the same as those in Equation I above.

[0142] In some specific embodiments, the compound of formula I of the present invention has the structure shown in formula VI:

[0143]

[0144] The definitions of R1, R2, R5, R6, and R7 are the same as those defined in Equation I above.

[0145] In some specific embodiments, the compound of formula I of the present invention has the following structure:

[0146]

[0147]

[0148]

[0149]

[0150]

[0151] .

[0152] Another object of the present application is to provide a process for the preparation of the compounds of formula I, which is as follows, wherein R4, R5, R6, R7, Ra, Rc, Rd and q in the general structures of the schemes are the same as defined in formula I above:

[0153] Scheme 1:

[0154]

[0155] As shown in Scheme 1, compounds such as la can be purchased through commercial channels or readily obtained through routine synthetic means in the art. Typically, la can be reacted with an appropriately functionalized amino-substituted benzene ring (or other 5-10 membered aromatic or heteroaromatic ring, as desired) to generate compounds such as lb. Typically, such reactions can be performed by microwave initiation in solvents such as dioxane, DMA, or NMP at 100 °C to 140 °C. Compounds such as lb can be condensed with an acid amine condensing agent (such as DIC, HOBT, DCC, EDCI, HATU, HBTU, and the like) to generate an active ester, which can be reacted with ethyl cyanoacetate under basic conditions (such as NaH) in a one-pot procedure to generate compounds such as lc. Halogenation of compounds such as lc to compounds such as Id can occur in the presence of various halogenating reagents (such as POCl3or SOCl2). Compounds such as Id can be subjected to nucleophilic substitution with an appropriately functionalized amine to generate compounds such as Formula II.

[0156] Scheme II:

[0157]

[0158] As shown in Scheme II, compounds such as 3a can be purchased through commercial channels or readily obtained through routine synthetic means in the art. Typically, 3a can be reacted with an appropriately functionalized amino-substituted benzene ring (or other 5-10 membered aromatic or heteroaromatic ring, as desired) via metal coupling reactions (such as palladium coupling) to generate compounds such as 3b. Compounds such as 3b can be hydrolyzed under basic conditions (such as KOH, NaOH, and the like) to generate compounds such as 3c, with solvents selected from alcoholic solvents / water. Compounds such as 3c can be condensed with an acid amine condensing agent (such as DIC, HOBT, DCC, EDCI, HATU, HBTU, and the like) to generate an active ester, which can be reacted with ethyl cyanoacetate under basic conditions (such as NaH) in a one-pot procedure to generate compounds such as 3d. Halogenation of compounds such as 3d to compounds such as 3e can occur in the presence of various halogenating reagents (such as POCl3or SOCl2). Compounds such as 3e can be subjected to nucleophilic substitution with an appropriately functionalized amine to generate compounds such as Formula III.

[0159] Scheme III:

[0160]

[0161] As shown in Scheme III, compounds such as 2a can be purchased through commercial channels or readily obtained by conventional synthetic means in the art. Typically, 2a can be reacted with an appropriately functionalized amino-substituted benzene ring (or other 5-10 membered aromatic or heteroaromatic ring, as desired) to generate compounds such as 2b. Typically, such reactions can be performed by microwave initiation in solvents such as dioxane, DMA, or NMP at 100 °C to 140 °C. Compounds such as 2b can be condensed with an acid amine condensing agent (such as DIC, HOBT, DCC, EDCI, HATU, HBTU, and the like) to generate an active ester, which can be reacted with ethyl cyanoacetate under basic conditions (such as NaH) in a one-pot procedure to generate compounds such as 2c. Halogenation of compounds such as 2c to compounds such as 2d can occur in the presence of various halogenating reagents (such as POCl3or SOCl2). Compounds such as 2d can be subjected to nucleophilic substitution with an appropriately functionalized amine to generate compounds of Formula IV.

[0162] Scheme IV:

[0163]

[0164] As shown in Scheme IV, compounds such as 4a can be purchased through commercial channels or readily obtained by conventional synthetic means in the art. Typically, 4a can be reacted with an appropriately functionalized amino-substituted benzene ring (or other 5-10 membered aromatic or heteroaromatic ring, as desired) via metal coupling reactions (such as palladium coupling) to generate compounds such as 4b. Compounds such as 4b can be hydrolyzed under basic conditions (such as KOH, NaOH, and the like) to generate compounds such as 4c, with solvents selected from alcoholic solvents / water. Compounds such as 4c can be condensed with an acid amine condensing agent (such as DIC, HOBT, DCC, EDCI, HATU, HBTU, and the like) to generate an active ester, which can be reacted with ethyl cyanoacetate under basic conditions (such as NaH) in a one-pot procedure to generate compounds such as 4d. Halogenation of compounds such as 4d to compounds such as 4e can occur in the presence of various halogenating reagents (such as POCl3or SOCl2). Compounds such as 4e can be subjected to nucleophilic substitution with an appropriately functionalized amine to generate compounds of Formula V.

[0165] Scheme V:

[0166]

[0167] As shown in Scheme V, compounds such as 5a can be purchased through commercial channels or readily obtained by conventional synthetic means in the art. Typically, 5a can be reacted with an appropriately functionalized amino-substituted benzene ring (or other 5-10 membered aromatic or heteroaromatic ring as desired) via a metal coupling reaction (such as a palladium coupling) to generate a compound such as 5b. Hydrolysis of a compound such as 5b under basic conditions (such as KOH, NaOH, and the like) in a solvent selected from an alcohol solvent / water affords a compound such as 5c. Condensation of a compound such as 5c with an acid amine condensing agent (such as DIC, HOBT, DCC, EDCI, HATU, HBTU, and the like) generates an active ester, which is then subjected to a one-pot reaction with ethyl cyanoacetate under basic conditions (such as NaH) to generate a compound such as 5d. Halogenation of a compound such as 5d to a compound such as 5e can occur in the presence of various halogenating reagents (such as POCl3or SOCl2). Nucleophilic substitution of a compound such as 5e with an appropriately functionalized amine affords a compound of Formula VI.

[0168] Scheme VI:

[0169]

[0170] As shown in Scheme VI, compounds such as 6a can be purchased through commercial channels or readily obtained by conventional synthetic means in the art. Typically, 6a can be reacted with an appropriately functionalized amino-substituted benzene ring (or other 5-10 membered aromatic or heteroaromatic ring as desired) to generate a compound such as 6b. Typically, such reactions can be carried out in a solvent such as DMSO, DMA, or NMP at room temperature, with commonly selected bases including potassium tert-butoxide and sodium tert-butoxide. Hydrolysis of a compound such as 6b under basic conditions (such as KOH, NaOH, and the like) in a solvent selected from an alcohol solvent / water affords a compound such as 6c. Condensation of a compound such as 6c with an acid amine condensing agent (such as DIC, HOBT, DCC, EDCI, HATU, HBTU, and the like) generates an active ester, which is then subjected to a one-pot reaction with ethyl cyanoacetate under basic conditions (such as NaH) to generate a compound such as 6d. Halogenation of a compound such as 6d to a compound such as 6e can occur in the presence of various halogenating reagents (such as POCl3or SOCl2). Nucleophilic substitution of a compound such as 6e with an appropriately functionalized amine affords a compound of Formula III.

[0171] Scheme VII:

[0172]

[0173] As shown in Scheme VII, compounds such as 7a are commercially available or readily available by routine synthetic means in the art. Typically, 7a can be coupled with an appropriately functionalized amino-substituted benzene ring (or other 5-10 membered aromatic or heteroaromatic ring, as desired) via a metal coupling reaction (such as a palladium coupling) to generate compounds such as 7b. Compounds such as 7b are hydrolyzed under basic conditions (such as KOH, NaOH, and the like) to generate compounds such as 7c, and the solvent can be selected from alcoholic solvents / water. Compounds such as 7c are first condensed with an acid amine condensing agent (such as DIC, HOBT, DCC, EDCI, HATU, HBTU, and the like) to generate an active ester, and then subjected to a one-pot reaction with ethyl cyanoacetate under basic conditions (such as NaH) to generate compounds such as 7d. Halogenation of compounds such as 7d to compounds such as 7e can occur in the presence of various halogenating reagents (such as POCl3or SOCl2). Compounds such as 7e can be subjected to nucleophilic substitution with an appropriately functionalized amine to generate compounds of Formula II.

[0174] It is another object of the present application to provide a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, or hydrate, or isomer, or prodrug, or mixture thereof, and a pharmaceutically acceptable excipient.

[0175] Another object of the present application is to provide the use of the aforementioned compound of Formula I, pharmaceutically acceptable salts, hydrates, isomers, prodrugs or mixtures thereof for the manufacture of a medicament for the treatment of MAT2a related diseases. In particular, the MAT2a related diseases according to the present application are cancer or tumor, further, the cancer or tumor includes neuroblastoma, intestinal cancer such as rectal cancer, colon cancer, familial adenomatous polyposis cancer and hereditary non- polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, kidney cancer, renal parenchymal carcinoma, ovarian cancer, cervical cancer, uterine body cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, breast cancer, urinary system cancer, melanoma, brain tumor such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumor, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia, hepatocellular carcinoma, gallbladder cancer, bronchial cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma and plasmacytoma. In one embodiment, the cancer is lung cancer, non-small cell lung cancer (NSLC), bronchioloalveolar cell lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, bladder cancer, kidney cancer or ureter cancer, renal cell carcinoma, renal pelvis carcinoma, mesothelioma, hepatocellular carcinoma, biliary tract cancer, chronic or acute leukemia, lymphocytic lymphoma Homa, central nervous system (CNS) tumor, spinal cord axis tumor, brain stem neuroglioma, glioblastoma multiforme, astrocytoma, schwannoma, ependymoma, medulloblastoma, meningioma, squamous cell carcinoma, pituitary adenoma, including refractory forms of any of the above cancers, or a combination of one or more of the above cancers.

[0176] Another object of the present application is to provide a method for treating cancer or tumor diseases, comprising administering to a patient in need thereof one or more of the aforementioned pharmaceutical compositions or the compound of Formula I or a pharmaceutically acceptable salt, hydrate, isomer, prodrug or mixture thereof.

[0177] Still another object of the present application is to provide a compound of the following formula represented by the structure

[0178]

[0179] wherein the definitions of R1, R4, R5, R6 are consistent with the foregoing definitions of the present application;

[0180] In certain embodiments, the compound is of the formula wherein R1is selected from phenyl or pyridyl, which R1is optionally substituted with 1 or 2 groups selected from -CH3, -OCH3, -F, -Cl, -Br, -CH2CH3, -OH, -CN, cyclopropyl;

[0181] In certain embodiments, the compound is of the formula wherein R4is selected from -H, -CH3, -CF3, substituted or unsubstituted cyclopropyl;

[0182] In certain embodiments, the compound is of the formula wherein R5is selected from H and R6is selected from H.

[0183] The present application further provides the use of a compound of the formula for the preparation of a compound of the formula or the formula of the present application.

[0184] The present application further provides the use of a compound of the formula for the preparation of a compound of the formula of the present application:

[0185] .

[0186] The present application also relates to the following embodiments:

[0187] 1. A compound of the formula I, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof:

[0188]

[0189] wherein Y represents N or CR4, X represents N or CR5, W represents N or CR6, and Z represents N or CR7;

[0190] R1is selected from a 5-10 membered aryl or heteroaryl group;

[0191] said R1group is optionally substituted with q R a groups, each of said R a groups is independently selected from -CH3, halogen, -CN, -CHF2, -CF3, -OCH3, -OCF3, -OCHF2, -OH, -(CH2) m OH, -NHSO2CH3, -COOH, -CONH2, -CONHCH3, -CH2COCH3, cyclopropyl, , , ;

[0192] q = 0, 1, 2;

[0193] R2is -NR c R d , -OH, -OCH3, -CH3, ethyl, isopropyl, -O-cyclopropyl;

[0194] wherein R c is selected from H or -CH3,

[0195] R d is selected from

[0196] 6) H;

[0197] 7) -COCH3;

[0198] 8) alkyl, said alkyl being substituted with one or more groups selected from methyl, hydroxyl, amino, cyano, methoxy, halogen, deuterium, -CH2OH, -NHCH3, -N(CH3)2, -SO2CH3, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, -CONHCH3, -CONH2, -SO2-morpholinyl, -SO2NH-cyclopropyl, -NHSO2NH2;

[0199] 9) -(CH2) n R3, wherein R3 is selected from C3-C6 cycloalkyl, 3-6 membered aliphatic heterocyclyl, 5-6 membered aromatic heterocyclyl, or phenyl, 4-10 membered bridged ring, said R3 is optionally substituted with one or more groups selected from halogen, alkyl, alkoxy, substituted or unsubstituted cycloalkyl, haloalkyl, hydroxyl, O, -CN, sulfone, -NR8R9, amide, haloalkoxy, substituted or unsubstituted aliphatic heterocyclyl;

[0200] 10) spirocyclic;

[0201] or, R c and R dtogether with the N atom to which they are attached form a ring A, and said ring A has only one heteroatom; said ring A is optionally substituted with one or more groups selected from methyl, halogen, -OCH3, -NH2, -NHCH3, -COOH, -(CH2) m OH, -CH2OCH3, -CN, -CONH2, -CON(CH3)2, -COOCH3, -CONHCH3;

[0202] m = 0, 1, 2, 3;

[0203] n = 0, 1, 2, 3;

[0204] R4is selected from hydrogen, halogen, -CN, -CF3, -CHF2, -CF2CH3, -C1-C4alkyl, -C2-C4alkenyl, -C2-C4alkynyl, -CH2OH, -OCF3, substituted or unsubstituted C3-C5cycloalkyl or heterocyclyl, -COOCH2CH3, -N(CH3)2;

[0205] R5is selected from hydrogen, halogen, -CH3, -OCH3, -SCH3, -CHF2, -CF3, -CN;

[0206] R6is selected from hydrogen, halogen, -OC1-C6alkyl, -OCH2CH2NH2, -OCHF2, -CH2OH;

[0207] R7is selected from hydrogen, -CH3, halogen;

[0208] R8, R9are each independently selected from H, C1-C4alkyl, hydroxyl substituted C1-C4alkyl, halogen substituted C1-C4alkyl, or, R8and R9together with the N atom to which they are attached form a ring B, and said ring B is optionally substituted with one or more groups selected from methyl, halogen, -OCH3, -NH2, -NHCH3, -COOH, -(CH2) t OH, -CH2OCH3, -CN, -CONH2, -CON(CH3)2, -COOCH3, -CONHCH3;

[0209] t = 0, 1, 2, 3.

[0210] 2. The compound according to item 1, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, characterized in that said R1is selected from imidazolyl, thiazolyl, pyrazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and , , , , , , 、 、 .

[0211] 3. The compound according to Clause 2, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, characterized in that R1 is selected from:

[0212] 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 .

[0213] 4. The compound according to Clause 2 or 3, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, characterized in that the R1 group is optionally substituted with q R a groups, each of said R a groups is independently selected from -CH3, -F, -Cl, -Br, -I, -CN, -CHF2, -CF3, -OCF3, -OCH3, -OCHF2, -OH, -(CH2) m OH, -NHSO2CH3, -COOH, -CONH2, -CONHCH3, -CH2COCH3, cyclopropyl, 、 、 wherein q = 0, 1, 2, m = 0, 1, 2, 3.

[0214] 5. The compound according to Clause 1, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, characterized in that R2 is -NR c R d .

[0215] 6. The compound according to any one of clauses 1-5, pharmaceutically acceptable salts, hydrates, isomers, prodrugs, and mixtures thereof, characterized in that R d is C1-C4 alkyl optionally substituted with one or more groups selected from methyl, hydroxyl, halogen, deuterium, -OCH3, -CN, -OCHF2, -N(CH3)2, -SO2CH3, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, -SO2-morpholinyl, -SO2NH-cyclopropyl, -NHSO2NH2, -CONHCH3, -CONH2, -CON(CH3)2.

[0216] 7. The compound according to any one of clauses 1-5, pharmaceutically acceptable salts, hydrates, isomers, prodrugs, and mixtures thereof, characterized in that R d is -(CH2) n R3, wherein R3 is selected from C3-C6 cycloalkyl, 3-6 membered aliphatic heterocyclyl, 5-6 membered aromatic heterocyclyl, or phenyl, 4-10 membered bridged ring; preferably, R3 is selected from cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thianyl, piperidinyl, pyrrolidinyl, phenyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl.

[0217] 8. The compound according to clause 7, pharmaceutically acceptable salts, hydrates, isomers, prodrugs, and mixtures thereof, characterized in that R d is -(CH2) n R3, wherein R3 is selected from:

[0218] , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 .

[0219] 9. The compound according to any one of clauses 1-8, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, wherein R3 is optionally substituted with one or more groups selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, C1-C4 haloalkyl, hydroxyl, O, -CN, sulfone, -NR8R9, amide, C1-C4 haloalkoxy, substituted or unsubstituted five to six membered aliphatic heterocycle, wherein the C3-C6 cycloalkyl, five to six membered aliphatic heterocycle is optionally substituted with methyl, F, Cl, Br or hydroxyl; preferably, R3 is optionally substituted with one or more groups selected from O, F, Cl, Br, -NH2, methyl, methoxy, hydroxyl, -CH2OH, -CF3, -CHF2, -CN, -OCHF2, cyclopropyl, morpholinyl, sulfone, amide, piperazinyl, thiomorpholinyl; n = 0, 1, 2, 3.

[0220] 10. The compound according to any one of clauses 1-5, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, wherein R d is selected from: 、 .

[0221] 11. The compound according to any one of clauses 1-5, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, wherein ring A is selected from: 、 、 、 ; ring A is optionally substituted with one or more groups selected from methyl, halogen, -OCH3, -NH2, -NHCH3, -COOH, -(CH2) m OH, -CH2OCH3, -CN, -CONH2, -CON(CH3)2, -COOCH3, -CONHCH3; m = 0, 1, 2, 3.

[0222] 12. The compound according to any one of clauses 1-11, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, wherein R1 is selected from:

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231] .

[0232] 13. The compound according to any one of clauses 1-12, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, characterized in that R2 is selected from:

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246] .

[0247] 14. The compound according to any one of clauses 1-13, pharmaceutically acceptable salts, hydrates, isomers, prodrugs, and mixtures thereof, wherein R4 is selected from the group consisting of H, -F, -Cl, -Br, -CN, -CF3, -CF2CH3, -CHF2, -CH3, ethyl, ethenyl, ethynyl, propyl, isopropyl, butyl, -CH2OH, -COOCH2CH3, -OCF3, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclopentyl, -N(CH3)2, , , , .

[0248] 15. The compound according to any one of clauses 1-14, pharmaceutically acceptable salts, hydrates, isomers, prodrugs, and mixtures thereof, wherein R5 is selected from the group consisting of H, -F, -Cl, -Br, -CN, -CF3, -CHF2, -CH3, -OCH3, -SCH3.

[0249] 16. The compound according to any one of clauses 1-15, pharmaceutically acceptable salts, hydrates, isomers, prodrugs, and mixtures thereof, wherein R6 is selected from the group consisting of H, -F, -Cl, -Br, -OCH3, ethyl, -OCHF2, -OCH(CH3)2, -OCH2C(CH3)3; and R7 is selected from the group consisting of H, -CH3, -F, -Cl, -Br.

[0250] 17. The compound according to clause 1, pharmaceutically acceptable salts, hydrates, isomers, prodrugs, and mixtures thereof, wherein the compound of Formula I has the structure of Formula II:

[0251]

[0252] wherein R1 is selected from the group consisting of 5-10 membered aryl or heteroaryl;

[0253] said R1 group is optionally substituted with q Ra groups, each said Ra group is independently selected from the group consisting of -CH3, halogen, -CN, -CHF2, -CF3, -OCF3, -OCH3, -OCHF2, -OH, -(CH2) m OH, -NHSO2CH3, -COOH, -CONH2, -CONHCH3, -CH2COCH3, cyclopropyl, , , ; q = 0, 1, 2.

[0254] R2 is -NRcRd, -OCH3, -CH3, ethyl, isopropyl, -O-cyclopropyl;

[0255] wherein Rc is selected from H or -CH3,

[0256] Rd is selected from

[0257] 1) H;

[0258] 2) -COCH3;

[0259] 3) alkyl, said alkyl being substituted with one or more groups selected from methyl, hydroxyl, amino, cyano, methoxy, halogen, deuterium, -CH2OH, -NHCH3, -N(CH3)2, -SO2CH3, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, -CONHCH3, -CONH2, -SO2-morpholinyl, -SO2NH-cyclopropyl, -NHSO2NH2;

[0260] 4) -(CH2)n n R3, wherein R3 is selected from C3-C6 cycloalkyl, 3-6 membered aliphatic heterocyclyl, 5-6 membered aromatic heterocyclyl, or phenyl, 4-10 membered bridged ring, said R3 is optionally substituted with one or more groups selected from halogen, alkyl, alkoxy, substituted or unsubstituted cycloalkyl, haloalkyl, hydroxyl, O, -CN, sulfone, -NR8R9, amide, haloalkoxy, substituted or unsubstituted aliphatic heterocyclyl;

[0261] 5) spirocyclic;

[0262] Alternatively, Rc and Rd, together with the N atom to which they are both attached, form a ring A, and said ring A has only one heteroatom; said ring A is optionally substituted with one or more groups selected from methyl, halogen, OCH3, NH2, NHCH3, COOH, (CH2)n m OH, CH2OCH3, CN, CONH2, CON(CH3)2, COOCH3, CONHCH3;

[0263] m = 0, 1, 2, 3;

[0264] n = 0, 1, 2, 3;

[0265] R4 is selected from hydrogen, halogen, -CN, -CF3, -CHF2, -CF2CH3, -C1-C4 alkyl, -C2-C4 alkenyl, -C2-C4 alkynyl, -CH2OH, -OCF3, substituted or unsubstituted C3-C5 cycloalkyl or heterocyclyl, -COOCH2CH3, -N(CH3)2;

[0266] R5 is selected from hydrogen, halogen, -CH3, -OCH3, -SCH3, -CHF2, -CF3, -CN;

[0267] R6is selected from the group consisting of hydrogen, halogen, OC1-C6alkyl, -OCH2CH2NH2, -OCHF2, -CH2OH;

[0268] R8, R9are each independently selected from the group consisting of H, C1-C4alkyl, hydroxy-substituted C1-C4alkyl, halogen-substituted C1-C4alkyl, or, R8and R9together with the N atom to which they are both attached form a ring B, said ring B is optionally substituted with one or more groups selected from methyl, halogen, -OCH3, -NH2, -NHCH3, -COOH, -(CH2) t OH, -CH2OCH3, -CN, -CONH2, -CON(CH3)2, -COOCH3, -CONHCH3;

[0269] t = 0, 1, 2, 3.

[0270] 18. The compound according to item 17, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, characterized in that said R1is selected from the group consisting of imidazolyl, thiazolyl, pyrazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and

[0271] , , , , , , , , .

[0272] 19. The compound according to item 18, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, characterized in that said R1is selected from the group consisting of:

[0273] , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 .

[0274] 20. The compound, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof according to either of clauses 18 or 19, wherein the R1 group is optionally substituted with q Ra groups, each of which is independently selected from -CH3, -F, -Cl, -Br, -I, -CN, -CHF2, -CF3, -OCF3, -OCH3, -OCHF2, -OH, -(CH2) m OH, -NHSO2CH3, -COOH, -CONH2, -CONHCH3, -CH2COCH3, cyclopropyl, 、 、 wherein, wherein q = 0, 1, 2, m = 0, 1, 2, 3.

[0275] 21. The compound, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof according to clause 17, wherein the R2 is -NRcRd.

[0276] 22. The compound, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof according to any one of clauses 17-21, wherein the Rd is C1-C4 alkyl optionally substituted with one or more groups selected from methyl, hydroxyl, halogen, deuterium, -OCH3, -CN, -OCHF2, -N(CH3)2, -SO2CH3, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, -SO2-morpholinyl, -SO2NH-cyclopropyl, -NHSO2NH2, -CONHCH3, -CONH2, -CON(CH3)2.

[0277] 23. The compound, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof according to any one of clauses 17-21, wherein the Rd is -(CH2) n R3, wherein R3 is selected from C3-C6 cycloalkyl, 3-6 membered aliphatic heterocyclyl, 5-6 membered aromatic heterocyclyl, or phenyl, 4-10 membered bridged ring; preferably, the R3 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thianyl, piperidinyl, pyrrolidinyl, phenyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl.

[0278] 24. The pharmaceutically acceptable salts, hydrates, isomers, prodrugs, and mixtures of the compounds described in item 23, characterized in that Rd is -(CH2). n R3, where R3 is selected from:

[0279] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0280] 25. A compound according to any one of items 17-24, a pharmaceutically acceptable salt, hydrate, isomer, prodrug, and mixture thereof, characterized in that R3 is optionally replaced by one or more five- to six-membered aliphatic groups selected from halogens, C1-C4 alkyl groups, C1-C4 alkoxy groups, substituted or unsubstituted C3-C6 cycloalkyl groups, C1-C4 haloalkyl groups, hydroxyl groups, O, -CN, sulfone groups, -NR8R9, amide groups, C1-C4 haloalkoxy groups, substituted or unsubstituted aliphatic groups. The ring is substituted with a group, wherein the C3-C6 cycloalkyl, five- to six-membered aliphatic heterocycle is optionally substituted with methyl, F, Cl, Br or hydroxyl; preferably, the R3 may be optionally substituted with one or more groups selected from O, F, Cl, Br, -NH2, methyl, methoxy, hydroxyl, -CH2OH, -CF3, -CHF2, -CN, -OCHF2, cyclopropyl, morpholino, sulfone, amide, piperazine, thiomorpholino; n = 0, 1, 2, 3.

[0281] 26. A compound according to any one of items 17-21, comprising a pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof, characterized in that the Rd is selected from: , .

[0282] 27. The compound, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof according to any one of clauses 17-21, wherein said ring A is selected from: , , , ; said ring A is optionally substituted with one or more groups selected from methyl, halogen, -OCH3, -NH2, -NHCH3, -COOH, -(CH2) m OH, -CH2OCH3, -CN, -CONH2, -CON(CH3)2, -COOCH3, -CONHCH3; m = 0, 1, 2, 3.

[0283] 28. The compound, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof according to any one of clauses 17-27, wherein said R1 is selected from:

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292] .

[0293] 29. The compound, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof according to any one of clauses 17-28, wherein said R2 is selected from:

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309] .

[0310] 30. The compound, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof according to any one of clauses 17-29, wherein R4 is selected from the group consisting of H, -F, -Cl, -Br, -CN, -CF3, -CF2CH3, -CHF2, -CH3, ethyl, ethenyl, ethynyl, propyl, isopropyl, butyl, -CH2OH, -COOCH2CH3, -OCF3, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclopentyl, -N(CH3)2, , , , .

[0311] 31. The compound, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof according to any one of clauses 17-30, wherein R5 is selected from the group consisting of H, -F, -Cl, -Br, -CN, -CF3, -CHF2, -CH3, -OCH3, -SCH3.

[0312] 32. The compound, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof according to any one of clauses 17-31, wherein R6 is selected from the group consisting of H, -F, -Cl, -Br, -OCH3, ethyl, -OCHF2, -OCH(CH3)2, -OCH2C(CH3)3.

[0313] 33. The compound of clause 1, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, wherein the compound of Formula I has the structure of Formula III: ###00019###

[0314]

[0315] wherein R1 is selected from a 5-10 membered aryl or heteroaryl group;

[0316] said R1 group is optionally substituted with q R a groups, each of said R a groups is independently selected from -CH3, halogen, -CN, -CHF2, -CF3, -OCF3, -OCH3, -OCHF2, -OH, -(CH2) m OH, -NHSO2CH3, -COOH, -CONH2, -CONHCH3, -CH2COCH3, cyclopropyl, 、 、 ; q = 0, 1, 2.

[0317] R2 is -NR c R d , -OH, -OCH3, -CH3, ethyl, isopropyl, -O-cyclopropyl;

[0318] wherein R c is selected from H or -CH3,

[0319] R d is selected from

[0320] 1) H;

[0321] 2) -COCH3;

[0322] 3) alkyl, said alkyl is substituted with one or more groups selected from methyl, hydroxyl, amino, cyano, methoxy, halogen, deuterium, -CH2OH, -NHCH3, -N(CH3)2, -SO2CH3, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, -CONHCH3, -CONH2, -SO2-morpholinyl, -SO2NH-cyclopropyl, -NHSO2NH2;

[0323] 4) -(CH2) nR3, wherein R3 is selected from C3-C6 cycloalkyl, 3-6 membered aliphatic heterocyclyl, 5-6 membered aromatic heterocyclyl, or phenyl, 4-10 membered bridged ring, said R3 is optionally substituted with one or more groups selected from halogen, alkyl, alkoxy, substituted or unsubstituted cycloalkyl, haloalkyl, hydroxyl, O, -CN, sulfone, -NR8R9, amide, haloalkoxy, substituted or unsubstituted aliphatic heterocyclyl;

[0324] 5) spirocyclic;

[0325] or, R c and R d together with the N atom to which they are attached form a ring A, and said ring A has only one heteroatom; said ring A is optionally substituted with one or more groups selected from methyl, halogen, -OCH3, -NH2, -NHCH3, -COOH, -(CH2) m OH, -CH2OCH3, -CN, -CONH2, -CON(CH3)2, -COOCH3, -CONHCH3;

[0326] m = 0, 1, 2, 3;

[0327] n = 0, 1, 2, 3;

[0328] R4 is selected from hydrogen, halogen, -CN, -CF3, -CHF2, -CF2CH3, -C1-C4 alkyl, -C2-C4 alkenyl, -C2-C4 alkynyl, -CH2OH, -OCF3, substituted or unsubstituted C3-C5 cycloalkyl or heterocyclyl, -COOCH2CH3, -N(CH3)2;

[0329] R5 is selected from hydrogen, halogen, -CH3, -OCH3, -SCH3, -CHF2, -CF3, -CN;

[0330] R6 is selected from hydrogen, halogen, -OC1-C6 alkyl, -OCH2CH2NH2, -OCHF2, -CH2OH;

[0331] R7 is selected from hydrogen, -CH3, halogen;

[0332] R8, R9 are each independently selected from H, C1-C4 alkyl, hydroxyl substituted C1-C4 alkyl, halogen substituted C1-C4 alkyl, or, R8 and R9 together with the N atom to which they are attached form a ring B, said ring B is optionally substituted with one or more groups selected from methyl, halogen, -OCH3, -NH2, -NHCH3, -COOH, -(CH2) t OH, -CH2OCH3, -CN, -CONH2, -CON(CH3)2, -COOCH3, -CONHCH3;

[0333] t = 0, 1, 2, 3;

[0334] and R1is not , , , , .

[0335] 34. The compound according to Clause 33, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, characterized in that said R1is selected from the group consisting of imidazolyl, thiazolyl, pyrazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and

[0336] , , , , , , , , .

[0337] 35. The compound according to Clause 34, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, characterized in that said R1is selected from the group consisting of:

[0338] , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0339] 36. The compound according to Clause 34 or 35, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, characterized in that said R1group is optionally substituted with q R a groups, each of said R​a groups are independently selected from -CH3, -F, -CI, -Br, -I, -CN, -CHF2, -CF3, -OCF3, -OCH3, -OCHF2, -OH, -(CH2) m OH, -NHSO2CH3, -COOH, -CONH2, -CONHCH3, -CH2COCH3, cyclopropyl, , , wherein, wherein q = 0, 1, 2, m = 0, 1, 2, 3.

[0340] 37. The compound according to Clause 33, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, characterized in that said R2 is -NR c R d .

[0341] 38. The compound according to any one of Clauses 33-37, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, characterized in that said R d is C1-C4 alkyl optionally substituted with one or more groups selected from methyl, hydroxyl, halogen, deuterium, -OCH3, -CN, -OCHF2, -N(CH3)2, -SO2CH3, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, -SO2-morpholinyl, -SO2NH-cyclopropyl, -NHSO2NH2, -CONHCH3, -CONH2, -CON(CH3)2.

[0342] 39. The compound according to any one of Clauses 33-37, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, characterized in that said R d is -(CH2) n R3, wherein R3 is selected from C3-C6 cycloalkyl, 3-6 membered aliphatic heterocyclyl, 5-6 membered aromatic heterocyclyl or phenyl, 4-10 membered bridged cyclyl; preferably, said R3 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thianyl, piperidinyl, pyrrolidinyl, phenyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl.

[0343] 40. The compound according to Clause 39, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, characterized in that said R d is -(CH2) n R3, wherein R3 is selected from:

[0344] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0345] 41. A compound according to any one of items 33-40, its pharmaceutically acceptable salt, hydrate, isomer, prodrug, and mixture, characterized in that R3 is optionally replaced by one or more five- to six-membered aliphatic groups selected from halogens, C1-C4 alkyl groups, C1-C4 alkoxy groups, substituted or unsubstituted C3-C6 cycloalkyl groups, C1-C4 haloalkyl groups, hydroxyl groups, O, -CN, sulfone groups, -NR8R9, amide groups, C1-C4 haloalkoxy groups, substituted or unsubstituted aliphatic groups. The ring is substituted with a group, wherein the C3-C6 cycloalkyl, five- to six-membered aliphatic heterocycle is optionally substituted with methyl, F, Cl, Br or hydroxyl; preferably, the R3 may be optionally substituted with one or more groups selected from O, F, Cl, Br, -NH2, methyl, methoxy, hydroxyl, -CH2OH, -CF3, -CHF2, -CN, -OCHF2, cyclopropyl, morpholino, sulfone, amide, piperazine, thiomorpholino; n = 0, 1, 2, 3.

[0346] 42. The compound according to any one of items 33-37, its pharmaceutically acceptable salt, hydrate, isomer, prodrug, and mixture, characterized in that the R d Selected from: , .

[0347] 43. The compound according to any one of items 33-37, its pharmaceutically acceptable salt, hydrate, isomer, prodrug, and mixture, characterized in that ring A is selected from: , 、 、 ; said ring A is optionally substituted with one or more groups selected from methyl, halogen, -OCH3, -NH2, -NHCH3, -COOH, -(CH2) m OH, -CH2OCH3, -CN, -CONH2, -CON(CH3)2, -COOCH3, -CONHCH3; m = 0, 1, 2, 3.

[0348] 44. The compound, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof according to any one of clauses 33-43, characterized in that said R1 is selected from:

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357] .

[0358] 45. The compound, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof according to any one of clauses 33-44, characterized in that said R2 is selected from:

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373] .

[0374] 46. The compound, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof according to any one of clauses 33-45, wherein R4 is selected from the group consisting of H, -F, -Cl, -Br, -CN, -CF3, -CF2CH3, -CHF2, -CH3, ethyl, ethenyl, ethynyl, propyl, isopropyl, butyl, -CH2OH, -COOCH2CH3, -OCF3, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclopentyl, -N(CH3)2, 、 、 、 .

[0375] 47. The compound, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof according to any one of clauses 33-46, wherein R5 is selected from the group consisting of H, -F, -Cl, -Br, -CN, -CF3, -CHF2, -CH3, -OCH3, -SCH3.

[0376] 48. The compound, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof according to any one of clauses 33-47, wherein R6 is selected from the group consisting of H, -F, -Cl, -Br, -OCH3, ethyl, -OCHF2, -OCH(CH3)2, -OCH2C(CH3)3; and R7 is selected from the group consisting of H, -CH3, -F, -Cl, -Br.

[0377] 49. The compound, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof according to clause 1, wherein the compound of Formula I has the following structure of Formula IV:

[0378]

[0379] wherein R1is selected from a 5-10 membered aryl or heteroaryl group;

[0380] said R1group is optionally substituted with q R a groups, each of said R a groups is independently selected from -CH3, halogen, -CN, -CHF2, -CF3, -OCF3, -OCH3, -OCHF2, -OH, -(CH2) m OH, -NHSO2CH3, -COOH, -CONH2, -CONHCH3, -CH2COCH3, cyclopropyl, , , ; q = 0, 1, 2.

[0381] R2is -NR c R d , -OH, -OCH3, -CH3, ethyl, isopropyl, -O-cyclopropyl;

[0382] wherein R c is selected from H or -CH3,

[0383] R d is selected from

[0384] 1) H;

[0385] 2) -COCH3;

[0386] 3) alkyl, said alkyl is substituted with one or more groups selected from methyl, hydroxyl, amino, cyano, methoxy, halogen, deuterium, -CH2OH, -NHCH3, -N(CH3)2, -SO2CH3, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, -CONHCH3, -CONH2, -SO2-morpholinyl, -SO2NH-cyclopropyl, -NHSO2NH2;

[0387] 4) -(CH2) n R3, wherein R3is selected from C3-C6 cycloalkyl, 3-6 membered aliphatic heterocyclyl, 5-6 membered aromatic heterocyclyl, or phenyl, 4-10 membered bridged ring, said R3is optionally substituted with one or more groups selected from halogen, alkyl, alkoxy, substituted or unsubstituted cycloalkyl, haloalkyl, hydroxyl, O, -CN, sulfone, -NR8R9, amide, haloalkoxy, substituted or unsubstituted aliphatic heterocyclyl;

[0388] 5) spirocyclic;

[0389] or, R c and R dwith the N atom to which they are attached forming a ring A, and said ring A having only one heteroatom; said ring A is optionally substituted with one or more groups selected from methyl, halogen, -OCH3, -NH2, -NHCH3, -COOH, -(CH2) m OH, -CH2OCH3, -CN, -CONH2, -CON(CH3)2, -COOCH3, -CONHCH3;

[0390] m = 0, 1, 2, 3;

[0391] n = 0, 1, 2, 3;

[0392] R4is selected from hydrogen, halogen, -CN, -CF3, -CHF2, -CF2CH3, -C1-C4alkyl, -C2-C4alkenyl, -C2-C4alkynyl, -CH2OH, -OCF3, substituted or unsubstituted C3-C5cycloalkyl or heterocyclyl, -COOCH2CH3, -N(CH3)2;

[0393] R6is selected from hydrogen, halogen, -OC1-C6alkyl, -OCH2CH2NH2, -OCHF2, -CH2OH;

[0394] R7is selected from hydrogen, -CH3, halogen;

[0395] R8, R9are each independently selected from H, C1-C4alkyl, hydroxyl substituted C1-C4alkyl, halogen substituted C1-C4alkyl, or, R8and R9together with the N atom to which they are attached form a ring B, said ring B is optionally substituted with one or more groups selected from methyl, halogen, -OCH3, -NH2, -NHCH3, -COOH, -(CH2) t OH, -CH2OCH3, -CN, -CONH2, -CON(CH3)2, -COOCH3, -CONHCH3;

[0396] t = 0, 1, 2, 3.

[0397] 50. The compound according to item 49, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, characterized in that said R1is selected from imidazolyl, thiazolyl, pyrazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and , , , , , , , , .

[0398] 51. The compound according to item 50, its pharmaceutically acceptable salts, hydrates, isomers, prodrugs, and mixtures, characterized in that R1 is selected from:

[0399] , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0400] 52. The compounds according to item 50 or 51, pharmaceutically acceptable salts, hydrates, isomers, prodrugs, and mixtures thereof, characterized in that the R1 group is selectively surrounded by q R groups. a Group substitution, each of the R groups a The groups are independently selected from -CH3, -F, -Cl, -Br, -I, -CN, -CHF2, -CF3, -OCF3, -OCH3, -OCHF2, -OH, and -(CH2). m OH, -NHSO2CH3, -COOH, -CONH2, -CONHCH3, -CH2COCH3, cyclopropyl, , , , where q=0, 1, 2, m=0, 1, 2, 3.

[0401] 53. The pharmaceutically acceptable salts, hydrates, isomers, prodrugs, and mixtures of the compounds described in item 49, characterized in that R2 is -NR. c R d .

[0402] 54. The compound according to any one of items 49-53, its pharmaceutically acceptable salt, hydrate, isomer, prodrug, and mixture, characterized in that the R dC1-C4 alkyl optionally substituted with one or more groups selected from methyl, hydroxyl, halogen, deuterium, -OCH3, -CN, -OCHF2, -N(CH3)2, -SO2CH3, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, -SO2-morpholinyl, -SO2NH-cyclopropyl, -NHSO2NH2, -CONHCH3, -CONH2, -CON(CH3)2.

[0403] 55. The compound according to any one of clauses 49-53, pharmaceutically acceptable salts, hydrates, isomers, prodrugs, and mixtures thereof, wherein R d -(CH2)2-6 n R3, wherein R3is selected from C3-C6 cycloalkyl, 3-6 membered aliphatic heterocyclyl, 5-6 membered aromatic heterocyclyl, or phenyl, 4-10 membered bridged ring; preferably, R3is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thianyl, piperidinyl, pyrrolidinyl, phenyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl.

[0404] 56. The compound according to clause 55, pharmaceutically acceptable salts, hydrates, isomers, prodrugs, and mixtures thereof, wherein R d -(CH2)2-6 n R3, wherein R3is selected from:

[0405] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0406] 57. The compound, pharmaceutically acceptable salt, hydrate, isomer, prodrug and mixture thereof according to any one of clauses 49-56, wherein R3 is optionally substituted with one or more groups selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, C1-C4 haloalkyl, hydroxyl, O, -CN, sulfone, -NR8R9, amide, C1-C4 haloalkoxy, substituted or unsubstituted five to six membered aliphatic heterocycle, wherein the C3-C6 cycloalkyl, five to six membered aliphatic heterocycle is optionally substituted with methyl, F, Cl, Br or hydroxyl; preferably, R3 is optionally substituted with one or more groups selected from O, F, Cl, Br, -NH2, methyl, methoxy, hydroxyl, -CH2OH, -CF3, -CHF2, -CN, -OCHF2, cyclopropyl, morpholinyl, sulfone, amide, piperazinyl, thiomorpholinyl; n = 0, 1, 2, 3.

[0407] 58. The compound, pharmaceutically acceptable salt, hydrate, isomer, prodrug and mixture thereof according to any one of clauses 49-53, wherein R d is selected from: , .

[0408] 59. The compound, pharmaceutically acceptable salt, hydrate, isomer, prodrug and mixture thereof according to any one of clauses 49-53, wherein ring A is selected from: , , , ; ring A is optionally substituted with one or more groups selected from methyl, halogen, -OCH3, -NH2, -NHCH3, -COOH, -(CH2) m OH, -CH2OCH3, -CN, -CONH2, -CON(CH3)2, -COOCH3, -CONHCH3; m = 0, 1, 2, 3.

[0409] 60. The compound, pharmaceutically acceptable salt, hydrate, isomer, prodrug and mixture thereof according to any one of clauses 49-59, wherein R1 is selected from:

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418] .

[0419] 61. The compound of any one of clauses 49-60, pharmaceutically acceptable salts, hydrates, isomers, prodrugs, and mixtures thereof, wherein R2 is selected from:

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435] .

[0436] 62. The compound, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof according to any one of clauses 49-61, wherein R4 is selected from H, -F, -Cl, -Br, -CN, -CF3, -CF2CH3, -CHF2, -CH3, ethyl, ethenyl, ethynyl, propyl, isopropyl, butyl, -CH2OH, -COOCH2CH3, -OCF3, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclopentyl, -N(CH3)2, , , , .

[0437] 63. The compound, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof according to any one of clauses 49-62, wherein R6 is selected from H, -F, -Cl, -Br, -OCH3, ethyl, -OCHF2, -OCH(CH3)2, -OCH2C(CH3)3; and R7 is selected from H, -CH3, -F, -Cl, -Br.

[0438] 64. The compound, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof according to clause 1, wherein the compound of Formula I has the following Formula V:

[0439]

[0440] R1 is selected from a 5-10 membered aryl or heteroaryl group;

[0441] said R1 group is optionally substituted with q R a groups, each of said R a groups is independently selected from -CH3, halogen, -CN, -CHF2, -CF3, -OCF3, -OCH3, -OCHF2, -OH, -(CH2) m OH, -NHSO2CH3, -COOH, -CONH2, -CONHCH3, -CH2COCH3, cyclopropyl, , , ;

[0442] q = 0, 1, 2;

[0443] R2 is -NR c R d , -OH, -OCH3, -CH3, ethyl, isopropyl, -O-cyclopropyl;

[0444] wherein R c is selected from H or -CH3,

[0445] R d selected from

[0446] 1) H;

[0447] 2) -COCH3;

[0448] 3) alkyl, said alkyl being substituted with one or more groups selected from methyl, hydroxyl, amino, cyano, methoxy, halogen, deuterium, -CH2OH, -NHCH3, -N(CH3)2, -SO2CH3, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, -CONHCH3, -CONH2, -SO2-morpholinyl, -SO2NH-cyclopropyl, -NHSO2NH2;

[0449] 4) -(CH2) n R3, wherein R3 is selected from C3-C6 cycloalkyl, 3-6 membered aliphatic heterocyclyl, 5-6 membered aromatic heterocyclyl, or phenyl, 4-10 membered bridged ring, said R3 is optionally substituted with one or more groups selected from halogen, alkyl, alkoxy, substituted or unsubstituted cycloalkyl, haloalkyl, hydroxyl, O, -CN, sulfone, -NR8R9, amide, haloalkoxy, substituted or unsubstituted aliphatic heterocyclyl;

[0450] 5) spirocyclic;

[0451] or, R c and R d together with the N atom to which they are attached form a ring A, and said ring A has only one heteroatom; said ring A is optionally substituted with one or more groups selected from methyl, halogen, -OCH3, -NH2, -NHCH3, -COOH, -(CH2) m OH, -CH2OCH3, -CN, -CONH2, -CON(CH3)2, -COOCH3, -CONHCH3;

[0452] m = 0, 1, 2, 3;

[0453] n = 0, 1, 2, 3;

[0454] R4 is selected from hydrogen, halogen, -CN, -CF3, -CHF2, -CF2CH3, -C1-C4 alkyl, -C2-C4 alkenyl, -C2-C4 alkynyl, -CH2OH, -OCF3, substituted or unsubstituted C3-C5 cycloalkyl or heterocyclyl, -COOCH2CH3, -N(CH3)2;

[0455] R5 is selected from hydrogen, halogen, -CH3, -OCH3, -SCH3, -CHF2, -CF3, -CN;

[0456] R7is selected from the group consisting of hydrogen, -CH3, halogen;

[0457] R8, R9are each independently selected from the group consisting of H, C1-C4alkyl, hydroxy-substituted C1-C4alkyl, halogen-substituted C1-C4alkyl, or, R8and R9together with the N atom to which they are both attached form a ring B, said ring B is optionally substituted with one or more groups selected from methyl, halogen, -OCH3, -NH2, -NHCH3, -COOH, -(CH2) t OH, -CH2OCH3, -CN, -CONH2, -CON(CH3)2, -COOCH3, -CONHCH3;

[0458] t = 0, 1, 2, 3.

[0459] 65. The compound according to Clause 65, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, characterized in that said R1is selected from the group consisting of imidazolyl, thiazolyl, pyrazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and , , , , , , , , .

[0460] 66. The compound according to Clause 66, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, characterized in that said R1is selected from the group consisting of:

[0461] , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0462] 67. The compound, pharmaceutically acceptable salt, hydrate, isomer, prodrug and mixture thereof according to any of clauses 65 or 66, wherein said R1 group is optionally substituted with q R a groups, each of said R a groups is independently selected from the group consisting of -CH3, -F, -Cl, -Br, -I, -CN, -CHF2, -CF3, -OCF3, -OCH3, -OCHF2, -OH, -(CH2) m OH, -NHSO2CH3, -COOH, -CONH2, -CONHCH3, -CH2COCH3, cyclopropyl, , , wherein q = 0, 1, 2, m = 0, 1, 2, 3.

[0463] 68. The compound, pharmaceutically acceptable salt, hydrate, isomer, prodrug and mixture thereof according to clause 64, wherein said R2 is -NR c R d .

[0464] 69. The compound, pharmaceutically acceptable salt, hydrate, isomer, prodrug and mixture thereof according to any of clauses 64-68, wherein said R d is C1-C4 alkyl optionally substituted with one or more groups selected from methyl, hydroxyl, halogen, deuterium, -OCH3, -CN, -OCHF2, -N(CH3)2, -SO2CH3, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, -SO2-morpholinyl, -SO2NH-cyclopropyl, -NHSO2NH2, -CONHCH3, -CONH2, -CON(CH3)2.

[0465] 70. The compound, pharmaceutically acceptable salt, hydrate, isomer, prodrug and mixture thereof according to any of clauses 64-68, wherein said R d is -(CH2) n R3, wherein R3 is selected from C3-C6 cycloalkyl, 3-6 membered aliphatic heterocyclyl, 5-6 membered aromatic heterocyclyl or phenyl, 4-10 membered bridged cyclyl; preferably, said R3 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thianyl, piperidinyl, pyrrolidinyl, phenyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl.

[0466] 71. The compound according to item 70, its pharmaceutically acceptable salts, hydrates, isomers, prodrugs, and mixtures, characterized in that the R d -(CH2) n R3, where R3 is selected from:

[0467] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0468] 72. The compound according to any one of items 64-71, its pharmaceutically acceptable salt, hydrate, isomer, prodrug, and mixture, characterized in that the R3 is optionally replaced by one or more groups selected from halogens, C1-C4 alkyl groups, C1-C4 alkoxy groups, substituted or unsubstituted C3-C6 cycloalkyl groups, C1-C4 haloalkyl groups, hydroxyl groups, O, -CN, sulfone groups, -NR8R9, amide groups, C1-C4 haloalkoxy groups, substituted or unsubstituted penta- or hexa-ester groups. The heterocyclic group is substituted, wherein the C3-C6 cycloalkyl, five- to six-membered aliphatic heterocycle is optionally substituted with methyl, F, Cl, Br or hydroxyl; preferably, the R3 may be optionally substituted with one or more groups selected from O, F, Cl, Br, -NH2, methyl, methoxy, hydroxyl, -CH2OH, -CF3, -CHF2, -CN, -OCHF2, cyclopropyl, morpholino, sulfone, amide, piperazine, thiomorpholino; n = 0, 1, 2, 3.

[0469] 73. The compound according to any one of items 64-68, its pharmaceutically acceptable salt, hydrate, isomer, prodrug, and mixture, characterized in that the R d Selected from: 、 .

[0470] 74. The compound, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof according to any one of clauses 64-68, wherein the ring A is selected from: 、 、 、 ; the ring A is optionally substituted with one or more groups selected from methyl, halogen, -OCH3, -NH2, -NHCH3, -COOH, -(CH2) m OH, -CH2OCH3, -CN, -CONH2, -CON(CH3)2, -COOCH3, -CONHCH3; m = 0, 1, 2, 3.

[0471] 75. The compound, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof according to any one of clauses 64-74, wherein the R1 is selected from:

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480] .

[0481] 76. The compound, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof according to any one of clauses 64-75, wherein the R2 is selected from:

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495] .

[0496] 77. The compound of any one of clauses 64-76, pharmaceutically acceptable salts, hydrates, isomers, prodrugs, and mixtures thereof, wherein R4 is selected from the group consisting of H, -F, -Cl, -Br, -CN, -CF3, -CF2CH3, -CHF2, -CH3, ethyl, ethenyl, ethynyl, propyl, isopropyl, butyl, -CH2OH, -COOCH2CH3, -OCF3, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclopentyl, -N(CH3)2, 、 、 、 .

[0497] 78. The compound of any one of clauses 64-77, pharmaceutically acceptable salts, hydrates, isomers, prodrugs, and mixtures thereof, wherein R5 is selected from the group consisting of H, -F, -Cl, -Br, -CN, -CF3, -CHF2, -CH3, -OCH3, -SCH3; and R7 is selected from the group consisting of H, -CH3, -F, -Cl, -Br.

[0498] 79. The compound of clause 1, pharmaceutically acceptable salts, hydrates, isomers, prodrugs, and mixtures thereof, wherein the compound of Formula I has the following structure of Formula VI:

[0499]

[0500] wherein R1 is selected from the group consisting of 5-10 membered aryl or heteroaryl;

[0501] said R1group is optionally substituted with q R a groups, each of said R a groups is independently selected from -CH3, halogen, -CN, -CHF2, -CF3, -OCF3, -OCH3, -OCHF2, -OH, -(CH2) m OH, -NHSO2CH3, -COOH, -CONH2, -CONHCH3, -CH2COCH3, cyclopropyl, , , ;

[0502] q = 0, 1, 2;

[0503] R2is -NR c R d , -OH, -OCH3, -CH3, ethyl, isopropyl, -O-cyclopropyl;

[0504] wherein R c is selected from H or -CH3,

[0505] R d is selected from

[0506] 1) H;

[0507] 2) -COCH3;

[0508] 3) alkyl, said alkyl is substituted with one or more groups selected from methyl, hydroxyl, amino, cyano, methoxy, halogen, deuterium, -CH2OH, -NHCH3, -N(CH3)2, -SO2CH3, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, -CONHCH3, -CONH2, -SO2-morpholinyl, -SO2NH-cyclopropyl, -NHSO2NH2;

[0509] 4) -(CH2) n R3, wherein R3 is selected from C3-C6 cycloalkyl, 3-6 membered aliphatic heterocyclyl, 5-6 membered aromatic heterocyclyl, or phenyl, 4-10 membered bridged ring, said R3 is optionally substituted with one or more groups selected from halogen, alkyl, alkoxy, substituted or unsubstituted cycloalkyl, haloalkyl, hydroxyl, O, -CN, sulfone, -NR8R9, amide, haloalkoxy, substituted or unsubstituted aliphatic heterocyclyl;

[0510] 5) spirocyclic;

[0511] or, R c and R dwith their common N atom forms a ring A, and said ring A has only one heteroatom; said ring A is optionally substituted with one or more groups selected from methyl, halogen, -OCH3, -NH2, -NHCH3, -COOH, -(CH2) m OH, -CH2OCH3, -CN, -CONH2, -CON(CH3)2, -COOCH3, -CONHCH3;

[0512] m = 0, 1, 2, 3;

[0513] n = 0, 1, 2, 3;

[0514] R5is selected from hydrogen, halogen, -CH3, -OCH3, -SCH3, -CHF2, -CF3, -CN;

[0515] R6is selected from hydrogen, halogen, -OC1-C6alkyl, -OCH2CH2NH2, -OCHF2, -CH2OH;

[0516] R7is selected from hydrogen, -CH3, halogen;

[0517] R8, R9are each independently selected from H, C1-C4alkyl, hydroxyl substituted C1-C4alkyl, halogen substituted C1-C4alkyl, or, R8and R9, together with their common N atom forms a ring B, said ring B is optionally substituted with one or more groups selected from methyl, halogen, -OCH3, -NH2, -NHCH3, -COOH, -(CH2) t OH, -CH2OCH3, -CN, -CONH2, -CON(CH3)2, -COOCH3, -CONHCH3;

[0518] t = 0, 1, 2, 3.

[0519] 80. The compound according to item 79, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, characterized in that said R1is selected from imidazolyl, thiazolyl, pyrazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and .

[0520] 81. The compound according to item 80, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, characterized in that said R1is selected from:

[0521] ​​​​​​​​​ 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 .

[0522] 82. The compound, pharmaceutically acceptable salt, hydrate, isomer, prodrug and mixture thereof according to Clause 80 or 81, wherein said R1 group is optionally substituted with q Ra groups, each said Ra group is independently selected from -CH3, -F, -Cl, -Br, -I, -CN, -CHF2, -CF3, -OCF3, -OCH3, -OCHF2, -OH, -(CH2) m OH, -NHSO2CH3, -COOH, -CONH2, -CONHCH3, -CH2COCH3, cyclopropyl, 、 、 wherein q = 0, 1, 2, m = 0, 1, 2, 3.

[0523] 83. The compound, pharmaceutically acceptable salt, hydrate, isomer, prodrug and mixture thereof according to Clause 79, wherein said R2 is -NRcRd.

[0524] 84. The compound, pharmaceutically acceptable salt, hydrate, isomer, prodrug and mixture thereof according to any one of clauses 79-83, wherein said Rd is C1-C4 alkyl optionally substituted with one or more groups selected from methyl, hydroxyl, halogen, deuterium, -OCH3, -CN, -OCHF2, -N(CH3)2, -SO2CH3, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, -SO2-morpholinyl, -SO2NH-cyclopropyl, -NHSO2NH2, -CONHCH3, -CONH2, -CON(CH3)2.

[0525] 85. The compound, pharmaceutically acceptable salt, hydrate, isomer, prodrug and mixture thereof according to any one of clauses 79-83, wherein said Rd is -(CH2) n R3, wherein R3 is selected from C3-C6 cycloalkyl, 3-6 membered aliphatic heterocyclyl, 5-6 membered aromatic heterocyclyl, or phenyl, 4-10 membered bridged ring; preferably, said R3 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thianyl, piperidinyl, pyrrolidinyl, phenyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl.

[0526] 86. The compound, pharmaceutically acceptable salt, hydrate, isomer, prodrug and mixture thereof according to clause 85, wherein said Rd is -(CH2) n R3, wherein R3 is selected from:

[0527] 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 .

[0528] 87. The compound, pharmaceutically acceptable salt, hydrate, isomer, prodrug and mixture thereof according to any one of clauses 79-86, wherein R3 is optionally substituted with one or more groups selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, C1-C4 haloalkyl, hydroxyl, O, -CN, sulfone, -NR8R9, amide, C1-C4 haloalkoxy, substituted or unsubstituted five to six membered aliphatic heterocycle, wherein the C3-C6 cycloalkyl, five to six membered aliphatic heterocycle is optionally substituted with methyl, F, Cl, Br or hydroxyl; preferably, R3 is optionally substituted with one or more groups selected from O, F, Cl, Br, -NH2, methyl, methoxy, hydroxyl, -CH2OH, -CF3, -CHF2, -CN, -OCHF2, cyclopropyl, morpholinyl, sulfone, amide, piperazinyl, thiomorpholinyl; n = 0, 1, 2, 3.

[0529] 88. The compound, pharmaceutically acceptable salt, hydrate, isomer, prodrug and mixture thereof according to any one of clauses 79-83, wherein Rdis selected from: , .

[0530] 89. The compound, pharmaceutically acceptable salt, hydrate, isomer, prodrug and mixture thereof according to any one of clauses 79-83, wherein ring A is selected from: , , , ; ring A is optionally substituted with one or more groups selected from methyl, halogen, -OCH3, -NH2, -NHCH3, -COOH, -(CH2) m OH, -CH2OCH3, -CN, -CONH2, -CON(CH3)2, -COOCH3, -CONHCH3; m = 0, 1, 2, 3.

[0531] 90. The compound, pharmaceutically acceptable salt, hydrate, isomer, prodrug and mixture thereof according to any one of clauses 79-89, wherein R1 is selected from:

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540] .

[0541] 91. The compound, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof according to any one of clauses 79-90, wherein R2 is selected from:

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555] .

[0556] 92. The compound, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof according to any one of clauses 79-91, wherein R5 is selected from H, -F, -Cl, -Br, -CN, -CF3, -CHF2, -CH3, -OCH3, -SCH3.

[0557] 93. The compound, pharmaceutically acceptable salt, hydrate, isomer, prodrug, and mixture thereof according to any one of clauses 79-92, wherein R6 is selected from H, -F, -Cl, -Br, -OCH3, ethyl, -OCHF2, -OCH(CH3)2, -OCH2C(CH3)3; and R7 is selected from H, -CH3, -F, -Cl, -Br.

[0558] 94. The compound, pharmaceutically acceptable salt, hydrate, isomer, prodrug, and mixture thereof according to any one of clauses 1-93, wherein the compound has a structure shown in the Examples.

[0559] 95. A pharmaceutical composition, comprising a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt, or a hydrate, or an isomer, or a prodrug, or a mixture thereof according to any one of clauses 1-94, and a pharmaceutically acceptable excipient.

[0560] 96. Use of the compound, pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof according to any one of clauses 1-94, for the manufacture of a medicament for treating a MAT2a-related disease.

[0561] 97. The use according to clause 96, wherein the MAT2a-related disease is cancer or tumor.

[0562] 98. The use according to item 97, wherein the cancer or tumor comprises neuroblastoma, intestinal cancer such as rectal cancer, colon cancer, familial adenomatous polyposis cancer and hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach 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, testicular cancer, breast cancer, urinary system cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumor, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), adult T-cell leukemia, hepatocellular carcinoma, gallbladder cancer, bronchial cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell carcinoma, teratocarcinoma, retinoblastoma, choroid melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma and plasmacytoma. In one embodiment, the cancer is lung cancer, non-small cell lung cancer (NSLC), bronchioloalveolar cell lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, bladder cancer, kidney cancer or ureter cancer, renal cell carcinoma, renal pelvis carcinoma, mesothelioma, hepatocellular carcinoma, biliary tract cancer, chronic or acute leukemia, lymphocytic lymphoma Hoomas, central nervous system (CNS) tumor, spinal axis tumor, brain stem glioma, glioblastoma multiforme, astrocytoma, schwannoma, ependymoma, medulloblastoma, meningioma, squamous cell carcinoma, pituitary adenoma, refractory forms of any of the above cancers, or a combination of one or more of the above cancers.

[0563] 99. A method of treatment comprising administering to a patient in need thereof one or more compounds of any one of items 1-95 or a pharmaceutically acceptable salt, hydrate, isomer, prodrug or mixture thereof or a pharmaceutical composition comprising the same.

[0564] Terminology

[0565] The following terms and phrases, as used herein, are intended to have the following meanings unless otherwise indicated. A particular term or phrase should not be construed as undefined or unclear without a specific definition, but should be interpreted according to the ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding product or active ingredient thereof.

[0566] The term "pharmaceutically acceptable" as used herein means suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio as well as amenable to formulation and

[0567] The term "pharmaceutically acceptable salt" means a salt of a compound of the present application that is found to possess the specific substituents of the compounds of the present application that is prepared from a relatively non-toxic acid or base. Alkali addition salts can be prepared from the neutral forms of the compounds of the present application by contacting the neutral forms in a pure solution or in a suitable inert solvent with a sufficient amount of a base to produce the salt. Acid addition salts can be prepared by contacting the neutral form of the compounds of the present application in a pure solution or in a suitable inert solvent with a sufficient amount of an acid to produce the salt.

[0568] The compounds of the present application can exist in particular geometric or stereoisomeric or atropisomeric forms. The present application contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)-isomers, as well as the racemic mixtures and other mixtures of the same, all of which are intended to be within the scope of the present application.

[0569] "Alkyl" means a straight-chain or branched-chain saturated aliphatic hydrocarbon group having from one to twelve carbon atoms, e.g., C 1-6 Alkyl-, C 1-4 Alkyl-, C 1-3 Alkyl-, C 1-2 Alkyl-. For example, C1-C4 alkyl means a saturated aliphatic hydrocarbon group having from one to four carbon atoms, including but not limited to methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and the like, and various isomers thereof.

[0570] "Alkoxy" means the group -OR, where R is alkyl as defined herein, including but not limited to methoxy, ethoxy, propyloxy, isopropoxy, n-butyloxy, t-butyloxy, and the like.

[0571] "Halo" or "halogen" means fluorine (-F), chlorine (-Cl), bromine (-Br), or iodine (-I).

[0572] "Halogenated alkyl" or "halogen-substituted alkyl" means that at least one (e.g., 1, 2, 3, 4, 5 or 6) hydrogen atoms in an alkyl group as defined above are replaced by halogen atoms, including but not limited to -CF3, -CHF2, -CF2CH3.

[0573] "Haloalkoxy" or "halogen-substituted alkoxy" means that at least one (e.g., 1, 2, 3, 4, 5 or 6) hydrogen atoms in the alkoxy group as defined above are replaced by halogen atoms, including but not limited to -OCF3, -OCHF2, -OC(CH3)F2.

[0574] The term "substituted or unsubstituted" means that the mentioned group can be substituted by one or more groups, or not substituted. When substituted, the substituents can be selected from C. 1-4 Alkyl, halogen, hydroxyl, C 3-6 Cycloalkyl- and hydroxy C 1-4 alkyl-.

[0575] "Cycloalkyl" refers to a monocyclic or polycyclic cyclic hydrocarbon substituent that is saturated or partially unsaturated. For example, "C3-C6 cycloalkyl" refers to a cycloalkyl group containing 3 to 6 carbon atoms. Typical C3-C6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl.

[0576] "Alicyclic group" refers to a saturated monocyclic hydrocarbon substituent in which one or more ring atoms are replaced by heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon. Preferably, the alicyclic group is a 3- to 6-membered alicyclic group, such as a 4-6-membered or 5-6-membered alicyclic group. For example, "3-6-membered alicyclic" refers to a saturated cyclic hydrocarbon substituent containing 3-6 ring atoms, in which one or more ring atoms are replaced by heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon. Specific examples include, but are not limited to: oxocyclic butyl, azacyclic butyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, tetrahydropyranyl, piperidine, tetrahydrothiaran, etc.

[0577] "Aromatic heterocyclic group" refers to an aromatic cyclic substituent in which one or more (e.g., 1, 2, 3, 4, 5 or 6) ring atoms are replaced by heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon. Preferably, the aromatic heterocyclic group is a 5- to 10-membered aromatic heterocyclic group, which preferably contains 1 to 3 heteroatoms; more preferably, it is a 5- to 6-membered aromatic heterocyclic group, which preferably contains 1 to 2 heteroatoms; for example, "5- to 6-membered aromatic heterocyclic" refers to an aromatic heterocyclic group containing 5 to 6 ring atoms, and specific examples include, but are not limited to, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, imidazo[1,2-a]pyridinyl, and 1H-benzo[d]imidazolyl.

[0578] "Heterocyclyl" refers to a saturated or unsaturated cyclic substituent of one or more (e.g., 1, 2, 3, 4, 5, or 6) ring atoms replaced by a heteroatom selected from N, O, S, including aliphatic heterocyclyl and aromatic heterocyclyl, for example, "3-5 membered heterocyclyl" refers to a saturated or unsaturated cyclic substituent comprising 3 to 5 ring atoms, wherein one or more of the ring atoms is replaced by a heteroatom selected from N, O, S, specific examples include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, thiazolyl, and the like.

[0579] "Heteroatom" refers to an atom other than carbon or hydrogen, herein heteroatoms are preferably independently selected from O, S, and N.

[0580] "5-10 membered aryl" refers to an aromatic cyclic group comprising 5 to 10 carbon ring atoms, examples of aryl moieties include phenyl, naphthyl, and the like.

[0581] "Spirocycle" or "spirocyclic" refers to a cyclic group formed by 2 or more (e.g., 3 or 4) rings spiroed together. Preferably, the spirocycle has 5-10, e.g., 5, 6, 7, 8, 9, or 10 ring members, optionally containing 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, or sulfur, with the remaining ring members being carbon atoms. Exemplary spirocycles include, but are not limited to , or .

[0582] "Fused ring" or "fused ring group" refers to a cyclic group formed by 2 or more (e.g., 3 or 4) rings fused together. "Fused" means that adjacent rings share a pair of adjacent atoms to form a polycyclic structure. Preferably, the fused ring group has 5-10, e.g., 5, 6, 7, 8, 9, or 10 ring members, optionally containing 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, or sulfur, with the remaining ring members being carbon atoms. Exemplary fused ring groups include, but are not limited to .

[0583] "…substituted with one or more groups" means that the group or moiety of interest is substituted with one or more groups, preferably 1, 2, or 3 groups.

[0584] "Amino" refers to a -CONH2 group.

[0585] "Sulfone" refers to -SO2-Rx, wherein Rxis alkyl as defined above, such as C1-C4 alkyl.

[0586] "Optionally" means that the event or circumstance subsequently described can, but need not, occur.

[0587] When any variable occurs more than one time, such as in substituted or heteroaryl, each occurrence is independent of the other. For example, if a group is substituted with 0-2 Ra, then said group is optionally substituted with up to two Ra, and at each occurrence Rahas an independent selection.

[0588] When the number of a linking group is 0, such as (CH2)m, when m = 0, it means that the linking group is a single bond.

[0589] It should be understood that the terminal "-" in the listed groups indicates the point of attachment of the group to the rest of the molecule, for example -SO2NHCH3 indicates that the group is attached to the rest of the molecule through the -SO2- moiety; hydroxy C1-C4alkoxy- indicates that the group is attached to the rest of the molecule through the alkoxy moiety. It should be understood that in some instances, a later embodiment, embodiment, claim refers back to and further limits an earlier embodiment, embodiment, claim, and for the sake of brevity, certain variables or features are not further limited, in which case, these variables or features have the meaning defined in the relevant earlier embodiment, embodiment, claim.

[0590] The abbreviations used in the present application are known to those skilled in the art, and represent the meanings as informed in the art, unless otherwise specified. For example: DMF refers to N,N-dimethylformamide; THF refers to tetrahydrofuran; Me refers to methyl.

[0591] It has been proved by experiments that the compounds of the present application have excellent MAT2a enzyme inhibitory activity, and at the same time have excellent inhibitory effect on the growth of cancer cells, so the compounds of the present application will have excellent therapeutic effect in MAT2a related cancer or tumor diseases. DETAILED DESCRIPTION

[0592] The compounds of the present application can be prepared by using the synthetic schemes 1 to 5 provided by the present application, and by using the synthetic means and conventional reagent materials well known to those skilled in the art. The synthesis methods of the compounds and intermediates of the present application are illustrated by examples below, which are only examples of the present application and should not be regarded as limiting the scope of the present application. Unless otherwise specified, the raw materials and reagents involved in the present application can be obtained through commercial channels, and the specific channel sources do not affect the implementation of the technical solutions of the present application.

[0593] Preparation Example 1: Preparation of 4-chloro-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile

[0594]

[0595] Step 1: Preparation of 2-(phenylamino)-6-(trifluoromethyl)nicotinic acid

[0596]

[0597] To a solution of 2-chloro-6-(trifluoromethyl)nicotinic acid (1.0 g) in 1,4-dioxane (10 mL) was added aniline (2.0 g) and the reaction was initiated by microwave at 120 °C for 5 h. LCMS showed most of the starting material was consumed. The system was concentrated under reduced pressure and the residue was added to petroleum ether with stirring. The filtrate was concentrated under reduced pressure and the resulting crude product was purified by column chromatography to give the title compound 1.0 g.

[0598] MS (ESI) m / z (M+H) + = 283.0.

[0599] 1 H NMR (400 MHz, DMSO-d6) δ 14.14 (brs, 1H), 10.59 (s, 1H), 8.47 (d, J= 7.8 Hz, 1H), 7.82-7.63 (m, 2H), 7.37 (dd, J = 8.5, 7.3 Hz, 2H), 7.29 (d, J= 7.9 Hz, 1H), 7.07 (td, J = 7.3, 1.1 Hz, 1H).

[0600] Step 2: Preparation of 4-hydroxy-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8- naphthyridine-3-carbonitrile

[0601]

[0602] To a solution of 2-(phenylamino)-6-(trifluoromethyl)nicotinic acid (400 mg) in tetrahydrofuran (10 mL) was added N,N'-diisopropylcarbodiimide (536 mg) and 1-hydroxybenzotriazole (574 mg) and the reaction was allowed to proceed at room temperature for 1 h. Sodium hydride (60%, 284 mg) was added portionwise to a solution of ethyl cyanoacetate (320 mg) in tetrahydrofuran (10 mL) and the reaction was allowed to proceed at room temperature for 1 h. The solution of 2-(phenylamino)-6-(trifluoromethyl)nicotinic acid was added dropwise to the solution of ethyl cyanoacetate and the reaction was allowed to proceed at room temperature for 2 h. LCMS showed the reaction was complete. The system was quenched by the addition of saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was purified by column chromatography to give the title compound 400 mg.

[0603] MS (ESI) m / z (M+H) + = 332.1.

[0604] 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 7.8Hz, 1H), 7.45 (dd, J = 8.3, 6.7 Hz, 2H), 7.41 – 7.34 (m, 1H), 7.21 – 7.17 (m,2H), 7.08 (s, 1H).

[0605] Step 3: Preparation of 4-chloro-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8- naphthyridine-3-carbonitrile

[0606]

[0607] To a solution of 4-hydroxy-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8- naphthyridine-3-carbonitrile (100 mg) in phosphorus oxychloride (2 mL) was heated at 90 °C for 2 h. LCMS showed the reaction was complete. The mixture was added to ice water dropwise, the process should be kept the solution weakly alkaline at all times, extracted with ethyl acetate, combined organic phase, dried over anhydrous sodium sulfate, filtered, concentrated, the obtained crude was purified by column chromatography to give the title compound 50 mg.

[0608] MS (ESI) m / z (M+H) + = 350.0.

[0609] 1 H NMR (400 MHz, Chloroform-d) δ 8.61 (d, J = 8.2 Hz, 1H), 7.71 (d, J= 8.2 Hz, 1H), 7.61-7.53 (m, 3H), 7.24 (dd, J = 8.1, 1.6 Hz, 2H).

[0610] Preparation Example 2: Preparation of 4-chloro-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2- dihydro-l,5-naphthyridine-3-carbonitrile

[0611]

[0612] Step 1: Preparation of 3-(phenylamino)-5-(trifluoromethyl)carbonitrilepyridine

[0613]

[0614] Pd(OAc)2(224.5 mg), 1,1'-binaphthalene-2,2'-diphenylphosphine (934 mg) and cesium carbonate (6.311 g) were dissolved in anhydrous 1,4-dioxane (50 mL) under nitrogen atmosphere, then 3-chloro-5-trifluoromethylcyanopyridine (2.0 g) and aniline (1.8 mL) were added, and the reaction was carried out at 80 °C for 2 hours. LCMS showed that the starting material was completely reacted. The system was poured into water, extracted with ethyl acetate for 3 times, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the obtained crude product was purified by column chromatography to obtain the target compound 2.21 g.

[0615] MS (ESI) m / z (M+H) + = 264.1.

[0616] Step 2: Preparation of 3-(phenylamino)-5-(trifluoromethyl)pyridine carboxylic acid

[0617]

[0618] 3-(phenylamino)-5-(trifluoromethyl) nitrile pyridine (1.0 g) was dissolved in ethanol / water (40 mL / 10 mL), and after stirring uniformly, potassium hydroxide (1.06 g) was added at one time. After refluxing for 3 hours, the ethanol was removed by concentration under reduced pressure, the pH was adjusted to about 3-4 by adding oxalic acid, and the organic phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was directly used in the next step without purification.

[0619] MS (ESI) m / z (M+H) + = 283.1.

[0620] Step 3: Preparation of 4-hydroxy-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,5- naphthyridine-3-carbonitrile

[0621]

[0622] To a solution of 3-(phenylamino)-5-(trifluoromethyl)picolinic acid (500 mg) in dry tetrahydrofuran was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (340 mg) followed by 1-hydroxybenzotriazole (240 mg). After 1 hour at room temperature, the reaction was monitored to completion, diluted with water, extracted with dichloromethane three times, the organic phases were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give the intermediate. The intermediate was dissolved in dry tetrahydrofuran and sodium hydride (354 mg) was added slowly dropwise to a solution of diethyl activated malonate (0.54 mL) in tetrahydrofuran. The reaction was continued at room temperature for 2 hours. LC-MS showed that the reaction was complete and the reaction was continued overnight, with complete conversion to the ester hydrolysis intermediate. The residue was dissolved in ethanol / water (4:1) and decarboxylation was complete after refluxing for 5 hours. The mixture was concentrated under reduced pressure and the crude product was purified by column chromatography to give the title compound 562.0 mg.

[0623] MS (ESI) m / z (M+H) + = 332.0.

[0624] Step 4: Preparation of 4-chloro-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydro- 1,5-naphthyridine-3-carbonitrile

[0625]

[0626] A solution of 4-hydroxy-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydro-l,5- naphthyridine-3-carbonitrile (50 mg) in phosphorus oxychloride (3 mL) was refluxed for 3 hours with a catalytic amount of N,N-diethylaniline. The reaction mixture was concentrated under reduced pressure and the crude product was used in the next step without purification.

[0627] MS (ESI) m / z (M+H) + = 350.0.

[0628] Preparation Example 3: Preparation of 4-chloro-2-oxo-l-phenyl-7- (trifluoromethyl)-l,2-dihydroquinoline-3-carbonitrile

[0629]

[0630] Step 1: Preparation of 2-(phenylamino)-4-(trifluoromethyl)benzonitrile

[0631]

[0632] Dissolve 2-fluoro-4-(trifluoromethyl)benzonitrile (2.06 g) and aniline (0.91 mL) in dry dimethylsulfoxide (5 mL), and add potassium tert-butoxide (2.36 g) portionwise. Stir at room temperature for 30 minutes, and monitor the reaction by LCMS until completion. Pour the reaction into water, extract with ethyl acetate, combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate. Purify the crude product by column chromatography to obtain 467 mg of the target compound.

[0633] MS (ESI) m / z (M+H) + = 263.1

[0634] Step 2: Preparation of 2-(phenylamino)-4-(trifluoromethyl)benzoic acid

[0635]

[0636] Dissolve 2-(phenylamino)-4-(trifluoromethyl)benzonitrile (467 mg) in ethanol / water (40 mL / 10 mL), and stir until uniform. Add potassium hydroxide (499 mg) in one portion, and reflux overnight. Concentrate under reduced pressure to remove ethanol, adjust the pH to about 3-4 with oxalic acid, extract with ethyl acetate, combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate. The residue can be used directly in the next step without further purification.

[0637] MS (ESI) m / z (M+H) + = 282.0.

[0638] Step 3: Preparation of 4-hydroxy-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2- dihydroquinoline-3-carbonitrile

[0639]

[0640] Dissolve 2-(phenylamino)-4-(trifluoromethyl)benzoic acid (505 mg) in anhydrous tetrahydrofuran, and add N,N'-diisopropylcarbodiimide (227.3 mg) and 1-hydroxybenzotriazole (243.2 mg) sequentially to the system. Stir at room temperature for 1 hour, and monitor the reaction by LCMS until completion. Slowly add the above reaction system dropwise to a sodium hydride (360 mg)-activated ethyl cyanacetate (0.38 mL) tetrahydrofuran system at room temperature, and stir for 2 hours. The reaction is complete, as indicated by LCMS. Quench the reaction by adding saturated ammonium chloride solution, extract with ethyl acetate, combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate. Purify the crude product by column chromatography to obtain 345.0 mg of the target compound.

[0641] MS (ESI) m / z (M+H) + = 331.1

[0642] Step 4: Preparation of 4-chloro-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2- dihydroquinoline-3-carbonitrile

[0643]

[0644] The 4-hydroxy-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydroquinoline-3- carbonitrile (100 mg) was dissolved in phosphorus oxychloride (5 mL) and refluxed overnight. The reaction mixture was concentrated under reduced pressure. The crude product was used in the next step without further purification.

[0645] MS (ESI) m / z (M+H) + = 349.0.

[0646] Preparation Example 4: Preparation of 4-chloro-7-methyl-2-oxo-l-phenyl-l,2- dihydro-l,8-naphthyridine-3-carbonitrile

[0647]

[0648] Step 1: Preparation of 6-methyl-2-(phenylamino)nicotinonitrile

[0649]

[0650] Palladium acetate (133 mg), cesium carbonate (3.86 g) and 1,1'-binaphthalene-2,2'-diphenylphosphine (738 mg) were dissolved in dry 1,4-dioxane. 2-Chloro-6-methylnicotinonitrile (800 mg) and aniline (1.1 g) were added. The reaction mixture was heated at 85 °C for 5 h. TLC showed that the starting material was consumed. The reaction was quenched with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography to give the target compound 1.4 g.

[0651] MS (ESI) m / z (M+H) + = 209.9.

[0652] Step 2: Preparation of 6-methyl-2-(phenylamino)nicotinic acid

[0653]

[0654] The 6-methyl-2-(phenylamino)nicotinonitrile (1.4 g) was dissolved in ethanol / water (4 / 1). Potassium hydroxide (2.25 g) was added in one portion. The reaction mixture was heated at 90 °C for 3 h. TLC showed that the starting material was consumed. The potassium hydroxide was filtered off. The crude product was purified by column chromatography to give the product 984 mg.

[0655] MS (ESI) m / z (M+H)+ = 229.0.

[0656] Step 3: Preparation of 4-hydroxy-7-methyl-2-oxo-l-phenyl-l,2-dihydro-l,8- naphthyridine-3-carbonitrile

[0657]

[0658] To a solution of 6-methyl-2-(phenylamino)nicotinic acid (450 mg) in dry dichloromethane was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (378 mg) followed by 1-hydroxybenzotriazole (267 mg). After one hour at room temperature, the reaction was monitored to completion, diluted with water, extracted with dichloromethane three times, the organic phases were combined, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give the intermediate. The intermediate was dissolved in dry tetrahydrofuran and sodium hydride (395 mg) was added slowly dropwise to a solution of ethyl cyanoacetate (447 mg) in tetrahydrofuran. The reaction was stirred at room temperature for 2 hours. TLC showed that the starting material was consumed and the reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give the product 650 mg.

[0659] MS (ESI) m / z (M+H) + = 278.1.

[0660] Step 4: Preparation of 4-chloro-7-methyl-2-oxo-l-phenyl-l,2-dihydro-l,8- naphthyridine-3-carbonitrile

[0661]

[0662] The crude 4-hydroxy-7-methyl-2-oxo-l-phenyl-l,2-dihydro-l,8-naphthyridine-3- carbonitrile (300 mg) was dissolved in phosphorus oxychloride and the reaction was stirred at 110 °C overnight. The reaction was monitored by LC-MS to completion. The phosphorus oxychloride was removed by concentration under reduced pressure and the residual solvent was quenched with water. The reaction mixture was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was used in the next step without further purification.

[0663] MS (ESI) m / z (M+H) + = 296.1.

[0664] Preparation Example 5: Preparation of 4-chloro-2-oxo-l-phenyl-7-(trifluoromethyl)- 1,2-dihydro-l,6-naphthyridine-3-carbonitrile

[0665]

[0666] Step 1: Preparation of ethyl 4-(phenylamino)-6-(trifluoromethyl)nicotinate

[0667]

[0668] Palladium acetate (22.5 mg), 1,1'-binaphthalene-2,2'-diphenylphosphine (93.4 mg), cesium carbonate (652.0 mg), aniline (182 μL) and ethyl 4-chloro-6-(trifluoromethyl)nicotinate (253 mg) were dissolved in anhydrous 1,4-dioxane (20 mL) under nitrogen atmosphere. After stirring well, the reaction was heated at 80 °C for 2 hours. LCMS showed that the starting material was completely consumed. The system was filtered to remove cesium carbonate, and the filtrate was concentrated. The crude product was purified by column chromatography to give the target compound 257.0 mg.

[0669] MS (ESI) m / z (M+H) + = 311.1.

[0670] Step 2: Preparation of 4-(phenylamino)-6-(trifluoromethyl)nicotinic acid

[0671]

[0672] Ethyl 4-(phenylamino)-6-(trifluoromethyl)nicotinate (257 mg) was dissolved in ethanol / water (20 mL / 2 mL). After stirring well, sodium hydroxide (165.8 mg) was added in one portion. After heating the reaction for 0.5 hours, ethanol was removed by concentration under reduced pressure. The pH was adjusted to about 3-4 by adding oxalic acid, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was used directly in the next step without purification.

[0673] MS (ESI) m / z (M+H) + = 283.1.

[0674] Step 3: Preparation of 4-hydroxy-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydro-l,6- naphthyridine-3-carbonitrile

[0675]

[0676] To a solution of 4-(phenylamino)-6-(trifluoromethyl)nicotinic acid (299 mg) in dry tetrahydrofuran was added N,N'-dicyclohexylcarbodiimide (104.8 mg) followed by 1-hydroxybenzotriazole (112.2 mg). After one hour at room temperature, the reaction was monitored to completion. The reaction mixture was diluted with water and extracted three times with dichloromethane. The organic layers were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give the intermediate. The intermediate was dissolved in dry tetrahydrofuran and added slowly to a solution of sodium hydride (166 mg) in dry tetrahydrofuran. Diethyl malonate (0.18 mL) was added slowly to the reaction mixture. The reaction was stirred at room temperature for 2 hours. The reaction was quenched with ethanol and the reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography to give 60 mg of the title compound.

[0677] MS (ESI) m / z (M+H) + = 332.1.

[0678] Step 4: Preparation of 4-chloro-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydro-l,6- naphthyridine-3-carbonitrile

[0679]

[0680] To a solution of 4-hydroxy-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydro-l,6- naphthyridine-3-carbonitrile (60 mg) in phosphorus oxychloride (8 mL) was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure. The residue was used in the next step without further purification.

[0681] MS (ESI) m / z (M+H) + = 349.9.

[0682] Preparation Example 6: Preparation of l-(lH-benzo[d]imidazol-4-yl)-4-chloro-2-oxo-7- (trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[0683]

[0684] Step 1: Preparation of l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-4- amine

[0685]

[0686] Under ice water bath condition, 1H-benzo[d]imidazol-4-amine (399 mg) was dissolved in tetrahydrofuran (10 mL), sodium hydride (720 mg) was added portion wise, after 10 minutes 2-(trimethylsilyl)ethoxymethyl chloride (960 mg) was added, the system was moved to room temperature and the reaction was continued overnight, LCMS showed no starting material left. Water (50 mL) was added slowly to quench the reaction, ethyl acetate (3* 50 mL) was used to extract, the organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated, the crude obtained was purified by column chromatography to give the title compound 562 mg.

[0687] MS (ESI) m / z (M+H) + = 264.0.

[0688] Step 2: Preparation of 6-(trifluoromethyl)-2-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H- benzo[d]imidazol-4-yl)amino)nicotinonitrile

[0689]

[0690] Under nitrogen atmosphere, 2-chloro-6-(trifluoromethyl)nicotinonitrile (413 mg), 1-((2- (trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-amine (562 mg), palladium acetate (45 mg), 1,1'-binaphthalene-2,2'-diphenylphosphine (187 mg) and cesium carbonate (1.3 g) were dissolved in 1,4-dioxane (20 mL), the system was heated at 90 °C for 5 hours, LCMS showed no starting material left. The reaction was filtered through celite, the filtrate was collected and concentrated, the crude was purified by column chromatography to give the title compound 100 mg.

[0691] MS (ESI) m / z (M+H) + = 434.0.

[0692] Step 3: Preparation of 6-(trifluoromethyl)-2-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H- benzo[d]imidazol-4-yl)amino)nicotinic acid

[0693]

[0694] To a solution of 6-(trifluoromethyl)-2-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H- benzo[d]imidazol-4-yl)amino)nicotinic acid (100 mg) in ethanol (12 mL) and water (3 mL) was added potassium hydroxide (65 mg) and the mixture was heated at 90 °C for 4 h. The reaction was concentrated and dissolved in water. The pH was adjusted to 4 by the addition of 2 N hydrochloric acid. A solid precipitated and was collected by filtration to give the title compound 100 mg.

[0695] MS (ESI) m / z (M+H) + = 453.0.

[0696] Step 4: Preparation of 4-hydroxy-2-oxo-7-(trifluoromethyl)-1-(1-(((2- (trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)-1,2-dihydro-1,8-naphthyridine- 3-carbonitrile

[0697]

[0698] To a solution of 6-(trifluoromethyl)-2-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H- benzo[d]imidazol-4-yl)amino)nicotinic acid (100 mg) in dichloromethane (10 mL) was added 1-hydroxybenzotriazole (45 mg) and 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (64 mg) and the mixture was stirred at room temperature for 30 min. The reaction was quenched by the addition of water (50 mL) and the mixture was extracted with dichloromethane (3 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was dissolved in tetrahydrofuran (5 mL) and sodium hydride (53 mg) was added under ice water bath. After stirring for 10 min, ethyl 2-cyanoacetate (50 mg) was added and the mixture was stirred at room temperature for 1 h. The reaction was quenched by the addition of water (50 mL) and the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give the title compound 100 mg.

[0699] MS (ESI) m / z (M+H) + = 502.0.

[0700] Step 5: Preparation of 1-(1H-benzo[d]imidazol-4-yl)-4-chloro-2-oxo-7- (trifluoromethyl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile

[0701]

[0702] Dissolve 4-hydroxy-2-oxo-7-(trifluoromethyl)-l-(l-(((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-4-yl)-l,2-dihydro-l,8- naphthyridine-3-carbonitrile (50 mg) in phosphorus oxychloride (5 mL), add N,N- diisopropylethylamine (0.5 mL), and the system is reacted at 90 °C for 1 hour. LCMS shows that the reaction is complete. Concentrate the reaction, and add the residue to saturated sodium bicarbonate solution (50 mL) under an ice water bath. Extract with ethyl acetate (3 * 50 mL), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate. Purify the crude product by column chromatography to obtain 30 mg of the title compound.

[0703] MS (ESI) m / z (M+H) + = 390.0.

[0704] Preparation Example 7: Preparation of 4-chloro-7-(difluoromethyl)-2-oxo-l- phenyl-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[0705]

[0706] Step 1: Preparation of 4-ethoxy-l,l-difluorobut-3-en-2-one

[0707]

[0708] Under a nitrogen atmosphere, add a mixed solution of vinyl ethyl ether (2.14 mL) and pyridine (1.73 mL) dropwise to a dichloromethane solution of difluoroacetic anhydride (3.3 g). React at room temperature overnight, extract with water / dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate at low temperature to remove the solvent to obtain the target product 2.89 g.

[0709] MS (ESI) m / z (M+H) + = 150.1.

[0710] Step 2: Preparation of 6-(difluoromethyl)-2-hydroxynicotinonitrile

[0711]

[0712] 4-Ethoxy-1,1-difluorobut-3-en-2-one (2.897 g) and 2-cyanoacetamide (1.6 g) were dissolved in anhydrous ethanol (20 ml), and sodium ethoxide (2.6 g) was added. After stirring thoroughly, the reaction system was heated at 90 °C for 2 h, and LC-MS showed that the reaction was complete. The solvent was removed by concentration, the reaction was quenched with water, the pH of the reaction solution was adjusted to approximately 5 with 6 N HCl, the mixture was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain 2.6 g of the target compound.

[0713] MS (ESI) m / z (M+H) + = 171.0.

[0714] Step 3: Preparation of 3-cyano-6-(difluoromethyl)pyridin-2-yltrifluoromethanesulfonate

[0715]

[0716] Under a nitrogen atmosphere, 1.032 g of 6-(difluoromethyl)-2-hydroxynicotinonitrile was dissolved in dichloromethane, and 1.8 g of triethylamine was added. Trifluoromethanesulfonic anhydride (2.6 g) was then slowly added dropwise at -60 °C. After the addition was complete, the system was allowed to stand at room temperature for 3 h, and the reaction was monitored by LC-MS to ensure complete reaction. The dichloromethane was removed by concentration under reduced pressure, and the crude product was purified by column chromatography to obtain 1 g of the target compound.

[0717] MS (ESI) m / z (M+H) + = 303.0

[0718] Step 4: Preparation of 6-(difluoromethyl)-2-(phenylamino)nicotinonitrile

[0719]

[0720] Under a nitrogen atmosphere, tris(dibenzylacetone)dipalladium (151 mg), cesium carbonate (1.075 g), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (95 mg) were dissolved in a toluene-dissolved mixture of 3-cyano-6-(difluoromethyl)pyridin-2-yltrifluoromethanesulfonate (500 mg) and aniline (384 mg). After stirring until homogeneous, the reaction mixture was placed at 110 °C for 2 h. TLC showed that the starting materials were completely consumed. The solvent was removed by concentration, the reaction was quenched with water, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated and purified by column chromatography to obtain 317 mg of the target compound.

[0721] MS (ESI) m / z (M+H) + = 246.0

[0722] Step 5: Preparation of 6-(difluoromethyl)-2-(phenylamino)nicotinic acid

[0723]

[0724] The 6-(difluoromethyl)-2-(phenylamino)nicotinonitrile (317 mg) was dissolved in ethanol / water (4 / 1, 10 mL), potassium hydroxide (508 mg) was added, and the system was refluxed at 100 °C overnight. LC-MS showed that the starting material was consumed completely. The ethanol was removed under reduced pressure, water was added for dilution, oxalic acid was added to adjust the pH to weakly acidic, and ethyl acetate was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the target compound 420 mg.

[0725] MS (ESI) m / z (M+H) + = 265.0

[0726] Step 6: Preparation of 7-(difluoromethyl)-4-hydroxy-2-oxo-l-phenyl-l,2-dihydro-l,8- naphthyridine-3-carbonitrile

[0727]

[0728] The 6-(difluoromethyl)-2-(phenylamino)nicotinic acid (420 mg) was dissolved in anhydrous dichloromethane, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (305 mg) and 1-hydroxybenzotriazole (215 mg) were added in sequence. The reaction was allowed to proceed at room temperature for one hour, and the reaction was monitored until it was complete. Water was added for dilution, and dichloromethane was used for extraction three times. The organic phases were combined, washed with saturated sodium chloride solution once, dried over anhydrous sodium sulfate, filtered, and concentrated to give an intermediate. The intermediate was dissolved in anhydrous tetrahydrofuran, and sodium hydride (382 mg) was added dropwise slowly to an ethyl cyanoacetate (360 mg) tetrahydrofuran system. The reaction was allowed to proceed at room temperature for 2 hours. TLC showed that the starting material was consumed completely, saturated ammonium chloride solution was used to quench the reaction, ethyl acetate was used for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography to give the title compound 297 mg.

[0729] MS (ESI) m / z (M+H) + = 314.0

[0730] Step 7: Preparation of 4-chloro-7-(difluoromethyl)-2-oxo-l-phenyl-l,2-dihydro-l,8- naphthyridine-3-carbonitrile

[0731]

[0732] Dissolve 7-(difluoromethyl)-4-hydroxy-2-oxo-l-phenyl-l,2-dihydro-l,8- naphthyridine-3-carbonitrile (297 mg) in phosphorus oxychloride and heat the mixture at 90 °C overnight. After the reaction is complete as monitored by LC-MS, concentrate to remove the phosphorus oxychloride, quench the residual solvent with water, extract with ethyl acetate, combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate to give 145 mg of crude product which is used in the next step without further purification.

[0733] MS (ESI) m / z (M+H) + = 332.0.

[0734] Preparation Example 8: Preparation of 3-cyano-7-ethoxy-2-oxo-l-phenyl-l,2- dihydro-l,8-naphthyridin-4-yl methanesulfonate

[0735]

[0736] Step 1: Preparation of ethyl 2-chloro-6-ethoxynicotinate

[0737]

[0738] Dissolve 2-chloro-6-hydroxynicotinic acid (2.0 g) in dry N,N-dimethylformamide (20 mL) and add sodium hydride (1.62 g) portionwise with ice water bath. After the addition is complete, maintain the temperature for 30 minutes and slowly add iodoethane (9.0 g) dropwise. Remove the ice water bath and allow the mixture to warm to room temperature and stir for 2 hours. After the reaction is complete as monitored by LCMS, extract with ethyl acetate, combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate to give 1.2 g of crude product which is purified by column chromatography to give the title compound.

[0739] MS (ESI) m / z (M+H) + = 230.1

[0740] Step 2: Preparation of ethyl 6-ethoxy-2-(phenylamino)nicotinate

[0741]

[0742] Dissolve palladium acetate (45 mg), 1,1'-binaphthalene-2,2'-diphenylphosphine (186.8 mg), and cesium carbonate (1.303 g) in dry 1,4-dioxane (25 mL) under nitrogen atmosphere. Add ethyl 2-chloro-6-ethoxynicotinate (0.5 g) and aniline (0.36 mL) and stir the mixture. Heat the mixture at 80 °C for 2 hours. After the reaction is complete as monitored by LCMS, remove the cesium carbonate by suction filtration and purify the crude product by column chromatography to give 0.52 g of the title compound.

[0743] MS (ESI) m / z (M+H) + = 287.1

[0744] 1 H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.13 (d, J = 8.6 Hz, 1H),7.68 (d, J = 7.8 Hz, 2H), 7.35 (t, J = 7.9 Hz, 2H), 7.05 (t, J = 7.4 Hz, 1H),6.24 (d, J = 8.6 Hz, 1H), 4.48-4.18 (m, 4H), 1.46-1.22 (m, 6H).

[0745] Step 3: Preparation of 6-ethoxy-2-(phenylamino)nicotinic acid

[0746]

[0747] Ethyl 6-ethoxy-2-(phenylamino)nicotinate (0.52 g) was dissolved in ethanol / water (20 mL / 5 mL), after stirring evenly, sodium hydroxide (0.37 g) was added, and the reaction was heated at 90 °C for 15 minutes. After the reaction was completed, ethanol was removed by concentration under reduced pressure, and the pH was adjusted to about 3-4 by adding oxalic acid. The organic phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue (0.47 g) was used directly in the next step without further purification.

[0748] MS (ESI) m / z (M+H) + = 259.1

[0749] Step 4: Preparation of 7-ethoxy-4-hydroxy-2-oxo-1-phenyl-1,2-dihydro-1,8-naphthyridine-3- carbonitrile

[0750]

[0751] Dissolve 6-ethoxy-2-(phenylamino)nicotinic acid (468 mg) in dry tetrahydrofuran, add N,N'-diisopropylcarbodiimide (228.6 mg) and 1-hydroxybenzotriazole (2444.6 mg) sequentially, and allow the reaction to proceed at room temperature for one hour. Dilute with water, extract with dichloromethane three times, wash the combined organic phases with saturated sodium chloride solution once, dry over anhydrous sodium sulfate, filter, and concentrate to give an intermediate. Dissolve the intermediate in dry tetrahydrofuran, and slowly add sodium hydride (362 mg) in ethyl cyanoacetate (0.39 mL) in tetrahydrofuran. Allow the reaction to proceed at room temperature for 2 hours. LCMS shows that the reaction is complete. Quench the reaction with saturated ammonium chloride solution, extract with ethyl acetate, dry the combined organic phases over anhydrous sodium sulfate, filter, and concentrate. Purify the crude product by column chromatography to give the title compound 427.0 mg.

[0752] MS (ESI) m / z (M+H) + = 308.1.

[0753] Step 5: Preparation of 3-cyano-7-ethoxy-2-oxo-l-phenyl-l,2-dihydro-l,8-naphthyridin-4- ylmethanesulfonate

[0754]

[0755] Dissolve 7-ethoxy-4-hydroxy-2-oxo-l-phenyl-l,2-dihydro-l,8-naphthyridine-3- carbonitrile (100 mg) in dry dichloromethane (10 mL) under an ice water bath, add methanesulfonyl chloride (50 uL) and triethylamine (91.7 uL) sequentially, and allow the reaction to proceed at room temperature for 20 minutes. LCMS shows that the reaction is complete. Quench the reaction with water, extract with ethyl acetate, dry the combined organic phases over anhydrous sodium sulfate, filter, and concentrate to give the title compound, which is used directly in the next reaction without further purification.

[0756] MS (ESI) m / z (M+H) + = 386.1.

[0757] Preparation Example 9: Preparation of 4-chloro-6-methyl-2-oxo-l-phenyl-7- (trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[0758]

[0759] Step 1: Preparation of 4-ethoxy-l,l,l-trifluoro-3-methylbut-3-en-2-one

[0760]

[0761] To a solution of trifluoroacetic anhydride (5.0 g) in dichloromethane was added dropwise allyl ethyl ether (3.03 mL) and pyridine (2.1 mL) under nitrogen atmosphere. The reaction was allowed to proceed at room temperature overnight. The reaction was quenched with water and extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound, 4.3 g.

[0762] MS (ESI) m / z (M+H) + = 183.1

[0763] Following the procedure of Preparation 7, Steps 2-7, the title compound was obtained, the structure of which is as follows:

[0764]

[0765] MS (ESI) m / z (M+H) + = 364.1.

[0766] Preparation 10: Preparation of 4-chloro-5-methyl-2-oxo-l-phenyl-7- (trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[0767]

[0768] The starting materials and reagents were obtained through commercial channels or by employing techniques conventional in the art. The title compound was obtained by following the synthetic route described above, and the detailed procedure was referred to Preparation 7.

[0769]

[0770] MS (ESI) m / z (M+H) + = 364.1.

[0771] Preparation 11: Preparation of 4-chloro-7-cyclopropyl-2-oxo-l-phenyl- 1,2-dihydro-l,8-naphthyridine-3-carbonitrile

[0772]

[0773] The starting materials and reagents were obtained through commercial channels or by employing techniques conventional in the art. The title compound was obtained by following the synthetic route described above, and the detailed procedure was referred to Preparation 4.

[0774]

[0775] MS (ESI) m / z (M+H)+ = 322.1.

[0776] 1H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 8.2 Hz, 1H), 7.96-7.84 (m, 1H), 7.55 (t, J = 7.3 Hz, 2H), 7.52-7.44 (m, 2H), 7.28 (d, J = 7.3 Hz, 1H), 2.22-2.07 (m, 1H), 0.99-0.80 (m, 2H), 0.59-0.50 (m, 2H).

[0777] Preparation Example 12: Preparation of 4-chloro-l-(4-chlorophenyl)-2-oxo-7- (trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[0778]

[0779] The title compound was obtained by the above synthetic route via commercial channels or by employing routine techniques in the art, with starting materials and reagents being obtained from commercial sources, with specific operating procedures referring to Preparation Example 4, and its structure was as follows:

[0780]

[0781] MS (ESI) m / z (M+H) + = 384.0

[0782] 1 H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J = 8.2 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.71 - 7.62 (m, 2H), 7.47 - 7.36 (m, 2H).

[0783] Preparation Example 13: Preparation of 4-chloro-2-oxo-l-(p-tolyl)-7- (trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[0784]

[0785] The title compound was obtained by the above synthetic route via commercial channels or by employing routine techniques in the art, with starting materials and reagents being obtained from commercial sources, with specific operating procedures referring to Preparation Example 4, and its structure was as follows:

[0786]

[0787] MS (ESI) m / z (M+H) + = 364.0

[0788] 1 H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 8.2Hz, 1H), 7.37 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 2.42 (s, 3H).

[0789] Preparation Example 14: Preparation of 2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-4-amine

[0790]

[0791] Dissolve 2-oxa-6-azaspiro[3.3]heptane (100 mg) in N-methylpyrrolidone (3 mL), and add 2-fluoropyridin-4-amine (226 mg). The system is warmed to 150 o C The reaction is initiated by microwave for 6 hours. After most of the starting material disappears as monitored by LCMS, the reaction solution is concentrated, and the crude product is purified by reverse-phase column chromatography to obtain 50 mg of the target compound.

[0792] MS (ESI) m / z (M+H) + = 192.0.

[0793] Preparation Example 15: Preparation of 2-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyridin-4-amine

[0794]

[0795] The starting materials and reagents are obtained through commercial channels or by using conventional technical means in the art, the title compound is obtained by using the above-mentioned synthetic route and referring to the specific operation steps of Preparation Example 14.

[0796] MS (ESI) m / z (M+H) + = 206.0.

[0797] Preparation Example 16: Preparation of 2-(1-fluorocyclopropyl)pyridin-4-amine

[0798]

[0799] Step 1: Preparation of 1H-benzo[d][1,2,3]thiazol-1-yl-1-fluorocyclopropane-1-carboxylate

[0800]

[0801] Dissolve 1-fluorocyclopropane-1-carboxylic acid (2.5 g) in tetrahydrofuran (30 mL), add 1-hydroxybenzotriazole (4.8 g) and N,N'-diisopropylcarbodiimide (4.6 g), and react at room temperature for 2 hours. Filter, wash the filter cake with dichloromethane (50 mL), collect the filtrate, and concentrate under reduced pressure. Purify the residue by column chromatography to obtain the target compound 3.5 g.

[0802] Step 2: Preparation of 1-(1-fluorocyclopropyl)-1-hydroxy-5-methoxy-penta-1,4- dien-3-one

[0803]

[0804] Dissolve 4-methoxybut-3-en-2-one (1.9 g) in tetrahydrofuran (30 mL) at -78 °C, and dropwise add lithium bis(trimethylsilyl)amide (23.7 mL, 1M in THF). After the dropwise addition is completed, react at -78 °C for 0.5 hours, and then add 1H-benzo[d][1,2,3]thiazol-1-yl-1-fluorocyclopropane-1-carboxylate (3.5 g), and continue to react at -78 °C for 4 hours. Add saturated aqueous ammonium chloride solution (50 mL) to terminate the reaction, extract three times with ethyl acetate (50 mL*3), dry the combined organic phases over anhydrous sodium sulfate, filter, and concentrate. Purify the residue by column chromatography to obtain the target compound 1.0 g.

[0805] MS (ESI) m / z (M+H) + = 187.1.

[0806] Step 3: Preparation of 2-(1-fluorocyclopropyl)-4H-pyran-4-one

[0807]

[0808] Dissolve 1-(1-fluorocyclopropyl)-1-hydroxy-5-methoxy-penta-1,4-dien-3-one (1.0 g) in dichloromethane (30 mL), and add trifluoroacetic acid (10 mL). React at room temperature overnight. After the disappearance of the raw material is monitored by LCMS, concentrate under reduced pressure, and purify the residue by column chromatography to obtain the target compound 620 mg.

[0809] MS (ESI) m / z (M+H) + = 155.1.

[0810] Step 4: Preparation of 2-(1-fluorocyclopropyl)pyridin-4-ol

[0811]

[0812] Dissolve 2-(1-fluorocyclopropyl)-4H-pyran-4-one (600 mg) in ammonia water (25%, 15 mL), warm to 100 °C, initiate reaction by microwave for 1 hour. After disappearance of starting material monitored by LCMS, concentrate under reduced pressure, purify the residue by reverse phase column chromatography to give the target compound 350 mg.

[0813] MS (ESI) m / z (M+H) + = 154.1.

[0814] Step 5: Preparation of 2-(1-fluorocyclopropyl)pyridin-4-yl trifluoromethanesulfonate

[0815]

[0816] Dissolve 2-(1-fluorocyclopropyl)pyridin-4-ol (350 mg) in dichloromethane (10 mL), add trifluoromethanesulfonic anhydride (1.13 g) and triethylamine (610 mg), react at room temperature for 2 hours. After disappearance of starting material monitored by LCMS, concentrate under reduced pressure, purify the residue by column chromatography to give the target compound 400 mg.

[0817] MS (ESI) m / z (M+H) + = 286.1.

[0818] Step 6: Preparation of N-(2-(1-fluorocyclopropyl)pyridin-4-yl)-1,1-diphenylmethanimine

[0819]

[0820] Dissolve 2-(1-fluorocyclopropyl)pyridin-4-yl trifluoromethanesulfonate (400 mg), benzophenone imine (510 mg), tris(dibenzylideneacetone)dipalladium (64 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (80 mg) and cesium carbonate (910 mg) in 1,4-dioxane (10 mL) under nitrogen atmosphere, warm to 100 °C, react for 3 hours. After disappearance of starting material monitored by LCMS, cool to room temperature, add water (30 mL) to terminate the reaction, extract with ethyl acetate (30 mL*3) for three times, combine the organic phase, dry over anhydrous sodium sulfate, filter, concentrate, purify the residue by column chromatography to give the target compound 250 mg.

[0821] MS (ESI) m / z (M+H) + = 317.1.

[0822] Step 7: Preparation of 2-(1-fluorocyclopropyl)pyridin-4-amine

[0823]

[0824] N-(2-(1-fluorocyclopropyl)pyridin-4-yl)-1,1-diphenylmethanimine (250 mg) was dissolved in acetonitrile (5 mL), hydrochloric acid (0.5 N, 5 mL) was added, and the reaction was allowed to proceed at room temperature for 2 hours. After the starting material was consumed as monitored by LCMS, the reaction was concentrated under reduced pressure, and the residue was adjusted to basic with saturated sodium bicarbonate solution and purified by reverse phase column chromatography to give the title compound 80 mg.

[0825] MS (ESI) m / z (M+H) + = 153.1.

[0826] Preparation Example 17: Preparation of 4-chloro-2-oxo-1-(pyridin-2-yl)-7- (trifluoromethyl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile

[0827]

[0828] Step 1: Preparation of 2-cyano-N-(pyridin-2-yl)acetamide

[0829]

[0830] Pyridin-2-amine (941 mg) and 2-cyanoacetic acid (1.27 g) were dissolved in 1,2-dichloroethane (15 mL), triethylamine (4.3 mL) was added, and 1-propylphosphonic anhydride (12.7 mL, 50% in EA) was added dropwise slowly. The system was allowed to react at 60 °C for 2 hours, and no starting material was detected by LCMS. The reaction solution was added to saturated sodium bicarbonate solution (50 mL), and the organic phase was extracted with ethyl acetate (3 * 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give the title compound 1.24 g.

[0831] MS (ESI) m / z (M+H) + = 162.0.

[0832] Step 2: Preparation of 2-chloro-6-(trifluoromethyl)nicotinoyl chloride

[0833]

[0834] 2-chloro-6-(trifluoromethyl)nicotinic acid (450 mg) was dissolved in dichloromethane (5 mL), and oxalyl chloride (0.39 mL) and 2 drops of N,N-dimethylformamide were slowly added under ice water bath conditions. The system was allowed to react at room temperature for 1 hour, and no starting material was detected by TLC. The reaction solution was concentrated to give the title compound 510 mg.

[0835] Step 3: Preparation of 4-hydroxy-2-oxo-l-(pyridin-2-yl)-7-(trifluoromethyl)- 1,2-dihydro-l,8-naphthyridine-3-carbonitrile

[0836]

[0837] To a solution of 2-cyano-N-(pyridin-2-yl)acetamide (322 mg) in tetrahydrofuran (5 mL) was added sodium hydride (480 mg) slowly under ice water bath. After 30 min at room temperature, a solution of 2-chloro-6-(trifluoromethyl)nicotinoyl chloride (510 mg) in tetrahydrofuran (5 mL) was added. After 1 h at room temperature, the reaction was continued at reflux overnight. LCMS showed no starting material left. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (50 mL). The organic phase was extracted with ethyl acetate (3 * 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography to give the title compound 350 mg.

[0838] MS (ESI) m / z (M+H) + = 333.0.

[0839] Step 4: Preparation of 4-chloro-2-oxo-l-(pyridin-2-yl)-7-(trifluoromethyl)- 1,2-dihydro-l,8-naphthyridine-3-carbonitrile

[0840]

[0841] To a solution of 4-hydroxy-2-oxo-l-(pyridin-2-yl)-7-(trifluoromethyl)- 1,2-dihydro-l,8-naphthyridine-3-carbonitrile (150 mg) in phosphorus oxychloride (3 mL) was added N,N-diisopropylethylamine (0.5 mL). The mixture was heated at 90 °C for 1 h. LCMS showed no starting material left. The reaction was concentrated and added to saturated sodium bicarbonate solution (50 mL). The organic phase was extracted with ethyl acetate (3 * 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography to give the title compound 90 mg.

[0842] MS (ESI) m / z (M+H) + = 351.0.

[0843] Preparation Example 18: Preparation of 2-(3-methoxyazetidin-l-yl)pyridin-4-amine

[0844]

[0845] The starting materials, reagents, and intermediates are either commercially available or can be readily prepared by ordinary synthetic procedures known in the art. The title compound is obtained by following the above synthetic scheme and by using appropriate starting materials and reagents, and by carrying out the procedures described in the above Preparations, or by modifications apparent to those skilled in the art.

[0846] MS (ESI) m / z (M+H) + = 180.1.

[0847] Preparation 19: Preparation of 2-(morpholinomethyl)pyridin-4-amine

[0848]

[0849] Step 1: Preparation of (4-aminopyridin-2-yl)(morpholino)methanone

[0850]

[0851] Methyl 4-aminopicolinate (500 mg) was dissolved in morpholine (5 mL) and the reaction was initiated by microwave irradiation at 150 °C for 2 h. After the starting material was consumed by LCMS, the reaction was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography to give the product 300 mg.

[0852] MS (ESI) m / z (M+H) + = 208.1.

[0853] Step 2: Preparation of 2-(morpholinomethyl)pyridin-4-amine

[0854]

[0855] (4-Aminopyridin-2-yl)(morpholino)methanone (300 mg) was dissolved in borane (5 mL, 1 M in THF) and the reaction was heated at 70 °C for 2 h. After the starting material was consumed by LCMS, the reaction was quenched by slow addition of methanol (5 mL) and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography to give the product 60 mg.

[0856] MS (ESI) m / z (M+H) + = 194.1.

[0857] Preparation 20: Preparation of l-(4-bromophenyl)-4-chloro-2-oxo-7- (trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[0858]

[0859] The starting materials, reagents, and intermediates are either commercially available or can be readily prepared by ordinary synthetic procedures known in the art. The title compound is obtained by following the above synthetic scheme and by using appropriate starting materials and reagents, and by carrying out the procedures described in the above Preparations, or by modifications apparent to those skilled in the art.

[0860] 1 H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J = 8.2 Hz, 1H), 7.98 (d, J = 8.3Hz, 1H), 7.80 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 8.6 Hz, 2H).

[0861] MS (ESI) m / z (M+H) + = 427.9, 429.9.

[0862] Example 1: Preparation of 4-methoxy-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2- dihydro-1,8-naphthyridine-3-carbonitrile

[0863]

[0864] 4-chloro-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyridine-3- carbonitrile (50 mg) was dissolved in N,N-dimethylformamide (3 mL), sodium methoxide (23 mg) was added, and the reaction was allowed to proceed at room temperature for 2 hours. The disappearance of the starting material was monitored by LCMS. The system was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC to obtain 15 mg of the target compound.

[0865] MS (ESI) m / z (M+H) + = 346.1.

[0866] 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 8.2 Hz, 1H), 7.82 (d, J = 8.2Hz, 1H), 7.55 (dd, J = 8.3, 6.4 Hz, 2H), 7.51-7.46 (m, 1H), 7.34-7.28 (m,2H), 4.59 (s, 3H).

[0867] Example 2: Preparation of 4-(methylamino)-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2- dihydro-1,8-naphthyridine-3-carbonitrile

[0868]

[0869] To a solution of 4-chloro-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8- naphthyridine-3-carbonitrile (30 mg) in tetrahydrofuran (2 M, 1 mL) was added methylamine and the reaction was stirred at room temperature for 30 minutes. The reaction was monitored by LCMS and was complete. The reaction was concentrated under reduced pressure and the residue was purified by preparative HPLC to give the title compound 8 mg.

[0870] MS (ESI) m / z (M+H) + = 345.1.

[0871] 1 H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J = 8.3 Hz, 1H), 8.63 (s, 1H),7.84 (d, J = 8.3 Hz, 1H), 7.50 (dd, J = 8.2, 6.5 Hz, 2H), 7.46-7.41 (m, 1H),7.27-7.21 (m, 2H), 3.40 (s, 3H).

[0872] Example 3: Preparation of 4-((3-(dimethylamino)ethyl)amino)-2-oxo-l-phenyl-7- (trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[0873]

[0874] To a solution of 4-chloro-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8- naphthyridine-3-carbonitrile (50 mg) in tetrahydrofuran (5 mL) was added N,N- dimethylethane-l,3-diamine (35 mg) and the reaction was stirred at room temperature for 0.5 hours. The reaction was monitored by LCMS and was complete. The reaction was concentrated under reduced pressure and the residue was purified by reverse phase preparative HPLC to give the title compound 25 mg.

[0875] MS (ESI) m / z (M+H) + = 402.1.

[0876] 1H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J = 8.3 Hz, 1H), 8.38 (s, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.50 (dd, J = 8.2, 6.5 Hz, 2H), 7.47-7.40 (m, 1H),7.31-7.20 (m, 2H), 3.95 (t, J = 6.6 Hz, 2H), 2.67 (t, J = 6.5 Hz, 2H), 2.25(s, 6H).

[0877] Example 4: Preparation of 4-((3-(dimethylamino)propyl)amino)-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthidine-3-carboxynitrile

[0878]

[0879] 4-Chloro-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthidium-3-carboxynitrile (50 mg) was dissolved in tetrahydrofuran (5 mL), and N,N-dimethylpropane-1,3-diamine (40 mg) was added. The mixture was reacted at room temperature for 0.5 hours. After the starting material disappeared as monitored by LCMS, the mixture was concentrated under reduced pressure. The residue was purified by reverse preparative HPLC to obtain 24 mg of the target compound.

[0880] MS (ESI) m / z (M+H) + = 416.1.

[0881] 1 H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.75 (d, J = 8.3 Hz, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.51 (dd, J = 8.2, 6.5 Hz, 2H), 7.47-7.41 (m, 1H), 7.26 (dd, J = 7.2, 1.7 Hz, 2H), 3.90 (t, J = 7.0 Hz, 2H), 2.41 (t, J = 6.6Hz, 2H), 2.21 (s, 6H), 1.91 (q, J = 6.8 Hz, 2H).

[0882] Example 5: Preparation of 4-(((1H-imidazol-5-yl)methyl)amino)-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthidine-3-carboxynitrile

[0883]

[0884] To a solution of 4-chloro-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8- naphthyridine-3-carbonitrile (50 mg) in tetrahydrofuran (5 mL) was added (l- methyl-lH-imidazol-5-yl)methanamine (40 mg) and the reaction mixture was stirred at room temperature for 0.5 h. After the starting material was consumed by LCMS, the reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase preparative HPLC to give the title compound 23 mg.

[0885] MS (ESI) m / z (M+H) + = 411.1.

[0886] 1 H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 8.98 (d, J = 8.3 Hz, 1H), 8.90 (s, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.65 (d, J = 1.2 Hz, 1H), 7.50 (dd, J = 8.3, 6.5 Hz, 2H), 7.46-7.40 (m, 1H), 7.30-7.21 (m, 2H), 7.16 (s, 1H), 4.99 (d, J = 5.6 Hz, 2H).

[0887] Example 6: Preparation of 4-(((l-methyl-lH-imidazol-5-yl)methyl)amino)-2-oxo-l- phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[0888]

[0889] To a solution of 4-chloro-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8- naphthyridine-3-carbonitrile (50 mg) in tetrahydrofuran (5 mL) was added (l- methyl-lH-imidazol-5-yl)methanamine (40 mg) and the reaction mixture was stirred at room temperature for 0.5 h. After the starting material was consumed by LCMS, the reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase preparative HPLC to give the title compound 23 mg.

[0890] MS (ESI) m / z (M+H) + = 425.1.

[0891] 1H NMR (400 MHz, DMSO-d6) δ 8.98 (d, J = 8.3 Hz, 1H), 8.92 (s, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.58 (d, J = 1.2 Hz, 1H), 7.50 (dd, J = 8.2, 6.5 Hz, 2H), 7.46-7.39 (m, 1H), 7.29-7.22 (m, 2H), 7.18 (d, J = 1.3 Hz, 1H), 4.95 (s, 2H), 3.64 (s, 3H).

[0892] Example 7: Preparation of 4-(((l-methyl-lH-imidazol-2-yl)methyl)amino)-2-oxo-l- phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[0893]

[0894] Example 7: Preparation of 4-(((l-methyl-lH-imidazol-2-yl)methyl)amino)-2-oxo-l- phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[0895] MS (ESI) m / z (M+H) + = 425.1.

[0896] 1 H NMR (400 MHz, DMSO-d6) δ 8.99 (d, J = 8.3 Hz, 1H), 8.92 (s, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.50 (dd, J = 8.2, 6.4 Hz, 2H), 7.47-7.39 (m, 1H), 7.31-7.22 (m, 2H), 7.18 (d, J = 1.1 Hz, 1H), 6.83 (d, J = 1.2 Hz, 1H), 5.10 (s, 2H), 3.65 (s, 3H).

[0897] Example 8: Preparation of 2-oxo-l-phenyl-4-(pyrrolidin-l-yl)-7-(trifluoromethyl)-l,2- dihydro-l,8-naphthyridine-3-carbonitrile

[0898]

[0899] To a solution of 4-chloro-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8- naphthyridine-3-carbonitrile (50 mg) in tetrahydrofuran (5 mL) was added (lH- imidazol-2-yl)methanamine (29 mg) and the reaction mixture was stirred at room temperature for 0.5 h. After the starting material was consumed by LCMS, the reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase preparative HPLC to give the title compound 23 mg.

[0900] MS (ESI) m / z (M+H) + = 385.1.

[0901] 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 8.3 Hz, 1H), 7.64 (d, J = 8.4Hz, 1H), 7.50 (dd, J = 8.3, 6.7 Hz, 2H), 7.47-7.40 (m, 1H), 7.27-7.16 (m,2H), 4.13-3.99 (m, 4H), 2.05-1.91 (m, 4H).

[0902] Example 9: Preparation of 4-(((lH-imidazol-2-yl)methyl)amino)-2-oxo-l-phenyl-7- (trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[0903]

[0904] To a solution of 4-chloro-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8- naphthyridine-3-carbonitrile (50 mg) in tetrahydrofuran (5 mL) was added (lH- imidazol-2-yl)methanamine (29 mg) and the reaction mixture was stirred at room temperature for 0.5 h. After the starting material was consumed by LCMS, the reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase preparative HPLC to give the title compound 23 mg.

[0905] MS (ESI) m / z (M+H) + = 411.0.

[0906] 1H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 8.94 (t, J = 7.8 Hz, 2H), 7.88 (d, J = 8.3 Hz, 1H), 7.51 (dd, J = 8.3, 6.6 Hz, 2H), 7.48-7.41 (m, 1H), 7.26 (dd, J = 7.3, 1.8 Hz, 2H), 7.03 (s, 2H), 5.12 (d, J = 4.5 Hz, 2H).

[0907] Example 10: Preparation of 4-(dimethylamino)-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthidine-3-carboxynitrile

[0908]

[0909] 4-Chloro-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthidium-3-carboxynitrile (50 mg) was dissolved in tetrahydrofuran (5 mL), and a tetrahydrofuran solution of dimethylamine (2 M, 0.5 mL) was added. The mixture was reacted at room temperature for 0.5 hours. After the starting material disappeared as monitored by LCMS, the mixture was concentrated under reduced pressure. The residue was purified by reverse preparative HPLC to obtain 25 mg of the target compound.

[0910] MS (ESI) m / z (M+H) + = 359.0.

[0911] 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 8.3 Hz, 1H), 7.71 (d, J = 8.3Hz, 1H), 7.52 (dd, J = 8.2, 6.5 Hz, 2H), 7.49-7.42 (m, 1H), 7.30-7.21 (m,2H), 3.40 (s, 6H).

[0912] Example 11: Preparation of 4-((2-hydroxyethyl)amino)-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthidine-3-carboxynitrile

[0913]

[0914] Dissolve 4-chloro-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8-naphthyridine- 3-carbonitrile (50 mg) in tetrahydrofuran (4 mL), add 2-aminoethanol (13.10 mg), react at room temperature for 0.5 hours, after the disappearance of the raw material is monitored by LCMS, concentrate under reduced pressure, purify the residue by reverse phase preparative HPLC to obtain 19.59 mg of the target compound.

[0915] MS (ESI) m / z (M+H) + = 375.0.

[0916] 1 H NMR (400 MHz, DMSO-d6) δ 8.97 (d, J = 8.3 Hz, 1H), 8.49 (t, J = 6.0Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.50 (dd, J = 8.2, 6.5 Hz, 2H), 7.47-7.41(m, 1H), 7.29-7.19 (m, 2H), 5.01 (t, J = 5.5 Hz, 1H), 3.94 (q, J = 5.6 Hz,2H), 3.77 (q, J = 5.5 Hz, 2H).

[0917] Example 12: Preparation of 4-((3-hydroxypropyl(amino)-2-oxo-l-phenyl-7- (trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[0918]

[0919] Dissolve 4-chloro-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8-naphthyridine- 3-carbonitrile (50 mg) in tetrahydrofuran (4 mL), add 3-aminopropan-l-ol (16.11 mg), react at room temperature for 0.5 hours, after the disappearance of the raw material is monitored by LCMS, concentrate under reduced pressure, purify the residue by reverse phase preparative HPLC to obtain 21.66 mg of the target compound.

[0920] MS (ESI) m / z (M+H) + = 389.1.

[0921] 1H NMR (400 MHz, DMSO-d6) δ 8.91 (d, J = 8.3 Hz, 1H), 8.49 (s, 1H),7.83 (d, J = 8.3 Hz, 1H), 7.50 (dd, J = 8.3, 6.6 Hz, 2H), 7.46-7.41 (m, 1H),7.29-7.21 (m, 2H), 4.65 (s, 1H), 3.91 (t, J = 7.1 Hz, 2H), 3.57 (t, J = 6.2Hz, 2H), 1.92 (p, J = 6.5 Hz, 2H).

[0922] Example 13: Preparation of 4-(((ls,3s)-3-hydroxycyclobutyl)amino)-2-oxo-l- phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[0923]

[0924] To 4-chloro-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3- carbonitrile (50 mg) in tetrahydrofuran (5 mL) was added cis-3- aminocyclobutanol hydrochloride (100 mg) and N,N-diisopropylethylamine (0.5 mL) and the reaction was stirred at room temperature for 0.5 hour. After disappearance of the starting material was monitored by LCMS, the reaction was concentrated under reduced pressure and the residue was purified by reverse phase preparative HPLC to give the target compound 21.83 mg.

[0925] MS (ESI) m / z (M+H) + = 401.0.

[0926] 1 H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 8.3 Hz, 1H), 8.41 (d, J = 6.5Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.50 (dd, J = 8.3, 6.5 Hz, 2H), 7.47-7.41(m, 1H), 7.25 (dd, J = 7.2, 1.8 Hz, 2H), 5.30 (d, J = 5.3 Hz, 1H), 4.31 (q, J= 7.5 Hz, 1H), 3.97 (q, J = 6.7 Hz, 1H), 2.85-2.75 (m, 2H), 2.26 (qd, J =8.4, 2.9 Hz, 2H).

[0927] Example 14: Preparation of 4-(((1r,3r)-3-hydroxycyclobutyl)amino)-2-oxo-1- phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile

[0928]

[0929] To a solution of 4-chloro-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8- naphthyridine-3-carbonitrile (50 mg) in tetrahydrofuran (5 mL) was added trans-3- aminocyclobutanol hydrochloride (100 mg) and N,N-diisopropylethylamine (0.5 mL) and the reaction mixture was stirred at room temperature for 0.5 h. After the starting material was consumed by LCMS, the reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase preparative HPLC to give the title compound 23 mg.

[0930] MS (ESI) m / z (M+H) + = 401.0.

[0931] 1 H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 8.4 Hz, 1H), 8.34 (s, 1H),7.87-7.80 (m, 1H), 7.50 (dd, J = 8.2, 6.5 Hz, 2H), 7.47-7.40 (m, 1H), 7.29-7.19 (m, 2H), 5.21 (d, J = 5.7 Hz, 1H), 4.77 (d, J = 5.2 Hz, 1H), 4.39 (q, J= 6.4 Hz, 1H), 2.66 (ddd, J = 11.3, 7.0, 3.7 Hz, 2H), 2.40-2.31 (m, 2H).

[0932] Example 15: Preparation of (R)-4-(3-hydroxypyrrolidin-1-yl)-2-oxo-1-phenyl-7- (trifluoromethyl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile

[0933]

[0934] Dissolve 4-chloro-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8-naphthyridine- 3-carbonitrile (50 mg) in tetrahydrofuran (5 mL), add (R)-3-pyrrolidinol (14.95 mg) and N,N-diisopropyl ethylamine (0.5 mL), react at room temperature for 0.5 hours, after the disappearance of the raw material is monitored by LCMS, concentrate under reduced pressure, purify the residue by reverse phase preparative HPLC to obtain 10.9 mg of the target compound.

[0935] MS (ESI) m / z (M+H) + = 401.0.

[0936] 1 H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.3Hz, 1H), 7.50 (dd, J = 8.3, 6.5 Hz, 2H), 7.47-7.41 (m, 1H), 7.29-7.19 (m,2H), 5.26 (d, J = 3.3 Hz, 1H), 4.45 (s, 1H), 4.31-4.18 (m, 2H), 4.07 (ddd, J= 10.8, 7.7, 3.1 Hz, 1H), 3.86 (d, J = 11.7 Hz, 1H), 2.07-1.94 (m, 2H).

[0937] Example 16: Preparation of (S)-4-(3-hydroxypyrrolidin-l-yl)-2-oxo-l-phenyl-7- (trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[0938]

[0939] Dissolve 4-chloro-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8-naphthyridine- 3-carbonitrile (50 mg) in tetrahydrofuran (5 mL), add (S)-3-pyrrolidinol (18.69 mg), react at room temperature for 0.5 hours, after the disappearance of the raw material is monitored by LCMS, concentrate under reduced pressure, purify the residue by reverse phase preparative HPLC to obtain 35.44 mg of the target compound.

[0940] MS (ESI) m / z (M+H) + = 401.1.

[0941] 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J = 8.3 Hz, 1H), 7.64 (d, J = 8.3Hz, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.44 (t, J = 7.3 Hz, 1H), 7.29-7.20 (m,2H), 5.25 (s, 1H), 4.45 (d, J = 4.0 Hz, 1H), 4.29-4.17 (m, 2H), 4.07 (dd, J =10.2, 6.9 Hz, 1H), 3.86 (d, J = 11.7 Hz, 1H), 2.03 (d, J = 17.2 Hz, 2H).

[0942] Example 17: Preparation of 2-oxo-l-phenyl-4-(pyridin-4-ylamino)-7- (trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[0943]

[0944] In a nitrogen atmosphere, 4-aminopyridine (16 mg) was dissolved in tetrahydrofuran (4 mL) and cooled to -78 °C with dry ice-ethanol. Lithium bis(trimethylsilyl)amide (2 M, 0.86 mL) was slowly added and the reaction was allowed to proceed for 30 minutes. 4-Chloro-2-oxo-l-phenyl-7- (trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile (50 mg) was dissolved in tetrahydrofuran (2 mL) and slowly added dropwise to the above reaction system. The reaction was allowed to proceed at -78 °C for 2 hours. LCMS showed that the reaction was complete. The reaction system was poured into saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by reverse phase preparative HPLC to obtain 35.0 mg of the target compound. o C, and the reaction was allowed to proceed for 30 minutes. 4-Chloro-2-oxo-l-phenyl-7- (trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile (50 mg) was dissolved in tetrahydrofuran (2 mL) and slowly added dropwise to the above reaction system. The reaction was allowed to proceed at -78 °C for 2 hours. LCMS showed that the reaction was complete. The reaction system was poured into saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by reverse phase preparative HPLC to obtain 35.0 mg of the target compound. o C, and the reaction was allowed to proceed for 30 minutes. 4-Chloro-2-oxo-l-phenyl-7- (trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile (50 mg) was dissolved in tetrahydrofuran (2 mL) and slowly added dropwise to the above reaction system. The reaction was allowed to proceed at -78 °C for 2 hours. LCMS showed that the reaction was complete. The reaction system was poured into saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by reverse phase preparative HPLC to obtain 35.0 mg of the target compound.

[0945] MS (ESI) m / z (M+H) + = 407.9.

[0946] 1H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 8.67 (d, J = 8.1 Hz, 1H),8.13-8.03 (m, 2H), 7.69 (d, J = 8.1 Hz, 1H), 7.52 (dd, J = 8.3, 6.7 Hz, 2H),7.48-7.42 (m, 1H), 7.30 (dd, J = 7.2, 1.7 Hz, 2H), 6.83 (s, 2H).

[0947] Example 18: Preparation of 4-ethyl-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2- dihydro-l,8-naphthyridine-3-carbonitrile

[0948]

[0949] Step 1: Preparation of N-methoxy-N-methyl-2-(phenylamino)-6- (trifluoromethyl)nicotinamide

[0950]

[0951] To a solution of 2-(phenylamino)-6-(trifluoromethyl)nicotinic acid (300 mg) in tetrahydrofuran (10 mL) was added N,N'-diisopropylcarbodiimide (400.9 mg) and 1-hydroxybenzotriazole (429.7 mg) slowly and the reaction mixture was stirred at room temperature for 60 min. Then triethylamine (536.3 mg) and N,O-dimethylhydroxylamine (77.59 mg) were added successively and the reaction mixture was stirred at room temperature for another 30 min. The reaction mixture was then heated at 50 °C overnight. LCMS showed the reaction was complete. The reaction mixture was poured into ice water (30 mL) and extracted with ethyl acetate for three times. The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to give the title compound 310 mg.

[0952] MS (ESI) m / z (M+H) + = 326.0.

[0953] Step 2: Preparation of l-(2-(phenylamino)-6-(trifluoromethyl)pyridin-3- yl)propan-l-one

[0954]

[0955] N-methoxy-N-methyl-2-(phenylamino)-6-(trifluoromethyl)nicotinamide (310 mg) was dissolved in anhydrous tetrahydrofuran (10 mL) under nitrogen atmosphere, the system was cooled to 0 °C, and ethyl magnesium bromide solution (1 M, 9.5 mL) was added slowly. After addition, the system was reacted at 0 °C for 1 hour. The system was restored to room temperature and continued to react overnight, LCMS showed that the reaction was complete. The reaction system was poured into saturated aqueous ammonium chloride solution (50 mL), extracted with ethyl acetate, the organic phase was combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by column chromatography to obtain the title compound 190 mg.

[0956] MS (ESI) m / z (M+H) + = 295.1.

[0957] Step 3: Preparation of 4-ethyl-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8- naphthyridine-3-carbonitrile

[0958]

[0959] 1-(2-(phenylamino)-6-(trifluoromethyl)pyridin-3-yl)propan-1-one (190 mg) was dissolved in ethyl cyanoacetate (4 mL), and then ammonium acetate (500 mg) was added, and the system was reacted at room temperature for 5 minutes, and then the system was heated to 165 °C for 1 hour, and LCMS showed that the reaction was complete. The obtained crude product was purified by reverse phase preparative HPLC to obtain the title compound 9.37 mg.

[0960] MS (ESI) m / z (M+H) + = 344.1.

[0961] 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 8.2 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.56 (dd, J = 8.3, 6.5 Hz, 2H), 7.53-7.47 (m, 1H), 7.38-7.30 (m, 2H), 3.24 (q, J = 7.6 Hz, 2H), 1.35 (t, J = 7.6 Hz, 3H).

[0962] The starting materials were prepared according to the methods similar to those described in the foregoing Preparation Examples, and the compounds of Examples 19-54 in the following table were prepared according to the methods similar to those described in the foregoing Examples:

[0963] The starting materials were prepared according to the methods similar to those described in the foregoing Preparation Examples, and the compounds of Examples 19-54 in the following table were prepared according to the methods similar to those described in the foregoing Examples:

[0964]

[0965]

[0966]

[0967]

[0968]

[0969]

[0970]

[0971]

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0981]

[0982]

[0983]

[0984]

[0985]

[0986]

[0987]

[0988]

[0989]

[0990]

[0991]

[0992]

[0993]

[0994]

[0995]

[0996]

[0997]

[0998]

[0999]

[1000]

[1001]

[1002]

[1003]

[1004]

[1005]

[1006]

[1007]

[1008]

[1009]

[1010]

[1011]

[1012]

[1013]

[1014]

[1015]

[1016]

[1017]

[1018]

[1019]

[1020]

[1021]

[1022]

[1023]

[1024]

[1025]

[1026]

[1027]

[1028]

[1029]

[1030]

[1031]

[1032]

[1033]

[1034]

[1035]

[1036]

[1037]

[1038]

[1039]

[1040]

[1041]

[1042]

[1043]

[1044]

[1045]

[1046]

[1047]

[1048]

[1049]

[1050]

[1051]

[1052]

[1053]

[1054]

[1055]

[1056]

[1057]

[1058] Example 81: Preparation of l-(2-hydroxyphenyl)-4-(methylamino)-2-oxo-7- (trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[1059]

[1060] In an argon atmosphere, 1-(2-methoxyphenyl)-4-(methylamino)-2-oxo-7- (trifluoromethyl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (30 mg) was dissolved in dichloromethane (5 mL), the system was cooled to -78 °C, and boron tribromide / dichloromethane solution (1 mL) was slowly added to the system and warmed to 0 °C for 1 hour. TLC showed that the reaction was complete. The reaction solution was quenched with saturated sodium bicarbonate solution (10 mL), extracted with dichloromethane / methanol (10:1, 3 * 15 mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by reverse-phase column chromatography to obtain 13 mg of the target compound.

[1061] Example 96: Preparation of 4-((2-aminopyridin-4-yl)amino)-2-oxo-1-phenyl-7- (trifluoromethyl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile

[1062]

[1063] Step 1: Preparation of 4-((2-nitropyridin-4-yl)amino)-2-oxo-1-phenyl-7- (trifluoromethyl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile

[1064]

[1065] In a nitrogen atmosphere, 4-amino-2-nitropyridine (24 mg) was dissolved in anhydrous tetrahydrofuran (5 mL), and lithium bis(trimethylsilyl)amide (1 M, 0.3 mL) was added dropwise at -78 °C. The reaction was allowed to proceed for 20 minutes. 4-Chloro-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (50 mg) was added, and the system was allowed to warm to room temperature for 30 minutes. After the disappearance of the starting material was monitored by LCMS, the reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was used directly in the next reaction without further purification.

[1066] Step 2: Preparation of 4-((2-aminopyridin-4-yl)amino)-2-oxo-1-phenyl-7- (trifluoromethyl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile

[1067]

[1068] 100 mg of 4-((2-nitropyridin-4-yl)amino)-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyl-3-carboxynitrile was dissolved in a mixture of ethanol and water. 50 mg of iron powder and 12 mg of ammonium chloride were added, and the mixture was heated to 85 °C for 2 hours. The reaction proceeded to completion as determined by LC-MS. The iron powder was filtered off, and the solvent was removed by concentration under reduced pressure. The crude product was purified by column chromatography to yield 7 mg of the target compound.

[1069] Example 97: Preparation of 4-((2-hydroxypyridin-4-yl)amino)-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyl-3-carboxynitrile

[1070]

[1071] Step 1: Preparation of 2-((4-methoxybenzyl)oxy)pyridine-4-amine

[1072]

[1073] p-Methoxybenzyl alcohol (0.9 mL) was dissolved in N-methylpyrrolidone (10 mL), and sodium hydride (600 mg) was added at 0 °C. After reacting for 30 minutes, 4-amino-2-chloro-pyridine (1 g) was added, and the reaction was initiated by microwave at 140 °C for 2 hours. The reaction was confirmed to be complete by LCMS. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain 1.2 g of the target compound.

[1074] Step 2: Preparation of 4-((2-((4-methoxybenzyl)oxy)pyridyl-4-yl)amino)-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthidine-3-nitrile)

[1075]

[1076] Under a nitrogen atmosphere, 2-((4-methoxybenzyl)oxy)pyridine-4-amine (66 mg) was dissolved in anhydrous tetrahydrofuran (5 mL), and bis(trimethylsilylamino)lithium (1 M, 0.3 mL) was added dropwise at -78 °C. After reacting for 20 minutes, 4-chloro-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyl-3-carboxynitrile (50 mg) was added, and the system was transferred to room temperature and the reaction was continued for 30 minutes. After the starting material disappeared as monitored by LCMS, the reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain 30 mg of the target compound.

[1077] Step 3: Preparation of 4-((2-hydroxypyridin-4-yl)amino)-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyl-3-carboxynitrile

[1078]

[1079] 30 mg of 4-((2-((4-methoxybenzyl)oxy)pyridyl-4-yl)amino)-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthidium-3-nitrile (30 mg) was dissolved in 5 mL of trifluoroacetic acid and heated at 50 °C for 0.5 h. The reaction proceeded to completion as determined by LC-MS. The solvent was removed by concentration under reduced pressure, and the solution was dissolved in methanol. The pH of the solution was adjusted to weakly alkaline with sodium bicarbonate, and the mixture was filtered. The crude product was purified by preparative HPLC to yield 7 mg of the target compound.

[1080] Example 103: Preparation of 4-((3-cyano-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthid-4-yl)amino)pyridinelineamide

[1081]

[1082] Step 1: Preparation of 4-((2-bromopyridin-4-yl)amino)-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyl-3-carboxylonitrile

[1083]

[1084] 2-Bromopyridine-4-amine (118.3 mg) was dissolved in tetrahydrofuran (6 mL) under a nitrogen atmosphere and heated at -78°C. o Under C conditions, bis(trimethylsilylaminolithium) (1.15 mL, 2 M) was slowly added, and the reaction was allowed to proceed for 30 minutes. 4-Chloro-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyl-3-carboxynitrile (200 mg) was dissolved in tetrahydrofuran (2 mL) and slowly added dropwise to the above reaction system. The reaction was continued for 2 h, and LC-MS showed complete reaction. The reaction system was poured into a saturated ammonium chloride aqueous solution (10 mL), extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give 150 mg of the title compound.

[1085] MS (ESI) m / z (M+H) + = 486.0, 488.0.

[1086] Step 2: Preparation of ethyl 4-((3-cyano-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2- dihydro-l,8-naphthyridin-4-yl)amino)picolinate

[1087]

[1088] Ethyl 4-((2-bromopyridin-4-yl)amino)-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2- dihydro-l,8-naphthyridine-3-carboxylate (150 mg) was dissolved in absolute ethanol (10 mL), [l,l'-bis(diphenylphosphino)ferrocene]palladium dichloride (22.6 mg) and triethylamine (93.8 mg) were added, carbon monoxide was bubbled in three times, the reaction was refluxed at 100 °C overnight, LCMS showed the reaction was complete. The solvent was removed by concentration, the obtained crude product was purified by column chromatography to give the title compound 100 mg.

[1089] MS (ESI) m / z (M+H) + = 480.0.

[1090] Step 3: Preparation of 4-((3-cyano-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydro- l,8-naphthyridin-4-yl)amino)picolinamide

[1091]

[1092] Ethyl 4-((3-cyano-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8-naphthyridin-4- yl)amino)picolinate (100 mg) was dissolved in ammonia-methanol solution (10 mL, 10 M), the reaction was carried out at room temperature overnight, LCMS showed the reaction was complete. The reaction system was concentrated, the obtained crude product was purified by preparative HPLC to give the title compound 2.2 mg.

[1093] Example 110: Preparation of 5-hydroxy-4-(methylamino)-2-oxo-l-phenyl-7- (trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[1094]

[1095] The starting materials and reagents were obtained through commercial channels or by employing routine techniques in the art. The product of Step 5 was obtained by following the synthetic route described above, with reference to the procedures described in Preparation Example 5 and Example 2.

[1096] Step 6: Preparation of 5-hydroxy-4-(methylamino)-2-oxo-l-phenyl-7- (trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[1097]

[1098] Dissolve 5-methoxy-4-(methylamino)-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2- dihydro-l,8-naphthyridine-3-carbonitrile (30 mg) in N,N-dimethylformamide (4 mL), add lithium chloride (34 mg), 120 o C for 2 h. LCMS monitoring shows the starting material is consumed. Add water (20 mL) to the reaction mixture, extract with ethyl acetate for 3 times, combine the organic phase, dry over sodium sulfate, filter, concentrate, the obtained crude is purified by prep-HPLC to give the target compound 16 mg.

[1099] Example 113: Preparation of 4-((2-(hydroxymethyl)pyridin-4-yl)amino)-2-oxo-l- phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[1100]

[1101] Step 1: Preparation of (4-aminopyridin-2-yl)methanol.

[1102]

[1103] In an ice water bath, dissolve methyl 4-aminopicolinate (500 mg) in tetrahydrofuran (6 mL), slowly add lithium aluminum hydride (623.5 mg), move the system to room temperature for 2 h, LCMS shows the reaction is complete. Cool the reaction system to 0 °C, slowly add sodium sulfate decahydrate (3.12 g), filter the reaction system, wash the filter cake with dichloromethane for 3 times, collect the filtrate, concentrate to give the title compound 350 mg.

[1104] MS (ESI) m / z (M+H) + = 125.0.

[1105] Step 2: Preparation of 2-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-4-amine

[1106]

[1107] In an ice water bath, dissolve (4-aminopyridin-2-yl)methanol (350 mg) in tetrahydrofuran (10 mL), slowly add methylimidazole (693.7 mg) and tert-butyldimethylsilyl chloride (637.5 mg), react for 30 min, LCMS shows the reaction is complete. Concentrate the system, the obtained crude is purified by column chromatography to give the title compound 120 mg.

[1108] MS (ESI) m / z (M+H)+ = 239.0.

[1109] Step 3: Preparation of 4-((2-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-4-yl)amino)-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyl-3-carboxynitrile)

[1110]

[1111] In a nitrogen atmosphere, 120 mg of 2-(tert-butyldimethylsilyl)oxy)methyl)pyridine-4-amine was dissolved in 4 mL of tetrahydrofuran at -78 °C. o Under C conditions, lithium bis(trimethylsilylamine) (2.52 mL, 2 M) was slowly added, and the reaction was allowed to proceed for 30 minutes. 4-Chloro-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyl-3-carboxynitrile (100 mg) was dissolved in tetrahydrofuran (2 mL) and slowly added dropwise to the above reaction system at -78°C. o The reaction was continued at C for 2 h, and LCMS showed that the reaction was complete. The reaction mixture was poured into a saturated ammonium chloride aqueous solution (10 mL), extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give 80 mg of the title compound.

[1112] MS (ESI) m / z (M+H) + = 552.0.

[1113] Step 4: Preparation of 4-((2-(hydroxymethyl)pyridin-4-yl)amino)-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyl-3-carboxynitrile

[1114]

[1115] 80 mg of 4-((2-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-4-yl)amino)-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyl-3-carboxynitrile) was dissolved in 6 mL of hydrochloric acid / 1,4-dioxane solution, and 16.8 mg of potassium fluoride was added. The reaction was carried out at room temperature for 2 h, and LC-MS showed that the reaction was complete. The system was concentrated, and the crude product was purified by preparative HPLC to give 55.0 mg of the title compound.

[1116] Example 117: Preparation of 4-((2-(1-oxomorpholinopyridine)-4-yl)amino)-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthidine-3-carboxylonitrile

[1117]

[1118] Step 1: Preparation of 2-thiomorpholinopyridine-4-amine

[1119]

[1120] 2-chloropyridine-4-amine (300 mg) was dissolved in thiomorpholine (1 mL) and the reaction was initiated by microwave at 160 °C for 3 hours. The reaction was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography to give the target compound 0.4 g.

[1121] MS (ESI) m / z (M+H) + = 196.0.

[1122] Step 2: Preparation of 2-oxo-l-phenyl-4-((2-thiomorpholinopyridin-4-yl)amino)-7- (trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[1123]

[1124] 2-thiomorpholinopyridine-4-amine (168 mg) was dissolved in tetrahydrofuran under nitrogen and lithium bis(trimethylsilyl)amide (0.5 mL) was added dropwise at -78 °C. The reaction was continued for 20 minutes and 4-chloro-2-oxo-l-phenyl-7- (trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile (200 mg) was added. The reaction was allowed to warm to room temperature and stirred for 30 minutes. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give the crude product 220 mg.

[1125] MS (ESI) m / z (M+H) + = 509.0.

[1126] Step 3: Preparation of 4-((2-(l-oxomorpholinopyridin)-4-yl)amino)-2-oxo-l-phenyl-7- (trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[1127]

[1128] To a solution of 2-oxo-l-phenyl-4-((2-thiomorpholino-pyridin-4-yl)amino)-7- (trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile (20 mg) in dichloromethane was added urea hydrogen peroxide (20 mg) and the reaction was stirred at room temperature for 1 h. The reaction was quenched with saturated sodium bisulfite solution and extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC to give the title compound 10 mg.

[1129] Example 118: Preparation of 4-((2-(l,l-dioxomorpholino-pyridin-4-yl)amino)-2- oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[1130]

[1131] To a solution of 2-oxo-l-phenyl-4-((2-thiomorpholino-pyridin-4-yl)amino)-7- (trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile (intermediate in example 117, 70 mg) in dichloromethane was added m-chloroperoxybenzoic acid (71 mg) and the reaction was stirred at room temperature for 1 h. The reaction was quenched with saturated sodium bisulfite solution and extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC to give the title compound 20 mg.

[1132] Example 131: Preparation of 4-((2-((2-hydroxyethyl)amino)pyridin-4-yl)amino)-2- oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[1133]

[1134] Step 1: Preparation of 4-bromo-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-2- amine

[1135]

[1136] To a solution of 4-bromo-2-chloropyridine (2.0 g) in isopropanol (6 mL) was added 2-((tert-butyldimethylsilyl)oxy)-l-amine (2.0 g) and N,N-diisopropylethylamine (3.0 g) and the reaction was initiated by microwave at 120 °C for 2 h. The reaction was concentrated under reduced pressure and the residue was purified by column chromatography to give the title compound 1.0 g.

[1137] MS (ESI) m / z (M+H) + = 331.1, 333.1.

[1138] Step 2: Preparation of N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4- ((diphenylmethylene)amino)pyridin-2-amine

[1139]

[1140] N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((diphenylmethylene)amino)pyridin-2- amine (800 mg), diphenylmethanamine (658 mg), cesium carbonate (1.58 g), tris(dibenzylideneacetone)dipalladium (222 mg) and 2-(dicyclohexylphosphino)-3,6- dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (260 mg) were dissolved in dioxane (20 mL) and heated at 90 °C for 2 hours. The system was concentrated under reduced pressure and the residue was purified by column chromatography to give the target compound 400 mg.

[1141] MS (ESI) m / z (M+H) + = 432.1.

[1142] Step 3: Preparation of tert-butyl (2-((tert-butyldimethylsilyl)oxy)ethyl)(4- ((diphenylmethylene)amino)pyridin-2-yl)carbamate

[1143]

[1144] N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((diphenylmethylene)amino)pyridin-2- amine (400 mg) was dissolved in dichloromethane (20 mL), di-tert-butyl dicarbonate (607 mg), triethylamine (281 mg) and 4-dimethylaminopyridine (34 mg) were added and the reaction was allowed to proceed at room temperature for 4 hours. LC-MS showed that the reaction was complete. The system was concentrated under reduced pressure and the residue was purified by column chromatography to give the target compound 290 mg.

[1145] MS (ESI) m / z (M+H) + = 532.1.

[1146] Step 4: Preparation of tert-butyl (4-aminopyridin-2-yl)(2- ((tert-butyldimethylsilyl)oxy)ethyl)carbamate

[1147]

[1148] Tert-butyl (2-((tert-butyldimethylsilyl)oxy)ethyl) (4- ((diphenylmethylene)amino)pyridin-2-yl)carbamate (290 mg) was dissolved in methanol (12 mL), 10% palladium on carbon (290 mg) was added, hydrogen was replaced, and the reaction was allowed to proceed at room temperature overnight. The reaction was filtered, and the resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give 40 mg of the target compound.

[1149] MS (ESI) m / z (M+H) + = 368.2.

[1150] Step 5: Preparation of tert-butyl (2-((tert-butyldimethylsilyl)oxy)ethyl) (4- ((3-cyano-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8-naphthyridin-4- yl)amino)pyridin-2-yl)carbamate

[1151]

[1152] Tert-butyl (4-aminopyridin-2-yl) (2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate (40 mg) was dissolved in tetrahydrofuran (6 mL) at -78 °C, lithium bis(trimethylsilyl)amide (1 M, 0.22 mL) was added, and the reaction was allowed to proceed for 0.5 hours. Then, 4-chloro-2-oxo-l-phenyl-7- (trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile (46 mg) was added, and the reaction was allowed to proceed for 1 hour. LC-MS showed that the starting material was completely consumed. The system was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was used directly in the next step.

[1153] MS (ESI) m / z (M+H) + = 681.3.

[1154] Step 6: Preparation of 4-((2-((2-hydroxyethyl)amino)pyridin-4-yl)amino)-2-oxo-l- phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[1155]

[1156] The crude tert-butyl (2-((tert-butyldimethylsilyl)oxy)ethyl) (4-((3-cyano-2-oxo-1- phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyridin-4-yl)amino)pyridin-2-yl) carbamate was dissolved in a mixture of dichloromethane / trifluoroacetic acid = 2:1 (4 mL / 2 mL) and stirred at room temperature for 6 hours. LC-MS showed that the starting material was completely reacted. The system was concentrated under reduced pressure. The pH was adjusted to weak alkaline with saturated aqueous sodium carbonate solution. The organic phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase preparative HPLC to obtain 15 mg of the target compound.

[1157] Example 141: Preparation of N-(4-((-cyano-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2- dihydro-1,8-naphthyridin-4-yl)amino)pyridin-2-yl)acetamide

[1158]

[1159] The 4-((2-aminopyridin-4-yl)amino)-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8- naphthyridine-3-carbonitrile (50 mg) was dissolved in tetrahydrofuran. Acetic anhydride (0.3 mL) and pyridine (0.2 mL) were added. The reaction was stirred at room temperature for 2 hours. LCMS showed that the starting material was consumed. The reaction was terminated by adding water (5 mL). The product was extracted with ethyl acetate (10 mL*3) three times. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase preparative HPLC to obtain 8 mg of the target compound.

[1160] Example 146: Preparation of 2-oxo-1-phenyl-4-((2-(piperazin-1-yl)pyridin-4-yl)amino)-7- (trifluoromethyl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile

[1161]

[1162] The starting materials and reagents were obtained through commercial channels or by using conventional techniques in the art. The above synthetic route was used to obtain the product of step 2.

[1163] Step 3: Preparation of 2-oxo-1-phenyl-4-((2-(piperazin-1-yl)pyridin-4-yl)amino)-7- (trifluoromethyl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile

[1164]

[1165] The crude tert-butyl 4-(4-((3-cyano-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2- dihydro-l,8-naphthyridin-4-yl)amino)pyridine-2-carboxylate was dissolved in a mixture of dichloromethane / trifluoroacetic acid = 2: 1 (4 mL / 2 mL) and stirred at room temperature for 2 hours. LC-MS showed that the starting material was completely reacted. The system was concentrated under reduced pressure, the residue was adjusted to weak alkaline with saturated aqueous sodium carbonate solution, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by reverse phase preparative HPLC to obtain 25 mg of the target compound.

[1166] Example 148: Preparation of (S)-4-((2-(3-hydroxypyrrolidin-l-yl)pyridin-4-yl)amino)-2- oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[1167]

[1168] The starting materials and reagents were obtained through commercial channels or by using conventional technical means in the art, and the target product was obtained by using the above-mentioned synthetic route and referring to the specific operation steps in Example 113 and Example 146.

[1169] Example 149: Preparation of (R)-4-((2-(3-hydroxypyrrolidin-l-yl)pyridin-4-yl)amino)-2- oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[1170]

[1171] The starting materials and reagents were obtained through commercial channels or by using conventional technical means in the art, and the target product was obtained by using the above-mentioned synthetic route and referring to the specific operation steps in Example 148.

[1172] Example 151: Preparation of 4-((2-(2-hydroxyethoxy)pyridin-4-yl)amino)-2-oxo-l-phenyl-7- (trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[1173]

[1174] The starting materials and reagents were obtained through commercial channels or by using conventional technical means in the art, and the target product was obtained by using the above-mentioned synthetic route and referring to the specific operation steps in Example 148.

[1175] Example 154: Preparation of (R)-2-oxo-l-phenyl-4-(pyrrolidin-3-ylamino)-7- (trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[1176]

[1177] The starting materials, reagents, and the like are obtained through commercial channels or otherwise made according to conventional techniques known to those of ordinary skill in the art. The starting materials are used according to the synthetic routes described above to yield the desired products.

[1178] Example 168: Preparation of 4-((2-(methylamino)pyridin-4-yl)amino)-2-oxo-l- phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[1179]

[1180] Step 1: Preparation of tert-butyl (4-((diphenylmethylene)-amino)-pyridin-2-yl)(methyl)carbamate

[1181]

[1182] Palladium acetate (22.5 mg), 1,1'-binaphthalene-2,2'-diphenylphosphine (125 mg), cesium carbonate (652.0 mg), tert-butyl (4-bromopyridin-2-yl)(methyl)carbamate (286 mg) and diphenyl imine (0.2 mL) were dissolved in anhydrous 1,4-dioxane (20 mL) and stirred well. The reaction mixture was heated to 80 °C for 3 hours. LCMS showed the starting material was consumed completely. The reaction mixture was filtered to remove the cesium carbonate and the filtrate was collected and concentrated. The crude product was purified by column chromatography to give the target compound 186.0 mg.

[1183] MS (ESI) m / z (M+H)+ = 388.1

[1184] Step 2: Preparation of tert-butyl (4-aminopyridin-2-yl)(methyl)carbamate

[1185]

[1186] Tert-butyl (4-((diphenylmethylene)-amino)-pyridin-2-yl)(methyl)carbamate (186 mg) was dissolved in anhydrous methanol. Sodium acetate (94.5 mg) and hydroxylamine hydrochloride (60.0 mg) were added. The reaction mixture was stirred at room temperature for 5 hours. TLC showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography to give the target compound 98 mg.

[1187] MS (ESI) m / z (M+H) + =224.1.

[1188] Step 3: Preparation of tert-butyl (4-((3-cyano-2-oxo-l-phenyl-7- (trifluoromethyl)-l,2-dihydro-l,8-naphthyridin-4-yl)amino)pyridin-2-yl)(methyl) carbamate

[1189]

[1190] Tert-butyl (4-aminopyridin-2-yl)(methyl)carbamate (98 mg) was dissolved in anhydrous tetrahydrofuran (10 mL), stirred uniformly and cooled to -30 °C, then lithium bis(trimethylsilyl)amide (1.32 mL, 1 M) was slowly added. After the reaction was carried out for 0.5 h, a solution of 4-chloro-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8- naphthyridine-3-carbonitrile (150 mg) in tetrahydrofuran was added dropwise. After the addition was completed, the reaction was continued for 0.5 h. The reaction was monitored by LCMS and was complete. The reaction was quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 150 mg of the target compound as a crude product.

[1191] MS (ESI) m / z (M+H) + = 537.2.

[1192] Step 4: Preparation of 4-((2-(methylamino)pyridin-4-yl)amino)-2-oxo-l-phenyl-7- (trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[1193]

[1194] Tert-butyl (4-((3-cyano-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8- naphthyridin-4-yl)amino)pyridin-2-yl)(methyl)carbamate (60 mg) was dissolved in anhydrous dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added dropwise, and the reaction was carried out at room temperature for 6 h. The reaction was monitored by TLC and was complete. The solvent was removed by concentration, and the crude product was purified by preparative HPLC to give 17 mg of the target product.

[1195] Example 169: Preparation of 4-((2-(l-hydroxycyclopropyl)pyridin-4-yl)amino)-2- oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[1196]

[1197] Step 1: Preparation of l-(4-bromopyridin-2-yl)ethan-l-one

[1198]

[1199] To a solution of 4-bromopyridine (5.0 g) in tetrahydrofuran (100 mL) was added methylmagnesium chloride (10.0 mL, 3 M in THF) dropwise at -40 °C. The mixture was stirred at -40 °C for 2 h. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (50 mL). The mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate (50 mL*3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give the target compound 3.1 g.

[1200] MS (ESI) m / z (M+H) + = 200.0, 202.0.

[1201] Step 2: Preparation of 4-bromo-2-(1-((tert-butyldimethylsilyl)oxy)vinyl)pyridine

[1202]

[1203] To a solution of 1-(4-bromopyridin-2-yl)ethan-1-one (3.0 g) in dichloromethane (20 mL) was added triethylamine (4.55 g) and tert-butyldimethylsilyl trifluoromethanesulfonate (4.75 g) at 0 °C. The mixture was stirred at room temperature for 4 h. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography to give the target compound 3.0 g.

[1204] MS (ESI) m / z (M+H) + = 314.0, 316.0.

[1205] Step 3: Preparation of 4-bromo-2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pyridine

[1206]

[1207] To a solution of diethylzinc solution (28.8 mL, 1 M in hexane) in dichloromethane (30 mL) was added chloroiodomethane (10.2 g) dropwise at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then a solution of 4-bromo-2-(1-((tert-butyldimethylsilyl)oxy)vinyl)pyridine (3.0 g) in dichloromethane (10 mL) was added. The mixture was stirred at 0 °C for 2 h. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (30 mL). The mixture was extracted with ethyl acetate (50 mL*3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give the target compound 2.1 g.

[1208] MS (ESI) m / z (M+H) + = 328.1, 330.1.

[1209] Step 4: Preparation of N-(2-(1-(((tert-butyldimethylsilyl)oxy)cyclopropyl)pyridin-4-yl)-1,1-diphenylmethanimine

[1210]

[1211] In a nitrogen atmosphere, 4-bromo-2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pyridine (2.1 g), benzophenone imine (2.3 g), tris(dibenzylideneacetone)dipalladium (300 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (370 mg) and cesium carbonate (4.2 g) were sequentially dissolved in 1,4-dioxane (20 mL), and the temperature was raised to 100 °C for 3 hours. After monitoring the disappearance of the raw material by LCMS, the reaction was terminated by adding water (50 mL) after cooling to room temperature, and the organic phase was extracted three times with ethyl acetate (50 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 2.5 g of the target compound.

[1212] MS (ESI) m / z (M+H) + = 429.2.

[1213] Step 5: Preparation of 2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pyridin-4-amine

[1214]

[1215] N-(2-(1-(((tert-butyldimethylsilyl)oxy)cyclopropyl)pyridin-4-yl)-1,1-diphenylmethanimine (500 mg) was dissolved in methanol (10 mL), and hydroxylamine hydrochloride (410 mg) and sodium acetate (480 mg) were added, and the reaction was carried out at room temperature for 2 hours. After monitoring the disappearance of the raw material by LCMS, it was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 250 mg of the target compound.

[1216] MS (ESI) m / z (M+H) + = 265.2.

[1217] Step 6: Preparation of 4-((2-(1-(((tert-butyldimethylsilyl)oxy)cyclopropyl)pyridin-4-yl)amino)-2-oxo-1-phenyl-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile

[1218]

[1219] Dissolve 2-(l-((tert-butyldimethylsilyl)oxy)cyclopropyl)pyridin-4-amine (55 mg) in tetrahydrofuran (5 mL), cool to -78 °C with dry ice bath, add lithium bis(trimethylsilyl)amide solution (0.28 mL, 1M in THF) dropwise, and continue to react for 0.5 hours. Add 4-chloro-2-oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3- carbonitrile (50 mg), and continue to react for 2 hours. After monitoring the disappearance of the starting material by LCMS, add water (0.5 mL) to terminate the reaction, and concentrate under reduced pressure. Purify the residue by column chromatography to obtain 40 mg of the target compound.

[1220] MS (ESI) m / z (M+H) + = 578.2.

[1221] Step 7: Preparation of 4-((2-(l-hydroxycyclopropyl)pyridin-4-yl)amino)-2-oxo-l- phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[1222]

[1223] Dissolve 4-((2-(l-(((tert-butyldimethylsilyl)oxy)cyclopropyl)pyridin-4-yl)amino)- 2-oxo-l-phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile (40 mg) in dichloromethane (2 mL), add trifluoroacetic acid (2 mL), and react at room temperature for 72 hours. After monitoring the disappearance of the starting material by LCMS, concentrate under reduced pressure, adjust the pH of the residue to about 8 with saturated sodium bicarbonate solution, and purify by reverse phase preparative HPLC to obtain 10 mg of the target compound.

[1224] Example 189: Preparation of 4-((2-(dimethylphosphoryl)pyridin-4-yl)amino)-2-oxo-l- phenyl-7-(trifluoromethyl)-l,2-dihydro-l,8-naphthyridine-3-carbonitrile

[1225]

[1226] In a nitrogen atmosphere, 4-((2-bromopyridin-4-yl)amino)-2-oxo-1-phenyl-7- (trifluoromethyl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (30 mg), dimethyl phosphine oxide (23 mg), tris(dibenzylideneacetone)dipalladium (6 mg), 1,1'- bis(diphenylphosphino)ferrocene (4 mg) and triethylamine (30 mg) were dissolved in 1,4- dioxane (5 mL), and the mixture was heated to 110 °C for 2 hours. After the disappearance of the starting material was monitored by LCMS, the residue was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give 15 mg of the target compound.

[1227] Biological test

[1228] Experimental Example 1: Enzymatic activity test

[1229] Method for detecting IC50 of the test compound on MAT2a using Colorimetric assay 50 .

[1230] The specific steps are as follows: the starting concentration of the compound test is 1 μM or 10 μM, which is diluted by 3 times to form 10 concentration points. 250 nL of the test compound solution at 10 different concentrations was taken and added to a 384-well plate for standby. A MAT2a enzyme (BPS Bioscience Inc., product number #71401-1) solution of 20 μg / mL was prepared with Assay buffer (50 mM Tris, 50 mM KCl, 10 mM MgCl2, 0.05% polyoxyethylene lauryl ether, pH 8.0), and 15 μL of the MAT2a enzyme solution at 20 μg / mL was added to the wells containing the test compound at different concentrations; 15 μL of Assay buffer was added to the negative control wells. After shaking and mixing, the mixture was incubated for 15 minutes. A substrate mixture solution (containing 400 μM ATP and 600 μM L-Methionine) was prepared with Assay buffer, and 10 μL of the substrate mixture solution was added to the positive control wells, the test compound wells and the negative control wells, respectively, to start the reaction, and the reaction time was 150 minutes. Then, 50 μL of a reaction termination solution (BIOMOL Green™ Reagent, Enzolife sciences, product number BML-AK111-1000) was added to terminate the reaction, and after centrifugation at 1000 rpm for 60 seconds, the mixture was incubated for 15 minutes. The OD620 was read, and the data was processed.

[1231] Calculation formula:

[1232] Inhibition% = (OD620 阳性对照孔 - OD620 待测化合物孔 ) / (OD620阳性对照孔 OD620 阴性对照孔 ) x 100

[1233] The IC values of each compound on enzyme activity were obtained by using the log(inhibitor) vs. response - Variable slope fitting dose-response curve of analysis software GraphPad Prism 8, with the log value of the concentration as the X axis and the percentage inhibition rate (Inhibition%) as the Y axis. 50 The experimental results are shown in Table 1 below:

[1234] Table 1 IC values of compounds of the present application on MAT2a 50

[1235]

[1236]

[1237]

[1238]

[1239] NA represents not detected

[1240] Conclusion: The above tests show that the compounds of the present application have excellent MAT2a enzyme inhibitory activity.

[1241] Experimental Example 2: Activity test of HCT116 MTAP homozygous deletion cells (HCT116 MTAP- / -) (source: Horizon company)

[1242] On day 1, cell plating: after trypsinizing the cells, resuspend the cells into the required density with RPMI-1640 culture medium (ATCC, item number 30-2001) containing 10% FBS (EXCELL, item number FND500), mix evenly, 100 μL / well into a 96-well plate, cell density 1000-3000 cells per well, and return to the incubator for cell adhesion growth. On day 2, add the test compound: before adding the compound, starve the cells with serum-free medium for 4 hours, then add 100 μL of complete medium containing the compound (the compound concentration in the medium is configured as follows: 3-fold gradient dilution from 60 μM, a total of 10 concentrations), 37°C, 5% CO2, culture for 120 hours. On day 7, remove the compound-treated cells and equilibrate to room temperature, add 50 μL of CellTiter-Glo (Promega company, item number G7571) reagent per well, shake at room temperature for 2 minutes to fully lyse the cells, then incubate for 60 minutes, and detect the fluorescence intensity. The calculation formula is:

[1243] ​Inhibition = 100 - (signal of the well with the test compound - signal of the well with cell-free medium only) / (signal of the well with cells but without the compound - signal of the well with cell-free medium only) x 100. The log value of the concentration is taken as the X axis, and the Inhibition is taken as the Y axis. The dose-effect curve is fitted by using nonlinear regression (dose response-variable slope) in the analysis software GraphPad Prism 8, and the IC50 value is calculated. Specifically, as shown in Table 2 below:

[1244] Table 2 Inhibitory activity of HCT116 MTAP homozygous deletion (HCT116 MTAP- / -) cells

[1245]

[1246] The HCT116 MTAP- / - cell activity test experiment shows that the compound of the present application, the preferred embodiment compound, has strong inhibitory activity on HCT116 MTAP- / - cells, and generally has an inhibitory activity of <1 μM, for example, 1-500 nM, preferably 1-100 nM.

[1247] Experimental Example 3: Inhibitory activity test of KP-4 cells (source: Nanjing Kebai Biological Technology Co., Ltd.)

[1248] On day 1, cell plating: after trypsin digestion of cells, resuspend the cells into 1*10 4 On day 2, add the test compound: add 100 μL of complete medium containing the compound (the compound concentration in the medium is configured as follows: 3-fold gradient dilution from 60 μM, a total of 10 concentration gradients) into the 96-well plate, and incubate at 37°C, 5% CO2 for 144 hours. On day 8, take out the compound-treated cells and equilibrate to room temperature, aspirate the excess medium in the well, and retain 50 μL of supernatant. Add 50 μL of Cell Counting-Lite 2.0 (Nanjing Nuowezan Biological Technology Co., Ltd., product number DD1101) reagent to each well, shake at room temperature for 10 minutes to fully lyse the cells, incubate for 5 minutes, and detect the fluorescence intensity.

[1249] Inhibition = 100 - (signal of the well with the test compound - signal of the well with cell-free medium only) / (signal of the well with cells but without the compound - signal of the well with cell-free medium only) x 100.

[1250] The log value of the concentration was taken as the X axis, and Inhibition as the Y axis. The dose-effect curve was fitted using nonlinear regression (dose response - variable slope) in the analysis software GraphPad Prism 8, and the IC50value was calculated. The results are shown in Table 3 below.

[1251] Table 3 KP-4 cell inhibition activity

[1252]

[1253] The KP-4 cell inhibition activity test showed that the compounds of the present application, preferably the example compounds, had strong inhibition activity on KP-4 cells, generally having an inhibition activity of <20 μM, for example 0.001-10 μM, in particular 0.01-10 μM, which was significantly superior to the prior art compounds (IC 50 which were generally higher than 30 μM.

[1254] Experimental Example 4 DOHH-2 cell (source: Creative Bioarray Company) inhibition activity test

[1255] On day 1, cell plating: the cells were resuspended to the required density with DMEM complete medium (Gibico Company, Catalog No. 10569010) containing 10% FBS (Gibco, 10099141C), mixed evenly, and 30 μL / well was added to a 384-well plate, with a cell density of 800 cells / well. Compound addition: 30 nL of a DMSO solution containing the compound was added (in which the compound concentration was configured to be 3-fold gradient dilution from 10 mM, a total of 10 concentration points), 37°C, 5% CO2, incubated for 120 hours. On day 6, the cells treated with the compound were taken out and equilibrated to room temperature, 30 μL of CellTiter-Glo (Promega Company, Catalog No. G7573) reagent was added to each well, and the cells were fully lysed by shaking at room temperature. Then, the cells were incubated at 37°C, 5% CO2, for 30 minutes in the dark, and the fluorescence intensity was detected.

[1256] Inhibition = 100 - (signal of the compound to be tested well - signal of the cell-free medium only well) / (signal of the cell-containing but not compound-added well - signal of the cell-free medium only well) x 100.

[1257] The log value of the concentration was taken as the X axis, and the Inhibition was taken as the Y axis. The dose-effect curve was fitted by nonlinear regression (dose response-variable slope) in the analysis software GraphPad Prism 8, and the IC50 value was calculated. The test results are shown in Table 4 below.

[1258] Table 4 DOHH-2 cell inhibition activity

[1259]

[1260] The DOHH-2 cell inhibition activity test shows that the compounds of the present application, preferably the compound of the preferred embodiment, have strong inhibition activity on DOHH-2 cells, usually having an inhibition activity of <1 μM, for example 0.1-100 nM, preferably 0.1-50 nM, which is significantly better than existing compounds, and has great development prospects.

[1261] Comparative Example

[1262] Using the methods of the aforementioned Experimental Examples 2-4, the inhibition activity of the following prior art compounds on HCT116 MTAP gene homozygous deletion cells, KP-4 cancer cells, and DOHH-2 cancer cells was detected, and the results are shown in Table 5 below.

[1263] Table 5 Cancer cell inhibition activity of the compound of the comparative example

[1264]

[1265] Experimental Example 5 SD Rat in vivo Pharmacokinetic Study

[1266] 1. Test animals

[1267] Species: SD rats, SPF level. Source: Shanghai Xipu-Bike Experimental Animal Co., Ltd. Quantity: 3 for each dosage form.

[1268] 2. Preparation of test sample

[1269] 2.1 Accurately weigh an appropriate amount of test sample, and sequentially add 5% DMSO, 10% polyethylene glycol-15 hydroxystearate, and 85% physiological saline (all by volume percentage), and vortex or ultrasonic to fully mix, to obtain a 0.2 mg / mL drug solution for intravenous injection.

[1270] 2.2 Accurately weigh an appropriate amount of test sample, and sequentially add 5% DMSO, 10% polyethylene glycol-15 hydroxystearate, and 85% physiological saline (all by volume percentage), and vortex or ultrasonic to fully mix, to obtain a 0.5 mg / mL drug solution for oral gavage administration.

[1271] 3. Experimental design

[1272]

[1273] 4. Dosing regimen

[1274] Weigh the animals before dosing, and calculate the dose according to the body weight. The drug is administered intravenously or orally by gavage.

[1275] 5. Blood sampling time points

[1276] Before dosing and at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after dosing.

[1277] 6. Sample collection and disposal

[1278] Blood is collected from the jugular vein or other suitable ways, and each sample is about 0.20 mL. The blood sample is anticoagulated with sodium heparin, and placed on ice after collection, and centrifuged to separate the plasma within 2 hours (centrifugal conditions: centrifugal force 6800 g, 6 minutes, 2-8°C). The collected plasma sample is stored in a -80°C refrigerator before analysis, and the remaining plasma sample is continuously stored in a -80°C refrigerator after analysis.

[1279] 7. Bioanalysis and data processing

[1280] The blood drug concentration of the test substance is detected, and 0 is recorded as the BLQ (the lowest detection limit) when drawing the plasma drug concentration-time curve. The concentration before dosing is calculated as 0 when calculating the pharmacokinetic parameters; the previous BLQ (including “No peak”) is calculated as 0; the BLQ (including “No peak”) after Cmax is not involved in the calculation at all. The pharmacokinetic parameters such as AUC(0-t), T max max, etc. are calculated by WinNonlin using the blood drug concentration data at different time points. 1 / 2

[1281] Table 6: In vivo pharmacokinetic study data of SD rats administered with the test compound intravenously and orally

[1282]

[1283] Example 6: In vivo pharmacokinetic study of ICR mice

[1284] 1. Test animals

[1285] Species: ICR mice, SPF level. Source: Shanghai Xipu-Bikai Experimental Animal Co., Ltd. Number: 3 for each dosage form.

[1286] 2. Preparation of test samples​

[1287] 2.1 Accurately weigh the appropriate amount of the test sample, and add 10% DMSO, 40% polyethylene glycol-400, and 50% normal saline (all by volume percentage) in sequence, and vortex or ultrasonic to fully mix, to obtain a 0.2 mg / mL administration solution for intravenous injection administration.

[1288] 2.2 Accurately weigh the appropriate amount of the test sample, and add 10% DMSO, 40% polyethylene glycol-400, and 50% normal saline (all by volume percentage) in sequence, and vortex or ultrasonic to fully mix, to obtain a 1 mg / mL administration solution for oral gavage administration.

[1289] 3. Experimental design

[1290]

[1291] 4. Administration method

[1292] Weigh before administration, and calculate the administration amount according to the body weight. Administer by intravenous or oral gavage.

[1293] 5. Blood sampling time points

[1294] Before administration, and 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration.

[1295] 6. Sample collection and disposal

[1296] Collect blood from the submandibular vein or other suitable means, and collect about 0.03 mL of each sample, and anticoagulate with sodium heparin. Place the blood sample on ice after collection, and centrifuge to separate the plasma within 1 hour (centrifugation conditions: centrifugal force 6800 g, 6 minutes, 2-8°C). Store the collected plasma sample in a -80°C refrigerator before analysis, and continue to store the remaining plasma sample in a -80°C refrigerator after analysis.

[1297] 7. Bioanalysis and data processing

[1298] Detect the blood drug concentration of the test subject, and record 0 for BLQ (the lowest detection limit) when drawing the plasma drug concentration-time curve. Calculate the concentration before administration as 0; calculate the previous BLQ (including “No peak”) as 0; and do not calculate the subsequent BLQ (including “No peak”) for Cmax. Calculate the pharmacokinetic parameters such as AUC(0-t), T max , and Cmax by using the blood drug concentration data at different time points and WinNonlin. 1 / 2

[1299] ​Table 7: In vivo pharmacokinetic study data of ICR mice intravenously and orally administered with test compounds

[1300]

[1301] It is demonstrated by the bioactivity test that the compound of the present application has an excellent effect of inhibiting the MAT2a enzyme activity, has an excellent effect of inhibiting the growth of various cancer cells, and particularly has a more sensitive inhibitory activity on cancer cells with MTAP gene deletion, and will have an excellent therapeutic effect in MAT2a-related cancer or tumor diseases.

Claims

1. Compounds represented by Formula I, their pharmaceutically acceptable salts, or mixtures thereof: in, Y represents CR4, X represents CR5, W represents CR6, and Z represents N; R1 is selected from: and ; R2 is selected from: and ; R4 is selected from hydrogen, halogen, -CN, -CF3, -CHF2, -CF2CH3, -C1-C4 alkyl, -CH2OH, -OCF3, C3-C5 cycloalkyl, -COOCH2CH3, -N(CH3)2; R5 is selected from hydrogen, halogen, -CH3, -OCH3, -SCH3, -CHF2, -CF3, -CN; R6 is selected from hydrogen, halogen, OC1-C6 alkyl, -OCH2CH2NH2, -OCHF2, and -CH2OH.

2. Compounds represented by Formula I, their pharmaceutically acceptable salts, and mixtures thereof. Where Y represents CR4, X represents CR5, W represents CR6, and Z represents N; R1 is selected from: ； The R1 group may be selectively substituted by q Ra groups, each Ra group being independently selected from -CH3, -F, -Cl, -Br, -I, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -OH, and -(CH2). m OH, -NHSO2CH3, -COOH, -CONH2, -CONHCH3, -CH2COCH3, cyclopropyl, where q = 0, 1 or 2; R2 is -NRcRd; Rc is selected from H or -CH3. Rd is selected from 1) H； 2)-COCH3; 3) C1-C4 alkyl group, wherein the C1-C4 alkyl group may be optionally substituted with one or more groups selected from methyl, hydroxyl, halogen, deuterium, -OCH3, -CN, -OCHF2, -N(CH3)2, -CONHCH3, -CONH2, -CON(CH3)2; 4)-(CH2) n R3, wherein R3 is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, tetrahydrofuranyl, pyrrolyl, phenyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl; wherein R3 may be selectively substituted by one or more groups selected from methyl, methoxy, hydroxy, -CH2OH, -CF3, -NH2, -CHF2, -CN, -OCHF2, cyclopropyl, morpholinyl; 5) 、 ； Alternatively, Rc and Rd, together with the N atom they are connected to, form a ring A, wherein ring A is selected from: The ring A may be selectively bound by one or more elements selected from methyl, halogen, -OCH3, -NH2, -NHCH3, -COOH, and -(CH2). m Substitution of groups such as OH, -CH2OCH3, -CN, -CONH2, -CON(CH3)2, -COOCH3, and -CONHCH3; m = 0, 1, 2 or 3; n = 0 or 1; R4 is selected from hydrogen, halogen, -CN, -CF3, -CHF2, -CF2CH3, -C1-C4 alkyl, -CH2OH, -OCF3, C3-C5 cycloalkyl, -COOCH2CH3, -N(CH3)2; R5 is selected from hydrogen, halogen, -CH3, -OCH3, -SCH3, -CHF2, -CF3, -CN; R6 is selected from hydrogen, halogen, OC1-C6 alkyl, -OCH2CH2NH2, -OCHF2, and -CH2OH.

3. The compound of claim 2, its pharmaceutically acceptable salt, and mixtures thereof, wherein R1 is selected from: phenyl, pyridyl, ... and .

4. The compound of claim 2, its pharmaceutically acceptable salt, and mixtures thereof, wherein the R1 group may be selectively substituted with q Ra groups, each of the Ra groups being independently selected from -CH3, -F, -Cl, -Br, -I, -CHF2, -CF3, -OCF3, -OCHF2, and -OH, wherein q = 0, 1, or 2.

5. The compound of claim 2, its pharmaceutically acceptable salt, and mixtures thereof, wherein Rd is -(CH2). n R3, wherein R3 is selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 6. The compound of claim 2, its pharmaceutically acceptable salt, and mixtures thereof, wherein R1 is selected from: 。 7. The compound of claim 2, its pharmaceutically acceptable salt, and mixtures thereof, wherein... R2 is selected from: 。 8. The compound of claim 2, its pharmaceutically acceptable salt, and mixtures thereof, wherein R4 is selected from H, -F, -Cl, -Br, -CN, -CF3, -CF2CH3, -CHF2, -CH3, ethyl, propyl, isopropyl, butyl, -CH2OH, -COOCH2CH3, -OCF3, cyclopropyl, -N(CH3)2.

9. The compound of claim 2, its pharmaceutically acceptable salt, and mixtures thereof, wherein R5 is selected from H, -F, -Cl, -Br, -CN, -CF3, -CHF2, -CH3, -OCH3, -SCH3; and / or R6 is selected from H, -F, -Cl, -Br, -OCH3, -OCHF2, -OCH(CH3)2, -OCH2C(CH3)3.

10. The following compounds, their pharmaceutically acceptable salts, and mixtures: 。 11. The following compounds, their pharmaceutically acceptable salts, and mixtures: 。 12. A pharmaceutical composition, characterized in that... The pharmaceutical composition comprises a therapeutically effective dose of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, or a mixture thereof, and a pharmaceutically acceptable excipient.

13. Use of any pharmaceutically acceptable salt or mixture of the compound of any one of claims 1-11 in the preparation of a medicament for treating MAT2a-related diseases.

14. The use according to claim 13, characterized in that... The MAT2a-related disease is tumor.

15. The use according to claim 14, characterized in that... The tumors include one or more of the following: lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, colon cancer, breast cancer, fallopian tube cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, bladder cancer, kidney cancer or ureteral cancer, mesothelioma, hepatocellular carcinoma, biliary tract cancer, chronic or acute leukemia, and central nervous system (CNS) tumors.

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