PCNA inhibitor and application thereof

Abstract

The present invention relates to compounds as PCNA inhibitors and uses thereof. Specifically, the compound disclosed by the invention has a structure as shown in a formula (I), and the definitions of all groups and substituent groups are described in the specification. The invention also discloses a preparation method of the compound and application of the compound in preparation of drugs for inhibiting PCNA protein or treating PCNA related diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technologies, and particularly to compounds used as PCNA inhibitors, and their applications in regulating PCNA activity or treating PCNA-related diseases. Background Art

[0002] Proliferating cell nuclear antigen (PCNA) is an evolutionarily conserved cell cycle-related protein. The PCNA protein is a nuclear protein necessary for proliferating cells to synthesize DNA. It is expressed and begins to increase in the late G1 phase of the cell proliferation cycle, reaches a peak at the G1 / S phase boundary, remains at a high level during the S phase, and significantly decreases in the G2 phase. As an auxiliary protein of DNA polymerase, PCNA is mainly expressed in normal proliferating cells, virus-infected cells, and tumor cells, participates in the initiation of cell proliferation, is an important indicator reflecting the cell proliferation state, plays an important role in the occurrence and development of various tumors, and is considered a tumor progression marker.

[0003] Studies have shown that PCNA is highly expressed in various tumors such as liver cancer, osteosarcoma, gastric cancer, breast cancer, and ovarian cancer, and is associated with poor prognosis. On the one hand, PCNA promotes the proliferation of tumor cells and their resistance to radiotherapy and chemotherapy drugs by regulating cell DNA synthesis and the cell cycle; on the other hand, PCNA on the surface of tumor cells can also bind to NKp44 on the surface of NK cells, promoting the immune escape of tumor cells. PCNA plays an important role in virus infections such as PRRSV, HCV, and HBV, and inhibiting PCNA has potential antiviral effects.

[0004] As an auxiliary protein of a DNA polymerase, PCNA participates in important regulatory processes such as DNA synthesis replication and damage repair, and is crucial for maintaining genomic integrity and cell proliferation and survival. This indicates that there is a risk in developing related tumor drugs targeting non-tumor cells. However, currently, the targeted PCNA drug AOH1996 has entered clinical phase I / II, indicating that the safety of drugs targeting this target is controllable. This drug has the characteristics of poor solubility and poor hydrolysis stability, and its activity is relatively low. Therefore, there is an urgent need to develop new drugs targeting the PCNA target with excellent drug activity, good solubility, and good hydrolysis stability. Summary of the Invention

[0005] The first aspect of the present invention provides a compound used as a PCNA inhibitor, which is a formula (I) as shown below or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope compound, or prodrug:

[0006]

[0007] Among them,

[0008] Ring A and ring B are each independently selected from a substituted or unsubstituted 6-10 membered aryl group, a substituted or unsubstituted 5- or 6-membered heteroaryl group, a substituted or unsubstituted 6-membered aryl or heteroaryl group fused with a 5-6 membered heteroaryl group, a substituted or unsubstituted 6-membered aryl group fused with a 5-6 membered cycloalkyl or heterocyclic group, a substituted or unsubstituted 5-6 membered heteroaryl group fused with a 5-6 membered cycloalkyl or heterocyclic group, a substituted or unsubstituted 5-6 membered cycloalkyl or heterocyclic group fused with a 5-6 membered cycloalkyl or heterocyclic group, a substituted or unsubstituted phenyl-heteroaryl group, a substituted or unsubstituted phenyl-phenyl group; optionally, two adjacent or non-adjacent substituents can be connected to form a substituted or unsubstituted 5-6 membered carbocyclic ring, a substituted or unsubstituted 5-6 membered heterocyclic ring, a substituted or unsubstituted aryl group, or a substituted or unsubstituted 5- or 6-membered heteroaryl group; the carbocyclic ring or heterocyclic ring can be saturated or partially unsaturated;

[0009] L is -L1-Y-, -L2-Y-L3- or -L2-CHY-L3-;

[0010] L1, L2, L3 are independently selected from -C(O)NR1-, -NR1C(O)-, -C(O)O-, -CO-, -O-, -NR2-, -SO2NR3-, -SO-, -S-, -CF2-, a substituted or unsubstituted 5- or 6-membered heteroaryl group; the substitution of the heteroaryl group means having one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 thioalkyl, C0-C6 alkylthio, C0-C6 alkylhydroxy;

[0011] R1, R2, R3 are independently selected from hydrogen, halogen, -CX 1 3, -CHX 1 2, -CH2X 1 , -CN, -COOH, -CONH2, -NO2, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted 2-10 membered heteroalkyl group, a substituted or unsubstituted 3-8 membered cycloalkyl group, a substituted or unsubstituted 3-8 membered heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted 5-6 membered heteroaryl group, a substituted or unsubstituted C0-C6 alkylamino group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C1-C6 thioalkyl group; or R1, R2, R3 can optionally be connected to ring A or ring B to form a substituted or unsubstituted 5-6 membered carbocyclic ring, a substituted or unsubstituted 5-6 membered heterocyclic ring, a substituted or unsubstituted aryl group, or a substituted or unsubstituted 5- or 6-membered heteroaryl group; the carbocyclic ring or heterocyclic ring can be saturated or partially unsaturated; X 1 is C1, Br, I or F;

[0012] Y is absent or selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C0-C6 alkyl C(O)OC1-C6 alkyl, substituted or unsubstituted 3-8-membered cycloalkyl, substituted or unsubstituted 3-8-membered heterocyclic group, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6-membered heteroaryl, substituted or unsubstituted C0-C3 alkylphenyl, substituted or unsubstituted C0-C3 alkyl-benzylindolyl; the substitution of said Y means having one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C0-C6 alkylamino, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 thioalkyl, C0-C6 alkylthio, C0-C6 alkylhydroxy, C0-C6 alkylcarboxy, C0-C6 alkylene-CO-O-C1-C6 alkyl, C0-C6 alkylene-O-CO-C1-C6 alkyl, C0-C6 alkylene-CO-Rx, C0-C6 alkylene-OCO-O-C1-C6 alkyl, 3-8-membered cycloalkyl, 3-8-membered heterocyclic group, phenyl, 5-6-membered heteroaryl; wherein, Rx is hydrogen, C1-C6 alkyl, NRaRb, hydroxy, C1-C6 haloalkyl, C1-C6 alkoxy; Ra and Rb are each independently selected from hydrogen, C1-C6 alkyl, halogen, amino, hydroxy;

[0013] m and n are independently selected from 0, 1, 2, 3, 4 or 5.

[0014] In another preferred embodiment, ring A and ring B are each independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted 6-membered heteroaryl, substituted or unsubstituted 5-membered heteroaryl, substituted or unsubstituted naphthyl, substituted or unsubstituted indolyl, substituted or unsubstituted azaindolyl, substituted or unsubstituted isoindolyl, substituted or unsubstituted azaisoindolyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted naphthyridinyl, substituted or unsubstituted indazolyl, substituted or unsubstituted azaindazolyl, substituted or unsubstituted quinazolinyl, substituted or unsubstituted azaquinazolinyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted azabenzimidazolyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted azabenzofuranyl, substituted or unsubstituted benzothienyl, substituted or unsubstituted azabenzothienyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted azabenzothiazolyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted azabenzoxazolyl, substituted or unsubstituted benzisoxazolyl, substituted or unsubstituted azabenzisoxazolyl; optionally, two adjacent or non-adjacent substituents may be linked to form a substituted or unsubstituted 5-6 membered carbocyclic ring, a substituted or unsubstituted 5-6 membered heterocyclic ring, a substituted or unsubstituted aryl group, or a substituted or unsubstituted 5- or 6-membered heteroaryl group; the carbocyclic or heterocyclic ring may be saturated or partially unsaturated.

[0015] In another preferred embodiment, the compound has the following formula:

[0016]

[0017] Wherein,

[0018] Ring B is selected from 6-10 membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered aryl or heteroaryl and 5-6 membered heteroaryl, 6-membered aryl and 5-6 membered cycloalkyl or heterocyclic group, 5-6 membered heteroaryl and 5-6 membered cycloalkyl or heterocyclic group, 5-6 membered cycloalkyl or heterocyclic group and 5-6 membered cycloalkyl or heterocyclic group, phenyl-5- or 6-membered heteroaryl, phenyl-phenyl;

[0019] R6 is absent or selected from the group consisting of: halogen, -CX 2 3, -CHX 2 2, -CH2X 2 , -CN, -SR 10 , -SOR 10 , -SO2R 10 , -SO3R 10 , -SO4R 10, -SONR7R8, -SO2NR7R8, -NHNH2, -ONR7R8, -NHC=(O)NHNH2, -NHC=(O)NR7R8, -NO, -NO2, -NR7R8, -C(O)R9, -C(O)-OR9, -Z-C(O)-OR9, -C(O)-Z-OR9, -C(O)NR7R8, -OR 10 , -NR7SO2R 10 , -NR7C=(O)R9, -NR7C(O)-OR9, -NR7OR9, -OCX 2 3, -OCHX 2 2, -OCH2X 2 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted 5-6 membered heteroaryl; Optionally, a substituted or unsubstituted 5-6 membered carbocyclic ring, a substituted or unsubstituted 5-6 membered heterocyclic ring, a substituted or unsubstituted aryl, or a substituted or unsubstituted 5- or 6-membered heteroaryl can be connected between two adjacent or spaced-apart R6; The carbocyclic ring or heterocyclic ring can be saturated or partially unsaturated;

[0020] R8, R9 and R 10 independently are hydrogen, halogen, -CX 3 3, -CHX 3 2, -CH2CN, -COOH, -CONH2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted 5-6 membered heteroaryl; Or the R7 and R8 substituents bonded to the same nitrogen atom can optionally be connected to form a substituted or unsubstituted 3-8 membered heterocyclic group, or a substituted or unsubstituted 5-6 membered heteroaryl;

[0021] Z is -O-, -NH-, or C1-C3 alkylene; X 2 , X 3 is C1, Br, I or F;

[0022] b is an integer from 0 to 7;

[0023] The definitions of ring A, L, m, and n are as defined above.

[0024] In another preferred example, the compound has the following formula:

[0025]

[0026] Among them,

[0027] ring A and ring B are each independently selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered aryl-fused 5-membered heteroaryl, 6-membered aryl-fused 5-membered cycloalkyl, 6-membered aryl-fused 5-membered heterocyclic group, 6-membered heteroaryl-fused 5-membered heteroaryl, 6-membered heteroaryl-fused 5-membered cycloalkyl, 6-membered heteroaryl-fused 5-membered heterocyclic group;

[0028] ring C is absent or selected from substituted or unsubstituted phenyl, substituted or unsubstituted 5-6-membered heteroaryl, substituted or unsubstituted 5-6-membered cycloalkyl, substituted or unsubstituted 5-6-membered heterocyclic group; optionally, two adjacent or alternate substituents may be connected to form a substituted or unsubstituted 5-6-membered carbocyclic ring, substituted or unsubstituted 5-6-membered heterocyclic ring, substituted or unsubstituted aryl, or substituted or unsubstituted 5-membered or 6-membered heteroaryl; the carbocyclic ring or heterocyclic ring may be saturated or partially unsaturated;

[0029] W is absent or selected from -O-, -NH-, -C1-C3 alkylene-, -CHF-, -CF2-, -OCF2-, -CO-, -S-, -NCH3-, -CH(OH)-, -CHCH3-, -SO-, -SO2-, -SO2NR3-;

[0030] R4 and R6 are each independently absent or selected from the following group: halogen, -CX 2 3, -CHX 2 2, -CH2X 2 , -CN, -SR 10 , -SOR 10 , -SO2R 10 , -SO3R 10 , -SO4R 10 , -SONR7R8, -SO2NR7R8, -NHNH2, -ONR7R8, -NHC=(O)NHNH2, -NHC=(O)NR7R8, -NO, -NO2, -NR7R8, -C(O)R9, -C(O)-OR9, -Z-C(O)-OR9, -C(O)-Z-OR9, -C(O)NR7R8, -OR 10 , -NR7SO2R 10 , -NR7C=(O)R9, -NR7C(O)-OR9, -NR7OR9, -OCX 2 3, -OCHX 2 2, -OCH2X 2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted 5-6 membered heteroaryl; Optionally, two adjacent or alternating R4 or R6 may be connected to form a substituted or unsubstituted 5-6 membered carbocyclic ring, a substituted or unsubstituted 5-6 membered heterocyclic ring, a substituted or unsubstituted aryl, or a substituted or unsubstituted 5- or 6-membered heteroaryl; The carbocyclic or heterocyclic ring may be saturated or partially unsaturated; R4 may be connected to ring C by a chemical bond, or ring A and ring C may be directly connected by a chemical bond;

[0031] a and b are integers from 0 to 7;

[0032] X 2 , R8, R9, R 10 , L, m, n, Z, R3 are as defined above.

[0033] In another preferred embodiment, the compound has the following formula:

[0034]

[0035] Wherein,

[0036] Ring A is selected from: substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, or substituted or unsubstituted pyrimidinyl;

[0037] Ring B is a substituted or unsubstituted group selected from the group consisting of: benzoheteroaryl, phenyl-heteroaryl, phenyl-phenyl, or naphthyl; wherein, the heteroaryl (including the heteroaryl in benzoheteroaryl) is a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S;

[0038] Provided that when ring B is naphthyl, ring A is substituted or unsubstituted pyridyl, or substituted or unsubstituted pyrimidinyl;

[0039] Ring C is a substituted or unsubstituted group selected from the group consisting of: phenyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl, 5-6 membered heterocyclic group;

[0040] Wherein, in ring A, ring B and ring C, the substitution respectively means that ring A is substituted by one or more R4, ring B is substituted by one or more R6, and ring C is substituted by one or more R5;

[0041] Ry is selected from: hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, wherein the substituent is deuterium, halogen, hydroxyl, methoxy, methylthio, carboxyl, ester group, amide group, amino, substituted or unsubstituted phenyl, guanidyl, 5-6 membered heteroaryl, benzo 5-6 membered heteroaryl;

[0042] R4, R5 and R6 are each independently none, halogen, hydroxyl, sulfonamide group, sulfonyl, or cyano; or are a substituted or unsubstituted group selected from the group consisting of: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylthio, C3-C6 cycloalkoxy, -NR7R8, -C(O)R9, -C(O)-OR9, -Z-C(O)-OR9, -C(O)-Z-OR9, -C(O)NR7R8;

[0043] Or two adjacent R4 and the ring atoms of ring A to which they are attached together form a substituted or unsubstituted 4-8 membered heterocycle containing 1-3 heteroatoms selected from N, O and S, or a substituted or unsubstituted C4-C8 carbocycle; two adjacent R5 and the ring atoms of ring C to which they are attached together form a substituted or unsubstituted 4-8 membered heterocycle containing 1-3 heteroatoms selected from N, O and S, or a substituted or unsubstituted C4-C8 carbocycle; and / or two adjacent R6 and the ring atoms of ring B to which they are attached together form a substituted or unsubstituted 4-8 membered heterocycle containing 1-3 heteroatoms selected from N, O and S, or a substituted or unsubstituted C4-C8 carbocycle;

[0044] Z is -O-, -NH-, or C1-C3 alkylene;

[0045] R7, R8 and R9 are each independently: hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl; or R7, R8 and the adjacent N atom together form a substituted or unsubstituted 4-8 membered heterocycle;

[0046] W is -O-, -NH-, C1-C3 alkylene, -CHF-, -CF2-, -OCF2-, -CO-, -S-, -NCH3-, -CH(OH)-, -CHCH3-, -SO-, -SO2-, or -SO2NR3-;

[0047] a, b and c are each independently an integer from 0 to 7;

[0048] Wherein, the said substitution means being substituted by one or more substituents selected from the group consisting of: deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, phenyl, benzyl, hydroxyl, C1-C6 alkoxy.

[0049] In another preferred example, the said ring B is selected from the group consisting of:

[0050]

[0051] In another preferred embodiment, ring B is a benzoheteroaryl group.

[0052] In another preferred embodiment, ring B is a benzoheteroaryl group, and the benzoheteroaryl group is linked through a phenyl group.

[0053] In another preferred embodiment, the linking site of ring B and the amide is on the benzene ring.

[0054] In another preferred embodiment, Ry is selected from the group consisting of: hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, wherein the substituent is deuterium, halogen, hydroxyl, methoxy, methylthio, carboxyl, ester group, amide group, amino, substituted or unsubstituted phenyl, guanidyl, 5- or 6-membered heteroaryl, benzo-5- or 6-membered heteroaryl.

[0055] In another preferred embodiment, Ry is selected from the group consisting of: hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, or hydroxyl-substituted C1-C6 alkyl.

[0056] In another preferred embodiment, Ry is selected from the group consisting of: hydrogen, or hydroxyl-substituted C1-C6 alkyl.

[0057] In another preferred embodiment, R4 is absent, halogen, or C1-C6 alkyl.

[0058] In another preferred embodiment, R5 is absent, halogen, hydroxyl, cyano, C1-C6 alkoxy, C1-C6 carboxyl, C2-C6 ester group, or -O-C2-C6 ester group.

[0059] In another preferred embodiment, R6 is absent, halogen, hydroxyl, cyano, C1-C6 alkoxy, C1-C6 carboxyl, C2-C6 ester group, or -O-C2-C6 ester group.

[0060] In another preferred embodiment, R4 is C1-C3 alkyl, preferably methyl.

[0061] In another preferred embodiment, R5 is halogen, C1-C3 alkoxy, or C2-C4 ester group.

[0062] In another preferred embodiment, two adjacent R5 and the ring atoms of ring C to which they are attached together form a substituted or unsubstituted 6-membered heterocycle containing 2 O heteroatoms.

[0063] In another preferred embodiment, in the 6-membered heterocycle, two adjacent R5 form -O-CH2-CH2-O-.

[0064] In another preferred embodiment, R6 is halogen, C1-C6 alkyl, or C1-C6 alkoxy.

[0065] In another preferred example, W is -O-, -NH-, C1-C3 alkylene, -CF2-, -CO-, or -S-.

[0066] In another preferred example, W is -O- or -S-.

[0067] In another preferred example, a is 0, 1, or 2.

[0068] In another preferred example, b is 0, 1, 2, or 3.

[0069] In another preferred example, c is 0, 1, 2, or 3.

[0070] In another preferred example, ring A is selected from

[0071] wherein,

[0072] For each case, a is independently 0, 1, 2, 3, or 4;

[0073] For each case, c is independently 0, 1, 2, 3, 4, or 5.

[0074] In another preferred example, R4 is absent or selected from halogen, C1-C3 alkyl, C1-C3 alkoxy.

[0075] In another preferred example, ring C is selected from phenyl, 5-membered or 6-membered heteroaryl.

[0076] In another preferred example, ring C is selected from

[0077] In another preferred example, R5 is absent or selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, -C(O)-O-C1-C3 alkyl; two adjacent or alternate R5s may optionally be linked to form a substituted or unsubstituted 5-6-membered carbocyclic ring, a substituted or unsubstituted 5-6-membered heterocyclic ring, a substituted or unsubstituted aryl group, or a substituted or unsubstituted 5-membered or 6-membered heteroaryl group; the carbocyclic or heterocyclic ring may be saturated or partially unsaturated.

[0078] In another preferred example, the compound is selected from the following:

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117] In another preferred example, the compound is selected from the following:

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128] The second aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, and a pharmaceutically acceptable carrier.

[0129] In another preferred example, the administration mode of the compound is selected from the following group: oral, intratumoral, rectal, parenteral.

[0130] In another preferred example, the pharmaceutical composition is a tablet, capsule, granule, syrup, suspension, solution, dispersion, sustained-release preparation for oral or non-oral administration, intravenous injection preparation, subcutaneous injection preparation, inhalation preparation, transdermal preparation, rectal or vaginal suppository.

[0131] The third aspect of the present invention provides the use of the compound of the first invention of the present invention, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, for preparing a PCNA inhibitor drug or a drug for treating PCNA-related diseases.

[0132] The fourth aspect of the present invention provides a method for treating and / or preventing PCNA-related diseases, comprising the step of administering to a subject in need a therapeutically effective amount of the compound of the first aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or the composition of the second aspect of the present invention.

[0133] In another preferred example, the PCNA-related disease is cancer or tumor.

[0134] In another preferred example, the cancer is selected from the group consisting of: brain cancer, breast cancer, cervical cancer, colon cancer, rectal cancer, head and neck cancer, leukemia, liver cancer, lung cancer, lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, gastric cancer, thyroid cancer.

[0135] In another preferred example, the subject is a mammal, such as a human.

[0136] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as in the examples) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be repeated one by one here. Description of the Drawings

[0137] None. Detailed Description of the Invention

[0138] Terms

[0139] "Alkyl" refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group. For example, "C1-8 alkyl" refers to a straight-chain alkyl and a branched-chain alkyl containing 1 to 8 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, etc.

[0140] "Alkenyl" is a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds that can occur at stable sites on the chain. Non-limiting examples include C2-C8 alkenyl (such as C2, C3, C4, C5, C6, C7, C8), C2-C6 alkenyl, and C2-C4 alkenyl. The specified ranges used herein represent alkenyls that can be considered as independent classes and have each value within the said ranges, as in the case of the alkyl moieties described herein. Examples of alkenyls include, but are not limited to, vinyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl). In one embodiment, the alkenyl is optionally substituted as described herein.

[0141] "Alkynyl" is a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that can occur at any stable site on the chain. For example, C2-C8 alkynyl (such as C2, C3, C4, C5, C6, C7, C8) or C2-C6 alkynyl. The specified ranges used herein represent alkynyls that can be considered as independent classes and have each value within the said ranges, as in the case of the alkyl moieties described herein. Examples of alkynyls include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl. In one embodiment, the alkynyl is optionally substituted as described herein.

[0142] "Cycloalkyl" refers to a saturated or partially unsaturated cycloalkyl having a monocyclic or polycyclic structure, including fused-ring, bridged-ring, and spiro-ring systems. The term "cycloalkyl" includes cycloalkenyl (i.e., a ring group having at least one double bond). As used herein, C 3-8 cycloalkyl has 3 to 8 ring carbon atoms (e.g., 3, 4, 5, 6, 7, or 8 ring carbon atoms). Examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and partially unsaturated groups such as cyclopentenyl and cyclohexenyl.

[0143] "Carbocyclic group", "carbocyclic moiety", "carbocycle", or "cycloalkyl" is a saturated or partially unsaturated (i.e., non-aromatic) group containing all carbocyclic atoms. A carbocyclic group typically contains a ring of 1 to 7 carbon atoms or two fused rings each containing 3, 4, 5, 6, or 7 carbon atoms. A cycloalkyl substituent can be attached to a substituted nitrogen or carbon atom as a side chain, or a substituted carbon atom having two substituents can have a cycloalkyl attached as a spiro group. Examples of carbocycles include cyclohexenyl, cyclohexyl, cyclopentenyl, cyclopentyl, cyclobutenyl, cyclobutyl, and the rings of cyclopropyl. In one embodiment, the carbocycle is optionally substituted as described herein. In one embodiment, the cycloalkyl is a partially unsaturated (i.e., non-aromatic) group containing all carbocyclic atoms. In another embodiment, the cycloalkyl is a saturated group containing all carbocyclic atoms.

[0144] "Heterocycloalkyl" is a saturated cyclic group. For example, it can have 1, 2, 3, or 4 heteroatoms independently selected from N, S, and O, and the remaining ring atoms are carbon atoms. In a representative embodiment, the heteroatom is nitrogen. Monocyclic heterocycloalkyl typically has 3 to about 8 ring atoms or 4 to 6 ring atoms. Examples of heterocycloalkyl include morpholinyl, piperazinyl, piperidinyl, pyrrolinyl.

[0145] "Aryl" refers to a fully carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group, a polycyclic group having a conjugated π-electron system (i.e., rings having adjacent pairs of carbon atoms), including but not limited to phenyl and naphthyl.

[0146] "Heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, said heteroatoms including nitrogen, oxygen, and S. For example, a 5-7 membered heteroaryl refers to a heteroaromatic system containing 5-7 ring atoms, and a 5-10 membered heteroaryl refers to a heteroaromatic system containing 5-10 ring atoms, including but not limited to furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc.

[0147] "Heteroalkyl" refers to a stable straight-chain or branched acyclic chain, or a combination thereof, including at least one carbon atom and at least one heteroatom (such as O, N, P, Si, or S). One or more heteroatoms (such as O, N, P, S, or Si) can be located at any internal position of the heteroalkyl group, or at the position where the alkyl group is connected to the rest of the molecule. Examples include but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-OCH3, -Si(CH3)3, -CH2-CH=N-OCH3-O-CH2-CH3, and -CN.

[0148] "Alkoxy" is an alkyl group as defined above covalently bonded by an oxygen bridge (-O-). Examples of alkoxy include but are not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-butoxy, tert-butoxy, n-pentyloxy, 2-pentyloxy, 3-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, 2-hexyloxy, 3-hexyloxy, and 3-methylpentyloxy. Similarly, an "alkylthio" or "thioalkyl" group is an alkyl group as defined above covalently bonded by a sulfur bridge (-S-). In one embodiment, the alkoxy is optionally substituted as described herein.

[0149] "Substituted" means that one or more hydrogen atoms on a specific group are replaced by specific substituents. The specific substituents are the substituents described correspondingly in the foregoing text, or the substituents appearing in each embodiment. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituents may be the same or different at each position. Those skilled in the art should understand that the combinations of substituents contemplated by the present invention are those that are stable or chemically achievable combinations. The substituents are, for example (but not limited to): halogen, hydroxyl, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic group, aryl, heteroaryl, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amino group, C1-C6 alkoxy group, C1-C10 sulfonyl group, etc.

[0150] Compound

[0151] The present invention provides a compound used as a PCNA inhibitor, which is a compound of formula (I) shown below or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope compound or prodrug thereof:

[0152]

[0153] Wherein,

[0154] Ring A and ring B are each independently selected from a substituted or unsubstituted 6- to 10-membered aryl group, a substituted or unsubstituted 5- or 6-membered heteroaryl group, a substituted or unsubstituted 6-membered aryl or heteroaryl group and a 5- to 6-membered heteroaryl group, a substituted or unsubstituted 6-membered aryl group and a 5- to 6-membered cycloalkyl or heterocyclic group, a substituted or unsubstituted 5- to 6-membered heteroaryl group and a 5- to 6-membered cycloalkyl or heterocyclic group, a substituted or unsubstituted 5- to 6-membered cycloalkyl or heterocyclic group and a 5- to 6-membered cycloalkyl or heterocyclic group, a substituted or unsubstituted phenyl-heteroaryl group, a substituted or unsubstituted phenyl-phenyl group; optionally, a substituted or unsubstituted 5- to 6-membered carbocyclic ring, a substituted or unsubstituted 5- to 6-membered heterocyclic ring, a substituted or unsubstituted aryl group, or a substituted or unsubstituted 5- or 6-membered heteroaryl group may be formed by connecting between two adjacent or spaced substituents; the carbocyclic ring or heterocyclic ring may be saturated or partially unsaturated;

[0155] L is -L1-Y-, -L2-Y-L3- or -L2-CHY-L3-;

[0156] L1, L2, L3 are independently selected from -C(O)NR1-, -NR1C(O)-, -C(O)O-, -CO-, -O-, -NR2-, -SO2NR3-, -SO-, -S-, -CF2-, substituted or unsubstituted 5- or 6-membered heteroaryl; the substitution of the heteroaryl means having one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 thioalkyl, C0-C6 alkylthio, C0-C6 alkylhydroxy;

[0157] R1, R2, R3 are independently selected from hydrogen, halogen, -CX 1 3, -CHX 1 2, -CH2X 1 , -CN, -COOH, -CONH2, -NO2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted 2-10-membered heteroalkyl, substituted or unsubstituted 3-8-membered cycloalkyl, substituted or unsubstituted 3-8-membered heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted 5-6-membered heteroaryl, substituted or unsubstituted C0-C6 alkylamino, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 thioalkyl; or R1, R2, R3 may optionally be connected to ring A or ring B to form a substituted or unsubstituted 5-6-membered carbocyclic ring, substituted or unsubstituted 5-6-membered heterocyclic ring, substituted or unsubstituted aryl, or substituted or unsubstituted 5- or 6-membered heteroaryl; the carbocyclic or heterocyclic ring may be saturated or partially unsaturated; X 1 is C1, Br, I or F;

[0158] Y is none or selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C0-C6 alkyl C(O)OC1-C6 alkyl, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted C0-C3 alkylphenyl, substituted or unsubstituted C0-C3 alkyl-benzoindolyl; the substitution of said Y means having one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C0-C6 alkylamino, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 thioalkyl, C0-C6 alkylthio, C0-C6 alkylhydroxy, C0-C6 alkylcarboxy, C0-C6 alkylene-CO-O-C1-C6 alkyl, C0-C6 alkylene-O-CO-C1-C6 alkyl, C0-C6 alkylene-CO-Rx, C0-C6 alkylene-OCO-O-C1-C6 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic group, phenyl, 5-6 membered heteroaryl; wherein, Rx is hydrogen, C1-C6 alkyl, NRaRb, hydroxy, C1-C6 haloalkyl, C1-C6 alkoxy; Ra and Rb are each independently selected from hydrogen, C1-C6 alkyl, halogen, amino, hydroxy;

[0159] m and n are independently selected from 0, 1, 2, 3, 4 or 5.

[0160] In another preferred embodiment, ring A and ring B are each independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted 6-membered heteroaryl, substituted or unsubstituted 5-membered heteroaryl, substituted or unsubstituted naphthyl, substituted or unsubstituted indolyl, substituted or unsubstituted azaindolyl, substituted or unsubstituted isoindolyl, substituted or unsubstituted azaisoindolyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted naphthyridinyl, substituted or unsubstituted indazolyl, substituted or unsubstituted azaindazolyl, substituted or unsubstituted quinazolinyl, substituted or unsubstituted az quinazolinyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted azabenzimidazolyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted azabenzofuranyl, substituted or unsubstituted benzothienyl, substituted or unsubstituted azabenzothienyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted azabenzothiazolyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted azabenzoxazolyl, substituted or unsubstituted benzisoxazolyl, substituted or unsubstituted azabenzisoxazolyl; two adjacent or alternating substituents may optionally be joined to form a substituted or unsubstituted 5-6 membered carbocyclic ring, substituted or unsubstituted 5-6 membered heterocyclic ring, substituted or unsubstituted aryl, or substituted or unsubstituted 5- or 6-membered heteroaryl; the carbocyclic or heterocyclic ring may be saturated or partially unsaturated.

[0161] In another preferred embodiment, the compound has the following formula:

[0162]

[0163] wherein,

[0164] ring B is selected from 6-10 membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered aryl or heteroaryl fused to a 5-6 membered heteroaryl, 6-membered aryl fused to a 5-6 membered cycloalkyl or heterocyclic group, 5-6 membered heteroaryl fused to a 5-6 membered cycloalkyl or heterocyclic group, 5-6 membered cycloalkyl or heterocyclic group fused to a 5-6 membered cycloalkyl or heterocyclic group, phenyl-5- or 6-membered heteroaryl, phenyl-phenyl;

[0165] R6 is absent or selected from the group consisting of: halogen, -CX 2 3, -CHX 2 2, -CH2X 2 , -CN, -SR 10 , -SOR 10 , -SO2R 10 , -SO3R 10 , -SO4R 10, -SONR7R8, -SO2NR7R8, -NHNH2, -ONR7R8, -NHC=(O)NHNH2, -NHC=(O)NR7R8, -NO, -NO2, -NR7R8, -C(O)R9, -C(O)-OR9, -Z-C(O)-OR9, -C(O)-Z-OR9, -C(O)NR7R8, -OR 10 , -NR7SO2R 10 , -NR7C=(O)R9, -NR7C(O)-OR9, -NR7OR9, -OCX 2 3, -OCHX 2 2, -OCH2X 2 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted 5-6 membered heteroaryl; Optionally, two adjacent or spaced R6s may be connected to a substituted or unsubstituted 5-6 membered carbocyclic ring, substituted or unsubstituted 5-6 membered heterocyclic ring, substituted or unsubstituted aryl, or substituted or unsubstituted 5- or 6-membered heteroaryl; The carbocyclic or heterocyclic ring may be saturated or partially unsaturated;

[0166] R8, R9 and R 10 are independently hydrogen, halogen, -CX 3 3, -CHX 3 2, -CH2CN, -COOH, -CONH2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted 5-6 membered heteroaryl; Alternatively, the R7 and R8 substituents bonded to the same nitrogen atom may optionally be connected to form a substituted or unsubstituted 3-8 membered heterocyclic group, or a substituted or unsubstituted 5-6 membered heteroaryl;

[0167] Z is -O-, -NH-, or C1-C3 alkylene; X 2 , X 3 is C1, Br, I or F;

[0168] b is an integer from 0 to 7;

[0169] The definitions of ring A, L, m, and n are as defined above.

[0170] In another preferred embodiment, the compound has the following formula:

[0171]

[0172] Among them,

[0173] ring A and ring B are each independently selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered aryl-fused 5-membered heteroaryl, 6-membered aryl-fused 5-membered cycloalkyl, 6-membered aryl-fused 5-membered heterocyclic group, 6-membered heteroaryl-fused 5-membered heteroaryl, 6-membered heteroaryl-fused 5-membered cycloalkyl, 6-membered heteroaryl-fused 5-membered heterocyclic group;

[0174] ring C is absent or selected from substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 5-6 membered cycloalkyl, substituted or unsubstituted 5-6 membered heterocyclic group; optionally, two adjacent or alternate substituents may be connected to form a substituted or unsubstituted 5-6 membered carbocyclic ring, a substituted or unsubstituted 5-6 membered heterocyclic ring, a substituted or unsubstituted aryl group, or a substituted or unsubstituted 5-membered or 6-membered heteroaryl group; the carbocyclic ring or heterocyclic ring may be saturated or partially unsaturated;

[0175] W is absent or selected from -O-, -NH-, -C1-C3 alkylene-, -CHF-, -CF2-, -OCF2-, -CO-, -S-, -NCH3-, -CH(OH)-, -CHCH3-, -SO-, -SO2-, -SO2NR3-;

[0176] R4 and R6 are each independently absent or selected from the following group: halogen, -CX 2 3, -CHX 2 2, -CH2X 2 、-CN, -SR 10 、-SOR 10 、-SO2R 10 、-SO3R 10 、-SO4R 10 、-SONR7R8, -SO2NR7R8, -NHNH2, -ONR7R8, -NHC=(O)NHNH2, -NHC=(O)NR7R8, -NO, -NO2, -NR7R8, -C(O)R9, -C(O)-OR9, -Z-C(O)-OR9, -C(O)-Z-OR9, -C(O)NR7R8, -OR 10 、-NR7SO2R 10 、-NR7C=(O)R9, -NR7C(O)-OR9, -NR7OR9, -OCX 2 3, -OCHX 2 2, -OCH2X 2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted 5-6 membered heteroaryl; Optionally, two adjacent or spaced R4 or R6 may be connected to form a substituted or unsubstituted 5-6 membered carbocyclic ring, substituted or unsubstituted 5-6 membered heterocyclic ring, substituted or unsubstituted aryl, or substituted or unsubstituted 5-membered or 6-membered heteroaryl; The carbocyclic ring or heterocyclic ring may be saturated or partially unsaturated; R4 may be connected to ring C by a chemical bond, or ring A and ring C may be directly connected by a chemical bond;

[0177] a and b are integers from 0 to 7;

[0178] X 2 , R8, R9, R 10 , L, m, n, Z, R3 are as defined above.

[0179] In another preferred embodiment, the compound has the following formula:

[0180]

[0181] Wherein,

[0182] Ring A is selected from: substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, or substituted or unsubstituted pyrimidinyl;

[0183] Ring B is a substituted or unsubstituted group selected from the group consisting of: benzheteroaryl, phenyl-heteroaryl, phenyl-phenyl, or naphthyl; wherein, the heteroaryl (including the heteroaryl in benzheteroaryl) is a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S;

[0184] Provided that when ring B is naphthyl, ring A is substituted or unsubstituted pyridyl, or substituted or unsubstituted pyrimidinyl;

[0185] Ring C is a substituted or unsubstituted group selected from the group consisting of: phenyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl, 5-6 membered heterocyclic group;

[0186] Wherein, in ring A, ring B and ring C, the substitution respectively means that ring A is substituted by one or more R4, ring B is substituted by one or more R6, and ring C is substituted by one or more R5;

[0187] Ry is selected from: hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, wherein the substituent is deuterium, halogen, hydroxyl, methoxy, methylthio, carboxyl, ester group, amide group, amino, substituted or unsubstituted phenyl, guanidyl, 5-6 membered heteroaryl, benzo 5-6 membered heteroaryl;

[0188] R4, R5 and R6 are each independently none, halogen, hydroxyl, sulfonamide group, sulfonyl, or cyano; or are a substituted or unsubstituted group selected from the group consisting of: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylthio, C3-C6 cycloalkoxy, -NR7R8, -C(O)R9, -C(O)-OR9, -Z-C(O)-OR9, -C(O)-Z-OR9, -C(O)NR7R8;

[0189] Or two adjacent R4 and the ring atoms of ring A to which they are attached together form a substituted or unsubstituted 4-8 membered heterocycle containing 1-3 heteroatoms selected from N, O and S, or a substituted or unsubstituted C4-C8 carbocycle; two adjacent R5 and the ring atoms of ring C to which they are attached together form a substituted or unsubstituted 4-8 membered heterocycle containing 1-3 heteroatoms selected from N, O and S, or a substituted or unsubstituted C4-C8 carbocycle; and / or two adjacent R6 and the ring atoms of ring B to which they are attached together form a substituted or unsubstituted 4-8 membered heterocycle containing 1-3 heteroatoms selected from N, O and S, or a substituted or unsubstituted C4-C8 carbocycle;

[0190] Z is -O-, -NH-, or C1-C3 alkylene;

[0191] R7, R8 and R9 are each independently: hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl; or R7, R8 and the adjacent N atom together form a substituted or unsubstituted 4-8 membered heterocycle;

[0192] W is -O-, -NH-, C1-C3 alkylene, -CHF-, -CF2-, -OCF2-, -CO-, -S-, -NCH3-, -CH(OH)-, -CHCH3-, -SO-, -SO2-, or -SO2NR3-;

[0193] a, b and c are each independently an integer from 0 to 7;

[0194] Wherein, the said substitution means being substituted by one or more substituents selected from the group consisting of: deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, phenyl, benzyl, hydroxyl, C1-C6 alkoxy.

[0195] In another preferred embodiment, the said ring B is selected from the group consisting of:

[0196]

[0197] In another preferred example, ring B is a benzoheteroaryl group.

[0198] In another preferred example, ring B is a benzoheteroaryl group, and the benzoheteroaryl group is connected through a phenyl group.

[0199] In another preferred example, the connecting site of ring B and the amide is on the benzene ring.

[0200] In another preferred example, Ry is selected from the group consisting of: hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, wherein the substituent is deuterium, halogen, hydroxyl, methoxy, methylthio, carboxyl, ester group, amide group, amino, substituted or unsubstituted phenyl, guanidyl, 5-6 membered heteroaryl, benzo 5-6 membered heteroaryl.

[0201] In another preferred example, Ry is selected from the following group: hydrogen, C1-C6 alkyl, halo C1-C6 alkyl, or hydroxyl-substituted C1-C6 alkyl.

[0202] In another preferred example, R4 is none, halogen, or C1-C6 alkyl.

[0203] In another preferred example, R5 is none, halogen, hydroxyl, cyano, C1-C6 alkoxy, C1-C6 carboxyl, C2-C6 ester group, or -O-C2-C6 ester group.

[0204] In another preferred example, R6 is none, halogen, hydroxyl, cyano, C1-C6 alkoxy, C1-C6 carboxyl, C2-C6 ester group, or -O-C2-C6 ester group.

[0205] In another preferred example, R4 is C1-C3 alkyl, preferably methyl.

[0206] In another preferred example, R5 is halogen, C1-C3 alkoxy, or C2-C4 ester group.

[0207] In another preferred example, two adjacent R5 and the ring atoms of ring C to which they are attached together form a substituted or unsubstituted 6-membered heterocycle containing 2 O heteroatoms.

[0208] In another preferred example, in the 6-membered heterocycle, two adjacent R5 form -O-CH2-CH2-O-.

[0209] In another preferred example, R6 is halogen, C1-C6 alkyl, or C1-C6 alkoxy.

[0210] In another preferred embodiment, W is -O-, -NH-, C1-C3 alkylene, -CF2-, -CO-, or -S-.

[0211] In another preferred embodiment, W is -O- or -S-.

[0212] In another preferred embodiment, a is 0, 1, or 2.

[0213] In another preferred embodiment, b is 0, 1, 2, or 3.

[0214] In another preferred embodiment, c is 0, 1, 2, or 3.

[0215] In another preferred embodiment, ring A is selected from

[0216] wherein,

[0217] for each case, a is independently 0, 1, 2, 3, or 4;

[0218] for each case, c is independently 0, 1, 2, 3, 4, or 5.

[0219] In another preferred embodiment, R4 is absent or selected from halogen, C1-C3 alkyl, C1-C3 alkoxy.

[0220] In another preferred embodiment, ring C is selected from phenyl, 5- or 6-membered heteroaryl.

[0221] In another preferred embodiment, ring C is selected from

[0222] In another preferred embodiment, R5 is absent or selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, -C(O)-O-C1-C3 alkyl; two adjacent or spaced R5s may optionally be linked to form a substituted or unsubstituted 5-6-membered carbocyclic ring, a substituted or unsubstituted 5-6-membered heterocyclic ring, a substituted or unsubstituted aryl, or a substituted or unsubstituted 5- or 6-membered heteroaryl; the carbocyclic or heterocyclic ring may be saturated or partially unsaturated.

[0223] "Pharmaceutically acceptable salts" refer to salts formed by the compounds of the present invention with acids or bases that are suitable for use as drugs. Pharmaceutically acceptable salts include inorganic salts and organic salts. Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, glutamic acid.

[0224] "Solvate" refers to a complex formed by the coordination of a compound of the present invention with solvent molecules in a specific ratio.

[0225] "Prodrug" includes those which may be biologically active or inactive per se, and which, when administered by an appropriate method, are metabolized or undergo a chemical reaction in the human body to be converted into a class of compounds of formula (I), or a salt or solution composed of a compound of formula (I). The prodrugs include (but are not limited to) carboxylic acid esters, carbonates, phosphates, nitrates, sulfates, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, etc. of the said compounds.

[0226] Preparation method

[0227] The preparation method of the compound of formula (I) of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily carried out by those skilled in the art to which the present invention pertains.

[0228] Typically, the preparation process flow of the compounds of the present invention is as shown in the examples of the present invention, and the raw materials and reagents used can be purchased through commercial channels without special instructions.

[0229] Pharmaceutical compositions and administration methods

[0230] Since the compounds of the present invention have excellent anti-tumor activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, as well as pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used for the treatment, prevention and alleviation of diseases related to tumors.

[0231] The pharmaceutical compositions of the present invention contain the compounds of the present invention or their pharmacologically acceptable salts and pharmacologically acceptable excipients or carriers within a safe and effective amount range. The "safe and effective amount" herein refers to: an amount of the compound sufficient to significantly improve the condition without causing serious side effects.

[0232] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatible" herein means that the components in the composition can be admixed with the compound of general formula (I) of the present invention, its pharmaceutically acceptable salts or solvates thereof, and with each other, without significantly reducing the efficacy of the active ingredient. Some examples of pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifying agents (such as ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0233] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.

[0234] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifying agents, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc. In addition to these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifying agents and suspending agents, sweetening agents, flavoring agents and fragrances.

[0235] In addition to the active ingredient, suspensions may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum monostearate and agar or mixtures of these substances, etc.

[0236] There is no particular limitation on the mode of administration of the compounds or pharmaceutical compositions of the present invention. Representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0237] Compositions for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyhydric alcohols and suitable mixtures thereof.

[0238] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).

[0239] The treatment method of the present invention can be administered alone, or in combination with other treatment means or therapeutic drugs.

[0240] Compared with the prior art, the present invention has the following main advantages:

[0241] (1) The compound has excellent PCNA function inhibitory activity.

[0242] (2) The compound has excellent solubility and stability.

[0243] (3) The compound has good metabolic stability and can resist the metabolism of hydrolytic enzymes and oxidase in vivo.

[0244] (4) The compound can be administered orally.

[0245] (5) The compound has good bioavailability.

[0246] (6) The compound has excellent selective inhibition or killing of tumor cells and low toxicity or no toxicity to normal cells.

[0247] The present invention will be further illustrated below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are usually carried out under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0248] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to persons skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the method of the present invention. The preferred methods and materials described herein are for illustrative purposes only.

[0249] Example 1: Synthesis of Compound 41004-84

[0250] The synthesis route is as follows:

[0251]

[0252] Synthesis of Intermediate 41004-84-01

[0253]

[0254] In a 250 mL three-necked flask, add 2-fluoro-3-nitropyridine (7.1 g, 0.05 mol, 1.0 eq.), 3-methoxyphenol (6.2 g, 0.05 mol, 1.0 eq.), potassium carbonate (13.8 g, 0.1 mol, 2.0 eq.) and 100 mL of DMF. Heat up to 50 °C and stir the reaction for 4 hours.

[0255] After the reaction is completed, add 500 mL of water to dissolve, then extract with 100 mL of ethyl acetate twice. Combine the organic phases and concentrate under reduced pressure to obtain a yellow oily substance. Then add 20 mL of dichloromethane to dissolve, add silica gel for sample mixing, concentrate to dryness under reduced pressure, and perform silica gel column chromatography. Use petroleum ether:ethyl acetate = 4:1 to elute the product. The obtained product is concentrated to dryness under reduced pressure to obtain 7.6 g of a yellow solid, with a yield of 61.8%.

[0256] Synthesis of Intermediate 41004-84-02

[0257]

[0258] In a 250 mL three-necked flask, add 41004-84-01 (7.6 g, 0.03 mol, 1.0 eq.), 10% wet palladium on carbon (0.8 g, 10% wt) and 100 mL of ethyl acetate. Stir at room temperature, exchange with hydrogen three times, and then stir overnight under hydrogen protection for 16 hours.

[0259] After the reaction is completed, filter, and concentrate the organic phase to dryness under reduced pressure to obtain 4.6 g of a pale yellow solid powder, with a yield of 71.0%.

[0260] Synthesis of 41004-84

[0261]

[0262] In a 250 mL three-necked flask, add 41004-87-03 (0.35 g, 0.0015 mol, 1.0 eq.), 41004-84-02 (0.32 g, 0.0015 mol, 1.0 eq.), EDCI (0.35 g, 0.0018 mol, 1.2 eq.), HOBT (0.24 g, 0.0018 mol, 1.2 eq.), triethylamine (0.45 g, 0.003 mol, 2.0 eq.) and 10 mL of dichloromethane. Protect with nitrogen and stir overnight at room temperature for 16 hours.

[0263] After detecting the completion of the reaction by LCMS, add silica gel for sample mixing, concentrate to dryness under reduced pressure, perform silica gel column chromatography, use petroleum ether:ethyl acetate = 2:1 to elute the product, and concentrate the product to dryness under reduced pressure to obtain 0.24 g of a white solid, with a yield of 37.4%.

[0264] LCMS: [M+1]+ = 428.0。

[0265] Example 2: Synthesis of Compound 41004-87

[0266] The synthetic route is as follows:

[0267]

[0268] Synthesis of Intermediate 41004-87-02

[0269]

[0270] Add 1-naphthoyl chloride (7.59 g, 0.04 mol, 1.0 eq.), triethylamine (8.34 g, 0.08 mol, 2.0 eq.) and 100 mL of dichloromethane to a 250 mL three-necked flask, and stir at room temperature. Then add tert-butyl glycinate (5.94 g, 0.044 mol, 1.1 eq.) dropwise. After the addition is complete, stir at room temperature overnight for 16 hours.

[0271] After the reaction is complete, filter, wash the filter cake with water three times to obtain 6.32 g of pale yellow solid powder, with a yield of 55.4%.

[0272] Synthesis of Intermediate 41004-87-03

[0273]

[0274] Add intermediate 41004-87-02 (5.7 g, 0.02 mol, 1.0 eq.) and 10 mL of dioxane to a 250 mL three-necked flask, and stir to dissolve at room temperature. Then add 4M hydrochloric acid dioxane solution dropwise. A large amount of white solid is produced during the addition. After stirring for half an hour, the white solid disappears and the reaction solution becomes a pale yellow transparent liquid.

[0275] After stirring at room temperature for 4 hours, the reaction ends. Directly concentrate under reduced pressure to obtain 3.5 g of the target crude product, with a yield of 76.4%.

[0276] Synthesis of Intermediate 41004-87-04

[0277]

[0278] Add 2-fluoro-3-nitropyridine (7.1 g, 0.05 mol, 1.0 eq.), 3,4-difluorophenol (6.5 g, 0.05 mol, 1.0 eq.), potassium carbonate (13.8 g, 0.1 mol, 2.0 eq.) and 100 mL of DMF to a 250 mL three-necked flask, and heat to 50 °C and stir for 5 hours.

[0279] After the reaction was completed, 500 mL of water was added for dissolution, and then it was extracted twice with 100 mL of ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain a yellow oily substance. Then, 20 mL of dichloromethane was added for dissolution, silica gel was added for sample mixing, and it was concentrated to dryness under reduced pressure. The silica gel column chromatography was carried out, and petroleum ether:ethyl acetate = 4:1 was used to elute the product. The obtained product was concentrated to dryness under reduced pressure to obtain 6.8 g of a white solid, with a yield of 54.0%.

[0280] Synthesis of Intermediate 41004-87-05

[0281]

[0282] 41004-87-04 (5.0 g, 0.04 mol, 1.0 eq.), 10% wet palladium carbon (0.5 g, 10% wt) and 100 mL of ethyl acetate were added to a 250 mL three-necked flask, stirred at room temperature, exchanged with hydrogen three times, and then stirred overnight for 16 hours under hydrogen protection.

[0283] After the reaction was completed, it was filtered, and the organic phase was concentrated to dryness under reduced pressure to obtain 3.5 g of a pale yellow solid powder, with a yield of 78.8%.

[0284] Synthesis of 41004-87

[0285]

[0286] 41004-87-03 (0.35 g, 0.0015 mol, 1.0 eq.), 41004-87-05 (0.33 g, 0.0015 mol, 1.0 eq.), EDCI (0.35 g, 0.0018 mol, 1.2 eq.), HOBT (0.24 g, 0.0018 mol, 1.2 eq.), triethylamine (0.45 g, 0.003 mol, 2.0 eq.) and 10 mL of dichloromethane were added to a 250 mL three-necked flask, protected by nitrogen, and stirred overnight for 16 hours at room temperature.

[0287] After the reaction was completed as detected by LCMS, silica gel was added for sample mixing, and it was concentrated to dryness under reduced pressure. The silica gel column chromatography was carried out, and petroleum ether:ethyl acetate = 2:1 was used to elute the product. The product was concentrated to dryness under reduced pressure to obtain 0.21 g of a white solid, with a yield of 32.3%.

[0288] LCMS: [M+1] + = 434.1.

[0289] 11H NMR (400 MHz, DMSO-d6) δ: 9.88 (s, 1H), 8.93 (t, 1H), 8.56 (d, 1H), 8.37 (d, 1H), 8.04 (d, 1H), 7.99 (d, 1H), 7.86 (d, 1H), 7.70 (d, 1H), 7.58 - 7.47 (m, 4H), 7.45 - 7.39 (m, 1H), 7.20 (dd, 1H), 7.10 (d, 1H), 4.27 (d, 2H).

[0290] Example 3: Synthesis of Compound 41004-92

[0291] The synthetic route is as follows:

[0292]

[0293] Synthesis of Intermediate 41004-92-01

[0294]

[0295] Add 2-fluoronitrobenzene (7.0 g, 0.05 mol, 1.0 eq.), 3-methoxyphenol (7.4 g, 0.06 mol, 1.2 eq.), cesium carbonate (16.3 g, 0.05 mol, 1.0 eq.) and 100 mL of acetonitrile to a 250 mL three-necked flask, and heat to 55 °C and stir for 2 hours.

[0296] After the reaction is completed, concentrate the reaction solution. Add the crude product to 150 mL of ethyl acetate, then wash it twice with 100 mL of water, concentrate it under reduced pressure to obtain a yellow oily substance, and then perform silica gel column chromatography. Use petroleum ether:ethyl acetate = 30:1 to elute the product. The obtained product is concentrated to dryness under reduced pressure to obtain 8.9 g of a white solid with a yield of 73.5%.

[0297] Synthesis of Intermediate 41004-92-02

[0298]

[0299] Add 41004-92-01 (2.0 g, 0.008 mol, 1.0 eq.), 5% wet palladium carbon (0.2 g, 10% wt) and 40 mL of methanol to a 250 mL three-necked flask, stir at room temperature, exchange with hydrogen three times, and then stir overnight for 16 hours under hydrogen protection.

[0300] After the reaction is completed, filter, concentrate the organic phase to dryness under reduced pressure to obtain 1.7 g of a pale yellow solid powder with a yield of 95.5%.

[0301] Synthesis of Intermediate 41004-92-03

[0302]

[0303] Add 41004-92-02 (0.5 g, 0.0023 mol, 1.0 eq.), Boc-glycine (0.41 g, 0.0023 mol, 1.0 eq.), HATU (1.32 g, 0.0035 mol, 1.5 eq.), DIEA (1.2 g, 0.009 mol, 4 eq.) and 10 mL of dichloromethane into a 250 mL three-necked flask. Under nitrogen protection, stir overnight at room temperature for 16 hours.

[0304] After the reaction was completed as detected by LCMS, the reaction solution was poured into ice water for liquid separation. The organic phase was dried and concentrated. The crude product was purified by silica gel column chromatography, and the product was eluted with petroleum ether: ethyl acetate = 3:1. The product was concentrated under reduced pressure to dryness to obtain 0.65 g of a white solid with a yield of 75.9%.

[0305] Synthesis of Intermediate 41004-92-04

[0306]

[0307] Add 41004-92-03 (0.65 g, 0.0017 mol, 1.0 eq.), trifluoroacetic acid (7 mL) and 20 mL of dichloromethane into a 100 mL single-necked flask. Stir at room temperature for 1 hour.

[0308] After the reaction was completed, add 20 mL of saturated sodium bicarbonate solution and wash twice. Extract with ethyl acetate. The organic phase was concentrated under reduced pressure to dryness to obtain 0.45 g of a pale yellow solid with a yield of 87%.

[0309] Synthesis of 41004-92

[0310]

[0311] Add 41004-92-04 (0.22 g, 0.0008 mol, 1.0 eq.), indazole-4-carboxylic acid (0.13 g, 0.0008 mol, 1.0 eq.), HATU (0.45 g, 0.0012 mol, 1.5 eq.), DIEA (0.41 g, 0.0032 mol, 4 eq.) and 10 mL of dichloromethane into a 250 mL three-necked flask. Under nitrogen protection, stir overnight at room temperature for 16 hours.

[0312] After the reaction was completed as detected by LCMS, the reaction solution was poured into ice water for liquid separation. The organic phase was dried and concentrated. The crude product was purified by silica gel column chromatography, and the product was eluted with petroleum ether: ethyl acetate = 1:1. The product was concentrated under reduced pressure to dryness to obtain 0.1 g of a white solid with a yield of 30%.

[0313] LCMS: [M+1] += 417.1。

[0314] 1 1H NMR (400 MHz, DMSO-d6) δ: 13.23 (s, 1H), 9.50 (s, 1H), 8.84 (t, 1H), 8.36 (s, 1H), 8.12 (d, 1H), 7.71 (d, 1H), 7.57 (d, 1H), 7.40 (t, 1H), 7.22 (t, 1H), 7.12 - 7.07 (m, 2H), 6.89 (d, 1H), 6.67 (d, 1H), 6.52 - 6.46 (m, 2H), 4.13 (d, 2H), 3.68 (s, 3H).

[0315] Example 4: Synthesis of Compound 41004-97

[0316] The synthetic route is as follows:

[0317]

[0318] Add 41004-92-04 (0.22 g, 0.001 mol, 1.0 eq.), indole-4-carboxylic acid (0.14 g, 0.001 mol, 1.0 eq.), HATU (0.45 g, 0.0012 mol, 1.2 eq.), DIEA (0.52 g, 0.004 mol, 4 eq.) and 10 mL of dichloromethane into a 250 mL three-necked flask. Under nitrogen protection, stir overnight at room temperature for 16 hours.

[0319] After detecting the completion of the reaction by LCMS, pour the reaction solution into ice water for liquid separation. The organic phase is dried and concentrated. The crude product is purified by silica gel column chromatography, and the product is eluted with petroleum ether: ethyl acetate = 1:1. The product is concentrated under reduced pressure to dryness to obtain 0.12 g of a white solid, with a yield of 28.9%.

[0320] LCMS: [M+1] + = 416.1。

[0321] 1 1H NMR (400 MHz, DMSO-d6) δ: 11.28 (s, 1H), 9.49 (s, 1H), 8.53 (s, 1H), 8.16 (d, 1H), 7.55 (d, 1H), 7.43 - 7.19 (m, 2H), 7.24 (t, 1H), 7.14 - 7.04 (m, 3H), 6.92 - 6.86 (m, 2H), 6.70 (d, 1H), 6.54 - 6.48 (m, 2H), 6.67 (d, 1H), 6.52 - 6.46 (m, 2H), 4.12 (d, 2H), 3.67 (s, 3H).

[0322] Example 5: Synthesis of Compound 41004-109 (also known as JBP4-002)

[0323] The synthesis route is as follows:

[0324]

[0325] Synthesis of Intermediate JBP4-002.1

[0326]

[0327] Dissolve JBP4-006.1 (600 mg, 3.41 mmol, 1.0 eq.) in DMF (15 mL), add NaH (163 mg, purity 60%, 4.07 mmol, 1.2 eq.) at 0 °C, stir the mixture at 0 °C for 1 hour, and then add 2-bromoacetamide (517 mg, 3.75 mmol, 1.1 eq.). Warm up to 30 °C and stir the reaction for 2 hours.

[0328] After the reaction is completed, quench with ice water and extract with ethyl acetate. Concentrate and dry the organic phase to obtain the crude product. Purify the crude product by silica gel column chromatography, elute the product with petroleum ether:ethyl acetate = 1:9 to obtain 250 mg of white solid, with a yield of 28%.

[0329] 1 H NMR (400 MHz, DMSO-d6): δ 8.39 (s, 1H), 7.94 - 7.84 (m, 2H), 7.61 (s, 1H), 7.54 - 7.50 (m, 1H), 7.28 (s, 1H), 5.14 (s, 2H), 3.96 (s, 3H).

[0330] Synthesis of Intermediate JBP4-002.2

[0331]

[0332] Dissolve JBP4-002.1 (250 mg, purity 90%, 0.965 mmol, 1.0 eq.) in a mixed solvent of THF / MeOH / H2O (6 mL, 1 / 1 / 1), and then add LiOH·H2O (81 mg, 1.9 mmol, 2.0 eq.). Stir the reaction at 30 °C for 3 hours.

[0333] After the reaction is completed, concentrate the reaction solution in vacuo to obtain 200 mg of white solid, with a yield of 82%.

[0334] LCMS: [M+1] + = 220.1.

[0335] Synthesis of JBP4-002

[0336]

[0337] In a 25 mL three-necked flask, JBP4-002.2 (100 mg, purity 87%, 0.397 mmol, 1.0 eq.), JBP4-017.5 (156 mg, purity 100%, 0.476 mmol, 1.2 eq.) and DMF (2 mL) were added. The mixture was cooled to 0 °C, and then DIEA (256 mg, 1.98 mmol, 5.0 eq.) and HATU (226 mg, 0.594, 1.5 eq.) were added successively. Under nitrogen protection, the reaction was stirred at 30 °C for 2 hours.

[0338] After the reaction was completed, water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and dried in vacuo to obtain the crude product, which was purified by prep-HPLC (acetonitrile: 0.1% aqueous ammonium bicarbonate solution = 5% - 95%) to obtain 65.8 mg of a white solid with a yield of 33%.

[0339] LCMS: [M+1] + = 493.1.

[0340] 1 1H NMR (400 MHz, DMSO-d6): δ 9.86 (s, 1H), 8.94 (t, J = 6.0 Hz, 1H), 8.49 (dd, J1 = 8.0 Hz, J2 = 1.6 Hz, 1H), 8.39 (s, 1H), 7.83 - 7.78 (m, 2H), 7.67 (d, J = 7.2 Hz, 1H), 7.58 (s, 1H), 7.49 - 7.45 (m, 1H), 7.26 - 7.21 (m, 2H), 7.12 (dd, J1 = 8.0 Hz, J2 = 4.8 Hz, 1H), 7.02 (dd, J1 = 7.6 Hz, J2 = 2.8 Hz, 1H), 6.73 - 6.69 (m, 1H), 5.11 (s, 2H), 4.26 (d, J = 6.0 Hz, 2H), 3.80 (s, 3H).

[0341] Example 6: Synthesis of Compound 41004-110 (also known as JBP4-003)

[0342] The synthesis route is as follows:

[0343]

[0344] Synthesis of Intermediate JBP4-003.2

[0345]

[0346] JBP4-003.1 (1250 mg, 1.60 mmol, 1.0 eq.) was added to a 100 mL three-necked flask equipped with a reflux condenser, along with 4-fluoro-3-methoxyphenol (252 mg, 1.77 mmol, 1.1 eq.), ACN (30 mL), and potassium carbonate (389 mg, 2.81 mmol, 1.8 eq.). Under nitrogen protection, the temperature was raised to 80 °C and the mixture was stirred for 8 hours.

[0347] After completion of the reaction, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and dried under vacuum to obtain a dark red solid. The solid was slurried with petroleum ether, filtered, and dried to obtain 400 mg of a dark red solid with a yield of 72%.

[0348] LCMS: [M+1] + = 279.1.

[0349] Synthesis of Intermediate JBP4-003.3

[0350]

[0351] JBP4-003.2 (400 mg, purity 80%, 1.15 mmol, 1.0 eq.) was added to a 50 mL single-necked flask equipped with a reflux condenser, along with Fe (370 mg, 6.62 mmol, 5.8 eq.), THF (5 mL), MeOH (5 mL), and NH4Cl (709 mg, 13.2 mmol, 11.5 eq.). Under nitrogen protection, the temperature was raised to 65 °C and the mixture was stirred for 2 hours.

[0352] After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated to obtain a brown solid. The crude product was purified by silica gel column chromatography, eluting the product with petroleum ether / ethyl acetate = 25 - 40%. The product was concentrated and dried under reduced pressure to obtain 300 mg of an off-white solid with a yield of 90%.

[0353] LCMS: [M+1] + = 249.1.

[0354] Synthesis of Intermediate JBP4-003.4

[0355]

[0356] JBP4-003.3 (300 mg, purity 86%, 1.04 mmol, 1.0 eq.) was added to a 25 mL three-necked flask, followed by (tert-butylcarbonyl)glycine (333 mg, 1.90 mmol, 1.8 eq) and DMF (5 mL). The mixture was cooled to 0 °C in an ice-water bath, and then DIEA (273 mg, 2.11 mmol, 2.0 eq.) and HATU (600 mg, 1.58 mmol, 1.5 eq.) were added successively. The reaction was stirred at 25 °C for 2 hours.

[0357] After the reaction was completed, water (50 mL) was added and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was washed with brine (80 mL × 2), dried over anhydrous Na2SO 4(s) and filtered. The filtrate was concentrated and dried in vacuo to obtain a brown oil, which was purified by passing through a C18 column (acetonitrile / water = 45 - 70%) to give 400 mg of an off-white solid with a yield of 90%.

[0358] LCMS: [M+1] + = 406.3.

[0359] Synthesis of Intermediate JBP4-003.5

[0360]

[0361] JBP4-003.4 (400 mg, purity 95%, 0.937 mmol, 1.0 eq.) was added to a 50 mL single-necked flask, and 4 M HCl / dioxane (5 mL) was added at 0 °C. The reaction was stirred at 25 °C for 4 hours.

[0362] After the reaction was completed, the reaction mixture was concentrated under reduced pressure, slurried with petroleum ether, filtered, and dried to obtain 300 mg of an off-white solid with a yield of 94%.

[0363] LCMS: [M+1] + = 306.1.

[0364] Synthesis of JBP4-003

[0365]

[0366] In a 25 mL three-necked flask, JBP4-003.5 (100 mg, purity 100%, 0.293 mmol, 1.0 eq.), 1-methyl-1H-indazole-4-carboxylic acid (52 mg, 0.30 mmol, 1.0 eq.), HATU (181 mg, 0.476 mmol, 1.6 eq.), DIEA (128 mg, 0.990 mmol, 3.4 eq.) and DMF (2 mL) were added. Under nitrogen protection, the mixture was stirred overnight at room temperature.

[0367] After the reaction was completed, the reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried and concentrated, and the crude product was purified by prep-HPLC (acetonitrile: 0.1% aqueous ammonium bicarbonate solution = 0% - 90%) to obtain 37.3 mg of a white solid with a yield of 27.2%.

[0368] LCMS: [M+1] + = 464.1.

[0369] 1 H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.92 - 8.89 (m, 1H), 8.37 (m, 1H), 7.88 - 7.83 (m, 2H), 7.69 - 7.67 (m, 1H), 7.51 - 7.47 (m, 1H), 7.22 - 7.17 (m, 1H), 7.06 - 7.04 (m, 1H), 6.90 - 6.87 (m, 1H), 6.64 - 6.60 (m, 1H), 4.18 - 4.16 (m, 2H), 4.08 (s, 3H), 3.78 (m, 3H), 2.25 (s, 3H).

[0370] Example 7: Synthesis of Compound 41004-111 (also known as JBP4-004)

[0371] The synthetic route is as follows:

[0372]

[0373] Synthesis of Intermediate JBP4-004.2

[0374]

[0375] At 30 °C, JBP4-004.1 (500 mg, 3.59 mmol, 1.0 eq.) and 4-chloro-3-methoxyphenol (570 mg, 3.59 mmol, 1.0 eq.) were dissolved in ACN (10 mL), and then potassium carbonate (994 mg, 7.19 mmol, 2.0 eq.) was added. The temperature was raised to 80 °C and the mixture was stirred overnight.

[0376] After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated and dried to obtain 1.3 g of a white solid with a yield of 95%.

[0377] LCMS: [M+1] + = 278.1.

[0378] Synthesis of Intermediate JBP4-004.3

[0379]

[0380] At 30 °C, JBP4-004.2 (1.3 g, purity 73%, 3.42 mmol, 1.0 eq.) was dissolved in IPA (10 mL), and then hydrazine (1 mL) was added. The temperature was raised to 80 °C and stirred overnight.

[0381] After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated and dried to obtain a crude product. The crude product was purified by prep-HPLC (acetonitrile: 0.1% aqueous ammonium bicarbonate solution = 0% - 90%) to obtain 600 mg of a white solid with a yield of 61%.

[0382] LCMS: [M+1] + = 290.1.

[0383] Synthesis of JBP4-004

[0384]

[0385] JBP4-004.3 (500 mg, purity 100%, 1.73 mmol, 1.0 eq.) and (1-methyl-1H-indazole-4-carbonyl) glycine (400 mg, 1.72 mmol, 1.0 eq.) were dissolved in pyridine (10 mL). The mixture was cooled to 0 °C, and then BOP-Cl (1.30 g, 5.11 mmol, 3.0 eq.) was added. The temperature was raised to room temperature and stirred overnight.

[0386] After the reaction was completed, water (30 mL) was added and extracted twice with ethyl acetate (30 mL). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and dried in vacuo to obtain a crude product. The crude product was purified by prep-HPLC (acetonitrile: 0.1% aqueous ammonium bicarbonate solution = 0% - 90%) to obtain 115 mg of a white solid with a yield of 12.8%.

[0387] LCMS: [M+1] + = 505.1.

[0388] 11H NMR (400 MHz, DMSO-d6): δ 12.95 (s, 1H), 9.87 (s, 1H), 8.77 (s, 1H), 8.33 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 6.8 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.30 - 7.23 (m, 3H), 6.87 (br s, 1H), 6.50 - 6.45 (m, 2H), 4.08 - 4.06 (m, 5H), 3.77 (s, 3H).

[0389] Example 8: Synthesis of Compound 41004-112 (also known as JBP4-005)

[0390] The synthetic route is as follows:

[0391]

[0392] Synthesis of Intermediate JBP4-005.2

[0393]

[0394] Dissolve JBP4-005.1 (300 mg, 2.32 mmol, 1.0 eq.) and 4-chloro-3-methoxyphenol (551 mg, 3.47 mmol, 1.5 eq.) in DMF (6 mL), and then add potassium carbonate (974 mg, 7.05 mmol, 3.0 eq.). Replace the air with nitrogen three times, heat to 100 °C and stir for reaction for 16 hours.

[0395] After the reaction is completed, add water (20 mL) and extract with ethyl acetate (30 mL x 3). Wash the organic phase with brine (50 mL x 2), dry over anhydrous sodium sulfate, and filter. Concentrate and dry the filtrate to obtain a yellow oil. Purify the crude product by silica gel column chromatography, elute the product with ethyl acetate / petroleum ether = 30 - 45%, and obtain 350 mg of a colorless oil with a yield of 60%.

[0396] LCMS: [M+1] + = 252.1.

[0397] Synthesis of Intermediate JBP4-005.3

[0398]

[0399] JBP4-005.2 (350 mg, purity 100%, 1.39 mmol, 1.0 eq.) and {[(tert-butoxy)carbonyl]amino}acetic acid (463 mg, 2.64 mmol, 1.9 eq.) were dissolved in DMF (8 mL). The mixture was cooled to 0 °C, and then DIEA (683 mg, 5.28 mmol, 3.8 eq.) and HATU (1.04 g, 2.74 mmol, 2.0 eq.) were added successively. The temperature was raised to 25 °C and the reaction was stirred for 16 hours.

[0400] After the reaction was completed, water (20 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with brine (60 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and dried to obtain a yellow oil. The crude product was purified by a C18 chromatographic column (acetonitrile / water = 45 - 70%) to obtain 500 mg of a colorless oil with a yield of 84%.

[0401] LCMS: [M+1] + = 409.3.

[0402] Synthesis of Intermediate JBP4-005.4

[0403]

[0404] JBP4-005.3 (500 mg, purity 96%, 1.17 mmol, 1.0 eq.) was dissolved in DCM (3 mL). 4M HCl / dioxane (3.5 mL) was added at 0 °C. The temperature was raised to 25 °C and the reaction was stirred for 4 hours.

[0405] After the reaction was completed, the reaction solution was concentrated and dried to obtain 450 mg of an off-white solid with a yield of 71%.

[0406] LCMS: [M+1] + = 309.1.

[0407] Synthesis of JBP4-005

[0408]

[0409] JBP4-005.4 (200 mg, purity 64%, 0.371 mmol, 1.0 eq.) and 1H-indazole-4-carboxylic acid (85 mg, 0.52 mmol, 1.4 eq.) were dissolved in DMF (6 mL). The mixture was cooled to 0 °C, and then DIEA (270 mg, 2.09 mmol, 5.6 eq.) and HATU (397 mg, 1.04 mmol, 2.8 eq.) were added successively. The temperature was raised to 25 °C and the reaction was stirred for 0.5 hour.

[0410] After the reaction was completed, water (20 mL) was added and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and dried to obtain a yellow oil. The crude product was purified by prep-HPLC ((XBridge C18 3.5 μm, 50 * 4.6 mm; 5-95% (v / v) acetonitrile / water (0.05% NH4HCO3)) to obtain 28.6 mg of a white solid with a yield of 17%.

[0411] LCMS: [M+1] + = 453.0.

[0412] 1 1H NMR (400 MHz, DMSO-d6): δ 13.26 (br s, 1H), 10.16 (br s, 1H), 9.29 (s, 1H), 8.90 (t, J = 5.6 Hz, 1H), 8.46 (s, 1H), 8.41 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 6.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.44 (t, J = 7.2 Hz, 1H), 7.14 (d, J = 2.4 Hz, 2H), 6.90 (dd, J = 8.8 Hz, J = 2.8 Hz, 1H), 4.29 (d, J = 5.6 Hz, 2H), 3.83 (s, 3H).

[0413] Example 9: Synthesis of Compound 41004-113 (also known as JBP4-006)

[0414] The synthetic route is as follows:

[0415]

[0416] Synthesis of Intermediate JBP4-006.2

[0417]

[0418] At room temperature, JBP4-006.1 (500 mg, 2.84 mmol, 1.0 eq.) was dissolved in DMF (10 mL), and then potassium carbonate (785 mg, 5.68 mmol, 2.0 eq.) and 1-iodo-2-methylpropane (783 mg, 4.25 mmol, 1.5 eq.) were added. The temperature was raised to 60 °C and the mixture was stirred for 4 hours.

[0419] After the reaction was completed, water was added and the mixture was extracted with ethyl acetate. The organic phase was concentrated and dried to obtain a crude product. The crude product was purified by silica gel column chromatography, and the product was eluted with petroleum ether:ethyl acetate = 10:1 to obtain 250 mg of a yellow oil with a yield of 34%.

[0420] 1 1H NMR (400 MHz, CDCl3): δ 8.49 (s, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 4.22 (d, J = 7.2 Hz, 2H), 4.02 (s, 3H), 2.39 - 2.32 (m, 1H), 0.93 (d, J = 6.8 Hz, 6H).

[0421] Synthesis of Intermediate JBP4-006.3

[0422]

[0423] At 30 °C, JBP4 - 006.2 (250 mg, purity 90%, 0.969 mmol, 1.0 eq.) was dissolved in a mixed solvent of THF / MeOH / H2O = 1 / 1 / 1 (6 mL), then sodium hydroxide (116 mg, 2.90 mmol, 3.0 eq.) was added, and then the mixture was stirred and reacted for 2 hours.

[0424] After the reaction was completed, the reaction solution was acidified to pH = 6 - 7 with 1 M hydrochloric acid, and then extracted with ethyl acetate. The organic phase was concentrated and dried to obtain 200 mg of a yellow solid, with a yield of 84%.

[0425] LCMS: [M + 1] + = 219.1.

[0426] Synthesis of JBP4-006

[0427]

[0428] JBP4 - 006.3 (100 mg, purity 89%, 0.408 mmol, 1.1 eq.) and JBP4 - 014.5 (126 mg, 91% purity, 0.370 mmol, 1.0 eq.) were dissolved in DMF (2 mL), then DIEA (264 mg, 2.04 mmol, 5.5 eq.) and HATU (233 mg, 0.613 mmol, 1.7 eq.) were added. Then the mixture was stirred and reacted at 30 °C for 2 hours.

[0429] After the reaction was completed, the reaction solution was extracted with ethyl acetate and water. The organic phase was concentrated and dried to obtain a crude product, and the crude product was purified by prep - HPLC (acetonitrile: 0.1% aqueous ammonium bicarbonate solution = 5% - 95%) to obtain 68 mg of a white solid, with a yield of 39%.

[0430] LCMS: [M + 1] + = 474.2.

[0431] 1 1H NMR (400 MHz, CDCl3): δ 8.71 (dd, J1 = 8.0 Hz, J2 = 1.6 Hz, 1H), 8.55 (s, 1H), 8.46 (s, 1H), 7.88 (dd, J1 = 4.8 Hz, J2 = 1.6 Hz, 1H), 7.59 - 7.54 (m, 2H), 7.39 (dd, J1 = 8.4 Hz, J2 = 7.2 Hz, 1H), 7.29 (t, J = 8.4 Hz, 1H), 7.10 - 7.01 (m, 2H), 6.79 - 6.70 (m, 3H), 4.44 (d, J = 5.6 Hz, 2H), 4.21 (d, J = 7.2 Hz, 2H), 3.79 (s, 3H), 2.39 - 2.30 (m, 1H), 0.92 (d, J = 6.8 Hz, 6H).

[0432] Example 10: Synthesis of Compound 41004 - 114 (also known as JBP4 - 007) and Compound 41004 - 115 (also known as JBP4 - 008)

[0433] The synthetic route is as follows:

[0434]

[0435] Synthesis of Intermediate JBP4 - 007.2

[0436]

[0437] Dissolve JBP4 - 014.5 (500 mg, purity 90%, 1.45 mmol, 1.0 eq.) in DMF (5 mL), add triethylamine (692 mg, 6.84 mmol, 4.7 eq.) at 0 °C, and then slowly dropwise add JBP4 - 007.1 (784 mg, 3.57 mmol, 2.5 eq.). Then warm up to 30 °C and stir the reaction for 2 hours.

[0438] After the reaction is completed, add water and extract with ethyl acetate. The organic phase is concentrated and dried to obtain a crude product. The crude product is purified by silica gel column chromatography, and the product is eluted with petroleum ether:ethyl acetate = 5:1 to obtain 500 mg of a white solid with a yield of 68%.

[0439] 11H NMR (400 MHz, CDCl3): δ 8.67 (d, J = 9.2 Hz, 1H), 8.45 (s, 1H), 7.97 (t, J = 1.6 Hz, 1H), 7.88 (dd, J1 = 5.2 Hz, J2 = 2.0 Hz, 1H), 7.74 - 7.64 (m, 2H), 7.33 - 7.28 (m, 2H), 7.04 - 6.99 (m, 2H), 6.80 - 6.70 (m, 3H), 4.36 (d, J = 5.2 Hz, 2H), 3.80 (s, 3H).

[0440] Synthesis of JBP4-007

[0441]

[0442] At room temperature, JBP4 - 007.2 (200 mg, purity 90%, 0.394 mmol, 1.0 eq.) and JBP4 - 007.3 (75 mg, 0.60 mmol, 1.5 eq.) were dissolved in 1,4 - dioxane (5 mL), then Pd(dppf)Cl2 (29 mg, 0.039 mmol, 0.1 eq.) and sodium carbonate (84 mg, 0.79 mmol, 2.0 eq.) were added. Under nitrogen protection, the temperature was raised to 90 °C and the mixture was stirred for 8 hours.

[0443] After the reaction was completed, water was added and the mixture was extracted with ethyl acetate. The organic phase was concentrated and dried to obtain a crude product, which was purified by prep - HPLC (acetonitrile: 0.1% aqueous ammonium bicarbonate solution = 5% - 95%) to obtain 95.3 mg of a white solid with a yield of 53%.

[0444] LCMS: [M + 1] + = 458.1.

[0445] 1 1H NMR (400 MHz, CDCl3): δ 8.74 (s, 1H), 8.70 - 8.67 (m, 1H), 7.91 - 7.74 (m, 4H), 7.63 (s, 1H), 7.55 - 7.44 (m, 2H), 7.27 (t, J = 8.4 Hz, 1H), 7.02 (dd, J1 = 7.6 Hz, J2 = 4.8 Hz, 1H), 6.77 - 6.70 (m, 3H), 4.40 (d, J = 5.2 Hz, 2H), 3.77 (s, 3H), 2.40 (s, 3H).

[0446] Synthesis of JBP4-008

[0447]

[0448] JBP4-007.2 (200 mg, purity 90%, 0.394 mmol, 1.0 eq.) and JBP4-008.1 (134 mg, 0.788 mmol, 2.0 eq.) were dissolved in 1,4-dioxane / water (4:1, 5 mL), and then sodium carbonate (125 mg, 1.18 mmol, 3.0 eq.) and Pd(dppf)Cl2 (29 mg, 0.039 mmol, 0.1 eq.) were added. Under nitrogen protection, the temperature was raised to 90 °C and the reaction was stirred for 8 hours.

[0449] After the reaction was completed, water was added and the mixture was extracted with ethyl acetate. The organic phase was concentrated and dried to obtain a crude product, which was purified by prep-HPLC (acetonitrile: 0.1% aqueous ammonium bicarbonate solution = 5% - 95%) to obtain 63 mg of a white solid with a yield of 31%.

[0450] LCMS: [M+1] + = 502.1.

[0451] 1H NMR (400 MHz, CDCl3): δ 8.67 (dd, J1 = 7.6 Hz, J2 = 1.2 Hz, 1H), 8.59 (s, 1H), 7.88 - 7.79 (m, 3H), 7.58 - 7.47 (m, 2H), 7.33 - 7.28 (m, 1H), 7.25 - 7.22 (m, 1H), 7.03 - 6.99 (m, 2H), 6.82 - 6.69 (m, 5H), 4.36 (d, J = 5.6 Hz, 2H), 3.77 - 3.76 (m, 6H).

[0452] Example 11: Synthesis of Compound 41004-116 (also known as JBP4-009)

[0453] The synthetic route is as follows:

[0454]

[0455] Synthesis of Intermediate JBP4-009.2

[0456]

[0457] JBP4-009.1 (500 mg, 2.44 mmol, 1.0 eq.), DMF (3 mL), potassium carbonate (785 mg, 5.68 mmol, 2.3 eq.) and methyl iodide (692 mg, 4.88 mmol, 2.0 eq.) were successively added to a 50 mL round-bottom flask. The temperature was raised to 60 °C and the reaction was stirred for 4 hours.

[0458] After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography, and the product was eluted with petroleum ether:ethyl acetate = 10:1. The obtained product was concentrated to dryness under reduced pressure to obtain 500 mg of a yellow oil, with a yield of 94%.

[0459] LCMS: [M+1] + = 220.1

[0460] Synthesis of Intermediate JBP4-009.3

[0461]

[0462] JBP4-009.2 (250 mg, purity 100%, 1.14 mmol, 1.0 eq.) was dissolved in a mixed solution of THF / MeOH / H2O = 1 / 1 / 1 (6 mL), and then sodium hydroxide (116 mg, 2.90 mmol, 2.5 eq.) was added. The reaction was stirred at 30 °C for 2 hours.

[0463] After the reaction was completed, the reaction solution was acidified to pH = 6 - 7 with 1 M hydrochloric acid and then extracted with ethyl acetate. The organic phase was concentrated and dried to obtain 200 mg of a yellow solid, with a yield of 85%.

[0464] LCMS: [M+1] + = 206.1

[0465] Synthesis of JBP4-009

[0466]

[0467] JBP4-014.5 (100 mg, purity 90%, 0.291 mmol, 1.0 eq.), JBP4-009.3 (75 mg, purity 100%, 0.37 mmol, 1.3 eq.) and HATU (209 mg, 0.550 mmol, 1.9 eq.) were dissolved in DMF (2 mL). The mixture was cooled to 0 °C, and then DIEA (148 mg, 1.45 mmol, 5.0 eq.) was added. Under nitrogen protection, the reaction was stirred at room temperature overnight.

[0468] After the reaction was completed, water (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to dryness in vacuo to obtain the crude product. The crude product was purified by prep-HPLC (acetonitrile:0.1% aqueous ammonium bicarbonate solution = 0% to 90%) to obtain 60.8 mg of a white solid, with a yield of 45%.

[0469] LCMS: [M+1] + = 461.1

[0470] 1H NMR (400 MHz, DMSO-d6): δ 9.76 (s, 1H), 8.52 - 8.49 (m, 1H), 8.33 - 8.30 (m, 1H), 7.97 (s, 1H), 7.82 - 7.81 (m, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.28 (t, J = 8.4 Hz, 1H), 7.14 - 7.11 (m, 1H), 6.86 - 6.84 (m, 1H), 6.80 - 6.77 (m, 2H), 6.70 - 6.67 (m, 1H), 4.15 - 4.13 (m, 2H), 3.79 (s, 3H), 3.73 - 3.72 (m, 6H).

[0471] Example 12: Synthesis of Compound 41004 - 117 (also known as JBP4 - 010)

[0472] The synthetic route is as follows:

[0473]

[0474] Dissolve JBP4 - 010.1 (60 mg, 0.34 mmol, 1.0 eq.), JBP4 - 017.5 (110 mg, purity 100%, 0.34 mmol, 1.0 eq.) and HATU (256 mg, 0.673 mmol, 2.0 eq.) in DMF (2 mL), add DIEA (87 mg, 0.67 mmol, 2.0 eq.) at 0 °C and stir the reaction for 2 hours.

[0475] After the reaction is completed, pour the reaction solution into water (20 mL) and extract twice with ethyl acetate (30 mL). The organic phase is dried over anhydrous sodium sulfate, filtered. The filtrate is concentrated and dried to obtain the crude product, and the crude product is purified by prep - HPLC (acetonitrile: 0.1% aqueous ammonium bicarbonate solution = 0% to 90%) to obtain 65 mg of white solid, with a yield of 43%.

[0476] LCMS: [M + 1] + = 452.0.

[0477] 1H NMR (400 MHz, DMSO-d6): δ 9.94 (s, 1H), 9.32 - 9.30 (m, 1H), 8.47 - 8.45 (m, 1H), 7.84 - 7.82 (m, 1H), 7.70 - 7.63 (m, 3H), 7.27 - 7.22 (m, 1H), 7.14 - 7.11 (m, 1H), 7.04 - 7.02 (m, 1H), 6.75 - 6.71 (m, 1H), 6.54 (s, 2H), 4.27 (d, J = 5.6 Hz, 2H), 3.81 (s, 3H).

[0478] Example 13: Synthesis of Compound 41004 - 118 (also known as JBP4 - 011)

[0479] The synthetic route is as follows:

[0480]

[0481] Synthesis of Intermediate JBP4-011.1

[0482]

[0483] Add JBP4 - 014.3 (600 mg, purity 88%, 2.44 mmol, 1.0 eq.), (tert - butylcarbonyl)-L - alanine (630 mg, 3.33 mmol, 1.4 eq.) and DMF (5 mL) into a 25 mL three - necked flask, cool to 0 °C, and then successively add DIEA (546 mg, 4.22 mmol, 1.7 eq.) and HATU (1.20 g, 3.16 mmol, 1.3 eq.). Under nitrogen protection, stir the reaction at 25 °C for 2 hours.

[0484] After the reaction is completed, pour the reaction solution into water (50 mL) and extract with ethyl acetate (30 mL × 3). Wash the organic phase with brine (80 mL × 2), dry and concentrate to obtain a brown oil. The crude product is purified by a C18 chromatographic column (acetonitrile / water = 45 - 70%) to obtain 1.0 g of an off - white solid, with a yield of 97%.

[0485] LCMS: [M + 1] + = 388.3.

[0486] Synthesis of Intermediate JBP4-011.2

[0487]

[0488] Add JBP4-011.1 (1.00 g, purity 92%, 2.37 mmol, 1.0 eq.) and DCM (5 mL) to a 50 mL single-necked flask, cool to 0 °C, and then add 4 M hydrochloric acid / dioxane (5 mL). Under nitrogen protection, stir the reaction at 25 °C for 4 hours.

[0489] After the reaction is completed, concentrate the reaction solution in vacuo to obtain an off-white solid. The solid is slurried with petroleum ether and filtered to obtain 700 mg of an off-white solid, with a yield of 91%.

[0490] LCMS: [M+1] + = 288.2.

[0491] Synthesis of JBP4-011

[0492]

[0493] Add JBP4-011.2 (150 mg, purity 100%, 0.463 mmol, 1.0 eq.), 1H-indole-4-carboxylic acid (75 mg, 0.463 mmol, 1.0 eq.), HATU (181 mg, 0.476 mmol, 1.03 eq.) and DMF (2 mL) to a 25 mL three-necked flask. Cool the mixture to 0 °C, and then add DIEA (128 mg, 0.990 mmol, 2.1 eq.). Under nitrogen protection, stir the reaction overnight at room temperature.

[0494] After the reaction is completed, add water (30 mL) and extract with ethyl acetate (30 mL × 2). The organic phase is dried over anhydrous Na2SO4 and filtered. The filtrate is concentrated and dried in vacuo to obtain the crude product. The crude product is purified by prep-HPLC (acetonitrile: 0.1% aqueous ammonium bicarbonate solution = 0% - 90%) to obtain 81.8 mg of a white solid, with a yield of 40%.

[0495] LCMS: [M+1] + = 432.1.

[0496] 1H NMR: (400 MHz, DMSO-d6): δ 13.24 (s, 1H), 9.79 (s, 1H), 8.81 (d, J = 7.2 Hz, 1H), 8.50 - 8.48 (m, 1H), 8.36 (s, 1H), 7.84 - 7.83 (m, 1H), 7.73 - 7.67 (m, 2H), 7.40 (t, J = 8.0 Hz, 1H), 7.29 (t, J = 8.4 Hz, 1H), 7.15 - 7.12 (m, 1H), 6.80 - 6.68 (m, 3H), 4.92 - 4.85 (m, 1H), 3.73 (s, 3H), 1.48 (d, J = 7.2 Hz, 3H).

[0497] Example 14: Synthesis of Compound 41004-119 (also known as JBP4-012)

[0498] The synthesis route is as follows:

[0499]

[0500] Synthesis of Intermediate JBP4-012.1

[0501]

[0502] Add JBP4-014.3 (200 mg, purity 88%, 0.814 mmol, 1.0 eq.), (tert-Butoxycarbonyl)-L-leucine (213 mg, 0.921 mmol, 1.1 eq.) and DMF (3 mL) into a 25 mL three-necked flask, cool to 0 °C, and then successively add DIEA (374 mg, 3.89 mmol, 4.8 eq.) and HATU (527 mg, 1.39 mmol, 1.7 eq.). Under nitrogen protection, stir the reaction at 25 °C for 2 hours.

[0503] After the reaction is completed, pour the reaction solution into water (50 mL) and extract with ethyl acetate (30 mL × 3). Wash the organic phase with brine (80 mL × 2), dry and concentrate to obtain a brown oil. The crude product is purified by a C18 chromatographic column (acetonitrile / water = 45-70%) to obtain 360 mg of an off-white solid, with a yield of 95%.

[0504] LCMS: [M+1] + = 430.4

[0505] Synthesis of Intermediate JBP4-012.2

[0506]

[0507] Add JBP4-012.1 (360 mg, purity 92%, 0.771 mmol, 1.0 eq.) and DCM (5 mL) into a 50 mL single-necked flask, cool to 0 °C, and then add 4M hydrochloric acid / dioxane (5 mL). Under nitrogen protection, stir the reaction at 25 °C for 4 hours.

[0508] After the reaction is completed, concentrate the reaction solution in vacuo to obtain an off-white solid. The solid is slurried with petroleum ether and filtered to obtain 300 mg of an off-white solid, with a yield of 86%.

[0509] LCMS: [M+1] + = 330.2

[0510] Synthesis of JBP4-012

[0511]

[0512] JBP4-012.2 (200 mg, purity 81%, 0.443 mmol, 1.0 eq.) was added to a 25 mL three-necked flask, followed by 1H-indazole-4-carboxylic acid (93 mg, 0.57 mmol, 1.0 eq.) and DMF (3 mL). The mixture was cooled to 0 °C, and then DIEA (233 mg, 1.80 mmol, 2.1 eq.) and HATU (329 mg, 0.865 mmol, 1.03 eq.) were added successively. Under nitrogen protection, the reaction was stirred at 25 °C for 2 hours.

[0513] After the reaction was completed, water (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and dried in vacuo to obtain the crude product, which was purified by a C18 column (acetonitrile / water = 45 - 70%) to give 136.1 mg of an off-white solid with a yield of 63%.

[0514] LCMS: [M+1] + = 474.1.

[0515] 1 H NMR: (400 MHz, DMSO-d6): δ 13.25 (s, 1H), 9.80 (s, 1H), 8.79 (d, J = 7.6 Hz, 1H), 8.44 - 8.42 (m, 1H), 8.33 (s, 1H), 7.86 - 7.84 (m, 1H), 7.73 - 7.66 (m, 2H), 7.39 (t, J = 8.4 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 7.16 - 7.12 (m, 1H), 6.79 - 6.76 (m, 1H), 6.69 - 6.65 (m, 2H), 4.91 - 4.86 (m, 1H), 3.72 (s, 3H), 1.88 - 1.78 (m, 2H), 1.68 - 1.64 (m, 1H), 0.95 (t, J = 6.8 Hz, 6H).

[0516] Example 15: Synthesis of Compound 41004-120 (also known as JBP4-013)

[0517] The synthetic route is as follows:

[0518]

[0519] Synthesis of Intermediate JBP4-013.1

[0520]

[0521] Add JBP4-014.3 (200 mg, purity 88%, 0.814 mmol, 1.0 eq.), N-(tert-butoxycarbonyl)-O-(tert-butyldiphenylsilyl)-L-serine (410 mg, 0.924 mmol, 1.1 eq.) and DMF (5 mL) to a 25 mL three-necked flask. Cool to 0 °C, and then sequentially add DIEA (374 mg, 3.70 mmol, 4.5 eq.) and HATU (527 mg, 1.39 mmol, 1.7 eq.). Protect with nitrogen and stir the reaction at 25 °C for 2 hours.

[0522] After the reaction is completed, pour the reaction solution into water (50 mL) and extract with ethyl acetate (30 mL × 3). Wash the organic phase with brine (80 mL × 2), dry and concentrate to obtain a brown oil. The crude product is purified by a C18 chromatographic column (acetonitrile / water = 45 - 70%) to obtain 500 mg of an off-white solid with a yield of 96%.

[0523] LCMS: [M+1] + = 642.5

[0524] Synthesis of Intermediate JBP4-013.2

[0525]

[0526] Add JBP4-013.1 (500 mg, purity 100%, 0.779 mmol, 1.0 eq.) and DCM (10 mL) to a 50 mL single-necked flask. Cool to 0 °C, and then add 4 M hydrochloric acid / dioxane (10 mL). Protect with nitrogen and stir the reaction at 25 °C for 4 hours.

[0527] After the reaction is completed, concentrate the reaction solution in vacuo to obtain an off-white solid. Pulverize the solid with petroleum ether, filter to obtain 400 mg of an off-white solid with a yield of 89%.

[0528] LCMS: [M+1] + = 542.3.

[0529] Synthesis of Intermediate JBP4-013.3

[0530]

[0531] JBP4-013.2 (200 mg, purity 100%, 0.346 mmol, 1.0 eq.) was added to a 25 mL three-necked flask, followed by 1H-indazole-4-carboxylic acid (60 mg, 0.37 mmol, 1.1 eq.) and DMF (3 mL). The mixture was cooled to 0 °C, and then DIEA (149 mg, 1.15 mmol, 3.3 eq.) and HATU (210 mg, 0.552 mmol, 1.6 eq.) were added successively. Under nitrogen protection, the reaction was stirred at 25 °C for 2 hours.

[0532] After the reaction was completed, water (30 mL) was added and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and dried in vacuo to obtain the crude product, which was purified by a C18 column (acetonitrile / water = 45 - 70%) to give 240 mg of an off-white solid in 90% yield.

[0533] LCMS: [M+1] + = 686.5.

[0534] Synthesis of JBP4-013

[0535]

[0536] At 0 °C, JBP4-013.3 (240 mg, purity 89%, 0.311 mmol, 1.0 eq.), THF (5 mL) and TBAF (122 mg, 0.467 mmol, 1.5 eq.) were added successively to a 25 mL three-necked flask. Then the reaction was stirred at 25 °C for 2 hours.

[0537] After the reaction was completed, water (50 mL) was added and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was washed with brine (80 mL × 2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and dried in vacuo to obtain a brown oil, which was purified by a C18 column (acetonitrile / water = 45 - 70%) to give 102.6 mg of an off-white solid in 73% yield.

[0538] LCMS: [M+1] + = 448.1.

[0539] 11H NMR (400 MHz, DMSO-d6): δ 13.28 (s, 1H), 9.84 (s, 1H), 8.58 - 8.52 (m, 2H), 8.39 (s, 1H), 7.84 - 7.82 (m, 1H), 7.74 - 7.66 (m, 2H), 7.42 (t, J = 7.2 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.15 - 7.12 (m, 1H), 6.80 - 6.77 (m, 1H), 6.73 - 6.69 (m, 2H), 5.25 (t, J = 5.6 Hz, 1H), 4.93 - 4.88 (m, 1H), 3.89 (t, J = 6.0 Hz, 2H), 3.73 (s, 3H).

[0540] Example 16: Synthesis of Compound 41004-121 (also known as JBP4-014)

[0541] The synthetic route is as follows:

[0542]

[0543] Synthesis of Intermediate JBP4-014.2

[0544]

[0545] In a 1 L round-bottom flask equipped with a condenser, JBP4-014.1 (25.0 g, 176 mmol, 1.0 eq.), 3-methoxyphenol (24.0 g, 193 mmol, 1.1 eq.), ACN (600 mL), and potassium carbonate (74.0 g, 535 mmol, 3.0 eq.) were added successively. Nitrogen was displaced, and the temperature was raised to 80 °C, followed by stirring the reaction for 8 hours.

[0546] After the reaction was completed, the reaction mixture was cooled to room temperature and then filtered. The filtrate was concentrated to obtain the crude product. The crude product was triturated with petroleum ether and filtered to obtain 43 g of a dark red solid with a yield of 89%.

[0547] 1 1H NMR (400 MHz, DMSO-d6) δ 8.57 (dd, J = 7.6 Hz, J = 1.6 Hz, 1H), 8.43 (dd, J = 4.8 Hz, J = 1.6 Hz, 1H), 7.40 - 7.33 (m, 2H), 6.87 - 6.86 (m, 1H), 6.83 - 6.82 (m, 1H), 6.79 - 6.76 (m, 1H), 3.76 (s, 3H).

[0548] Synthesis of Intermediate JBP4-014.3

[0549]

[0550] In a 2500 mL round-bottom flask, JBP4-014.2 (38.0 g, purity 90%, 139 mmol, 1.0 eq.), THF (500 mL), MeOH (500 mL) and Pd / C (14.8 g, 13.9 mmol, 0.1 eq.) were added in sequence. Under a hydrogen atmosphere (50 psi), the reaction was stirred at 25 °C for 16 hours.

[0551] After the reaction was completed, the reaction solution was filtered and concentrated to obtain a brown solid. Then, it was purified by silica gel column chromatography, and the product was eluted with ethyl acetate / petroleum ether = 25 - 40%. The obtained product was concentrated to dryness under reduced pressure to obtain 20 g of an off-white solid with a yield of 59%.

[0552] -97-

[0553] LCMS: [M+1] + = 217.1.

[0554] Synthesis of Intermediate JBP4-014.4

[0555]

[0556] In a 250 mL three-necked flask, JBP4-014.3 (5.00 g, purity 88%, 20.4 mmol, 1.0 eq.), (tert-butoxycarbonyl)glycine (5.78 g, 33.0 mmol, 1.6 eq.) and DMF (60 mL) were added. The mixture was cooled to 0 °C, and then TEA (9.2 mL, 66 mmol, 3.2 eq.) and HATU (15.1 g, 39.7 mmol, 1.9 eq.) were added in sequence. Under nitrogen protection, the reaction was stirred at 25 °C for 2 hours.

[0557] After the reaction was completed, the reaction solution was poured into water (200 mL) and extracted with ethyl acetate (200 mL × 3). The organic phase was washed with brine (200 mL x 2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to dryness in vacuo to obtain a crude product, and the crude product was purified by a C18 chromatographic column (acetonitrile / water = 45 - 70%) to obtain 8 g of an off-white solid with a yield of 100%.

[0558] LCMS: [M+1] + = 374.3.

[0559] Synthesis of JBP4-014.5

[0560]

[0561] JBP4-014.4 (8.00 g, purity 95%, 20.4 mmol, 1.0 eq.) and DCM (50 mL) were added to a 250 mL single-necked flask. The mixture was cooled to 0 °C, and then 4 M HCl / dioxane (50 mL) was added. The reaction mixture was stirred at 25 °C for 4 hours.

[0562] After completion of the reaction, the reaction mixture was concentrated in vacuo to obtain the crude product. The crude product was slurried with petroleum ether and filtered to obtain 5.2 g of an off-white solid, with a yield of 75%.

[0563] LCMS: [M+1] + = 274.2.

[0564] Synthesis of JBP4-014

[0565]

[0566] JBP4-014.5 (150 mg, purity 91%, 0.441 mmol, 1.0 eq.), benzothiazole-4-carboxylic acid (79 mg, 0.44 mmol, 1.0 eq.), HATU (168 mg, 0.441 mmol, 1.0 eq.) and DMF (2 mL) were added to a 25 mL three-necked flask. The mixture was cooled to 0 °C, and then DIEA (57 mg, 0.44 mmol, 1.0 eq.) was added. The reaction was stirred overnight at room temperature under nitrogen protection.

[0567] After completion of the reaction, the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL × 2). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and dried in vacuo to obtain the crude product. The crude product was purified by prep-HPLC (acetonitrile: 0.1% aqueous ammonium bicarbonate solution = 0% - 90%) to obtain 109.7 mg of a white solid, with a yield of 57%.

[0568] LCMS: [M+1] + = 435.0.

[0569] 1 H NMR (400 MHz, DMSO-d6): δ 10.24 (t, J = 5.6 Hz, 1H), 9.99 (s, 1H), 9.70 (s, 1H), 8.50 - 8.43 (m, 2H), 8.27 - 8.24 (m, 1H), 7.85 - 7.83 (m, 1H), 7.66 (t, J = 7.6 Hz, 1H), 7.30 (t, J = 8.4 Hz, 1H), 7.15 - 7.12 (m, 1H), 6.81 - 6.78 (m, 1H), 6.73 - 6.69 (m, 2H), 4.47 (d, J = 5.2 Hz, 2H), 3.75 (s, 3H).

[0570] Example 17: Synthesis of Compound 41004-122 (also known as JBP4-015)

[0571] The synthesis route is as follows:

[0572]

[0573] Synthesis of Intermediate JBP4-015.2

[0574]

[0575] In a 100 mL round-bottom flask equipped with a condenser, JBP4-015.1 (250 mg, 1.76 mmol, 1.0 eq.), 3,4-difluorophenol (252 mg, 1.94 mmol, 1.1 eq.), ACN (30 mL) and potassium carbonate (389 mg, 2.81 mmol, 1.6 eq.) were successively added. After displacing nitrogen, the temperature was raised to 80 °C and the mixture was stirred and reacted for 8 hours.

[0576] After the reaction was completed, the reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated to obtain a crude product. The crude product was slurried with petroleum ether and filtered to obtain 400 mg of a dark red solid with a yield of 90%.

[0577] LCMS: [M+1] + = 253.0

[0578] Synthesis of Intermediate JBP4-015.3

[0579]

[0580] In a 50 mL round-bottom flask, JBP4-015.2 (400 mg, purity 100%, 1.59 mmol, 1.0 eq.), Fe powder (370 mg, 6.62 mmol, 4.2 eq.), THF (5 mL), MeOH (5 mL) and ammonium chloride (709 mg, 13.3 mmol, 8.4 eq.) were successively added. After displacing nitrogen, the temperature was raised to 65 °C and the mixture was stirred and reacted for 2 hours.

[0581] After the reaction was completed, the reaction solution was filtered and concentrated to obtain a brown solid. Then it was chromatographed on silica gel, and the product was eluted with ethyl acetate / petroleum ether = 25-40%. The obtained product was concentrated to dryness under reduced pressure to obtain 400 mg of an off-white solid with a yield of 100%.

[0582] LCMS: [M+1] + = 223.1

[0583] Synthesis of Intermediate JBP4-015.4

[0584]

[0585] In a 25 mL three-necked flask, JBP4-015.3 (400 mg, purity 88%, 1.58 mmol, 1.0 eq.), (tert-butoxycarbonyl)glycine (333 mg, 1.90 mmol, 1.2 eq.) and DMF (5 mL) were added. The mixture was cooled to 0 °C, and then DIEA (273 mg, 2.11 mmol, 1.3 eq.) and HATU (600 mg, 1.58 mmol, 1.0 eq.) were added successively. Under nitrogen protection, the reaction was stirred at 25 °C for 2 hours.

[0586] After the reaction was completed, the reaction solution was poured into water (50 mL) and extracted with ethyl acetate (30 mL × 3). The organic phase was washed with brine (80 mL × 2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and dried in vacuo to obtain a crude product, and the crude product was purified by a C18 chromatographic column (acetonitrile / water = 45 - 70%) to obtain 400 mg of an off-white solid with a yield of 67%.

[0587] LCMS: [M+1] + = 380.2.

[0588] Synthesis of JBP4-015.5

[0589]

[0590] In a 50 mL single-necked flask, JBP4-015.4 (400 mg, purity 100%, 1.05 mmol, 1.0 eq.) and DCM (5 mL) were added. The mixture was cooled to 0 °C, and then 4M HCl / dioxane (5 mL) was added. The reaction solution was stirred at 25 °C for 4 hours.

[0591] After the reaction was completed, the reaction solution was concentrated in vacuo to obtain a crude product, and the crude product was slurried with petroleum ether and filtered to obtain 300 mg of an off-white solid with a yield of 90%.

[0592] LCMS: [M+1] + = 280.1.

[0593] Synthesis of JBP4-015

[0594]

[0595] In a 25 mL three-necked flask, JBP4-015.5 (100 mg, purity 100%, 0.317 mmol, 1.0 eq.), 1-methyl-1H-benzo[d]imidazole-4-carboxylic acid (56 mg, 0.318 mmol, 1.0 eq.), HATU (181 mg, 0.476 mmol, 1.5 eq.) and DMF (2 mL) were added. The mixture was cooled to 0 °C, and then DIEA (128 mg, 0.990 mmol, 3.1 eq.) was added. Under nitrogen protection, the reaction was stirred at room temperature overnight.

[0596] After the reaction was completed, the reaction solution was poured into water (30 mL) and extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and dried in vacuo to obtain the crude product, which was purified by prep-HPLC (acetonitrile: 0.1% aqueous ammonium bicarbonate solution = 0% - 90%) to obtain 70.6 mg of a white solid with a yield of 51%.

[0597] LCMS: [M+1] + = 438.1.

[0598] 1 1H NMR (400 MHz, DMSO-d6): δ 10.17 (t, J = 5.2 Hz, 1H), 9.98 (s, 1H), 8.51 - 8.48 (m, 2H), 7.94 - 7.92 (m, 1H), 7.85 - 7.83 (m, 2H), 7.52 - 7.35 (m, 3H), 7.18 - 7.14 (m, 1H), 7.05 - 7.03 (m, 1H), 4.45 (d, J = 5.2 Hz, 2H), 3.94 (s, 3H).

[0599] Example 18: Synthesis of Compound 41004-123 (also known as JBP4-016)

[0600] The synthetic route is as follows:

[0601]

[0602] Synthesis of Intermediate JBP4-016.2

[0603]

[0604] JBP4-016.1 (500 mg, 2.84 mmol, 1.0 eq.) was dissolved in DMF (5 mL). At 0 °C, NaH (purity 60%, 227 mg, 5.67 mmol, 2.0 eq.) was added and the reaction was stirred for 10 minutes. Then 2-(bromomethyl)cyclopropane (460 mg, 3.41 mmol, 1.2 eq.) was added, and the temperature was maintained at 0 °C and the reaction was stirred for 1 hour.

[0605] After the reaction was completed, the reaction solution was quenched with ice water (20 mL), and extracted twice with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography, eluting with petroleum ether:ethyl acetate = 10:1 to give 280 mg of a yellow oil, with a yield of 41%.

[0606] LCMS: [M+1] + = 231.2.

[0607] 1 1H NMR (400 MHz, CDCl3): δ 8.49 (s, 1H), 7.93 - 7.91 (m, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.45 - 7.41 (m, 1H), 4.31 (d, J = 6.8 Hz, 2H), 4.02 (s, 3H), 1.38 - 1.31 (m, 1H), 0.60 - 0.57 (m, 2H), 0.42 - 0.40 (m, 2H).

[0608] Synthesis of Intermediate JBP4-016.3

[0609]

[0610] JBP4-016.2 (280 mg, purity 95%, 1.16 mmol, 1.0 eq.) and sodium hydroxide (138 mg, 3.45 mmol, 3.0 eq.) were dissolved in a mixed solvent of methanol (1 mL), water (1 mL) and tetrahydrofuran (1 mL), and then stirred at 0 °C for 2 hours.

[0611] After the reaction was completed, the reaction solution was adjusted to pH 5 with 1 M hydrochloric acid aqueous solution, and then extracted three times with ethyl acetate (20 mL). The organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure to obtain 240 mg of a white solid, with a yield of 96%.

[0612] LCMS: [M+1] + = 217.1.

[0613] Synthesis of JBP4-016

[0614]

[0615] At 0 °C, JBP4-016.3 (240 mg, purity 100%, 1.11 mmol, 1.0 eq.), JBP4-017.5 (430 mg, purity 100%, 1.31 mmol, 1.2 eq.), HATU (845 mg, 2.22 mmol, 2.0 eq.) and DIEA (430 mg, 3.33 mmol, 3.0 eq.) were dissolved in DMF (5 mL), protected by nitrogen, and stirred for reaction for 2 hours.

[0616] After the reaction was completed, the reaction solution was poured into water (20 mL) and extracted with ethyl acetate (30 mL × 2). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and dried in vacuo to obtain a crude product, which was purified by prep-HPLC (acetonitrile: 0.1% aqueous ammonium bicarbonate solution = 0% to 90%) to obtain 220 mg of a white solid with a yield of 40%.

[0617] LCMS: [M+1] + = 490.0.

[0618] 1 1H NMR (400 MHz, DMSO-d6): δ 9.84 (s, 1H), 8.95 - 8.92 (m, 1H), 8.49 (d, J = 8.0 Hz, 1H), 8.38 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.83 - 7.81 (m, 1H), 7.66 - 7.64 (m, 1H), 7.48 - 7.44 (m, 1H), 7.26 - 7.21 (m, 1H), 7.14 - 7.11 (m, 1H), 7.03 - 7.00 (m, 1H), 6.73 - 6.69 (m, 1H), 4.35 (d, J = 6.8 Hz, 2H), 4.25 (d, J = 5.6 Hz, 2H), 3.80 (s, 3H), 1.31 - 1.22 (m, 1H), 0.50 - 0.46 (m, 2H), 0.41 - 0.37 (m, 2H). 19 19F NMR (376 MHz, DMSO-d6): δ -140.29 (s, 1F).

[0619] Example 19: Synthesis of Compound 41004-124 (also known as JBP4-017)

[0620] The synthetic route is as follows:

[0621]

[0622] Synthesis of Intermediate JBP4-017.2

[0623]

[0624] In a 100 mL round-bottom flask equipped with a condenser, JBP4-017.1 (2.00 g, 14.1 mmol, 1.0 eq.), 4-fluoro-3-methoxyphenol (2.00 g, 14.1 mmol, 1.0 eq.), ACN (30 mL), and potassium carbonate (3.89 g, 28.1 mmol, 2.0 eq.) were added in sequence. After purging with nitrogen three times, the temperature was raised to 80 °C, and the mixture was stirred and reacted for 8 hours.

[0625] After the reaction was completed, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and dried, then slurried with petroleum ether and filtered again to obtain 3.5 g of a dark red solid with a yield of 94%.

[0626] LCMS: [M+1] + = 265.1.

[0627] Synthesis of Intermediate JBP4-017.3

[0628]

[0629] To a mixed solvent of THF (50 mL) and MeOH (50 mL), JBP4-017.2 (3.50 g, purity 100%, 13.3 mmol, 1.0 eq.), Fe powder (3.70 g, 66.3 mmol, 5.0 eq.), and ammonium chloride (7.09 g, 133 mmol, 10.0 eq.) were added. After purging with nitrogen three times, the temperature was raised to 65 °C and the mixture was stirred and reacted for 2 hours.

[0630] After the reaction was completed, the reaction mixture was filtered, concentrated, and dried to obtain a brown solid. The crude product was purified by silica gel column chromatography, and the product was eluted with ethyl acetate / petroleum ether = 25 - 40% to obtain 2.6 g of an off-white solid with a yield of 80%.

[0631] LCMS: [M+1] + = 235.1.

[0632] Synthesis of Intermediate JBP4-017.4

[0633]

[0634] JBP4-017.3 (2.60 g, purity 95%, 10.6 mmol, 1.0 eq.) and (tert-butoxycarbonyl)glycine (2.77 g, 15.8 mmol, 1.5 eq.) were dissolved in DMF (30 mL), and then DIEA (2.73 g, 21.1 mmol, 2.0 eq.) and HATU (6.01 g, 15.8 mmol, 1.5 eq.) were added sequentially at 0 °C. Under nitrogen protection, the mixture was stirred and reacted at 25 °C for 2 hours.

[0635] After the reaction was completed, the reaction solution was poured into water (200 mL) and extracted with ethyl acetate (200 mL × 2). The organic phase was washed with brine (200 mL × 2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and dried in vacuo to obtain a brown oil. The crude product was purified by a C18 column (acetonitrile / water = 45 - 70%) to obtain 3.5 g of an off-white solid with a yield of 85%.

[0636] LCMS: [M+1] + = 392.3

[0637] Synthesis of Intermediate JBP4-017.5

[0638]

[0639] JBP4-017.4 (3.50 g, purity 100%, 8.94 mmol, 1.0 eq.) was dissolved in DCM (50 mL), and then 4 M HCl / dioxane (50 mL) was added at 0 °C. The temperature was raised to 25 °C and the reaction was stirred for 4 hours.

[0640] After the reaction was completed, the reaction solution was concentrated and dried to obtain a crude product. The crude product was purified by trituration with petroleum ether to obtain 2.7 g of an off-white solid with a yield of 97%.

[0641] LCMS: [M+1] + = 292.1

[0642] Synthesis of Intermediate JBP4-017.6

[0643]

[0644] JBP4-006.1 (600 mg, 3.41 mmol, 1.0 eq.) was dissolved in DMF (10 mL), and then iodoethane (797 mg, 5.11 mmol, 1.5 eq.) and potassium carbonate (940 mg, 6.80, 2.0 eq.) were added. The reaction solution was stirred at 30 °C for 16 hours.

[0645] After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and dried in vacuo to obtain a crude product. The crude product was purified by column chromatography on silica gel, and the product was eluted with petroleum ether:ethyl acetate = 5:1 to obtain 300 mg of a yellow solid with a yield of 39%.

[0646] 11H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 1.2 Hz, 1H), 7.92 (dd, J1 = 7.2 Hz, J2 = 0.8 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.44 (dd, J1 = 8.4 Hz, J2 = 7.2 Hz, 1H), 4.48 (q, J = 7.2 Hz, 2H), 4.02 (s, 3H), 1.53 (t, J = 7.2 Hz, 3H).

[0647] Synthesis of Intermediate JBP4-017.7

[0648]

[0649] JBP4-017.6 (300 mg, purity 90%, 1.32 mmol, 1.0 eq.) was dissolved in a mixed solvent of MeOH / H2O / THF = 1:1:1 (6 mL), and then sodium hydroxide (159 mg, 3.98 mmol, 3.0 eq.) was added. The reaction mixture was stirred at 30 °C for 3 hours.

[0650] After the reaction was completed, the pH was adjusted to 6 - 7 with 1 M aqueous hydrochloric acid, and then extracted with ethyl acetate. The organic phase was concentrated and dried in vacuo to obtain 200 mg of a white solid with a yield of 80%.

[0651] LCMS: [M+1] + = 191.1.

[0652] Synthesis of JBP4-017

[0653]

[0654] JBP4-017.7 (100 mg, purity 100%, 0.526 mmol, 1.1 eq.) and JBP4-017.5 (153 mg, purity 100%, 0.467 mmol, 1.0 eq.) were dissolved in DMF (2 mL), and then DIEA (340 mg, 2.63 mmol, 5.6 eq.) and HATU (300 mg, 0.789 mmol, 1.7 eq.) were added successively at 0 °C. Under nitrogen protection, the reaction was stirred at 30 °C for 2 hours.

[0655] After the reaction was completed, water was added and the mixture was extracted with ethyl acetate. The organic phase was concentrated and dried in vacuo to obtain a crude product, which was purified by prep-HPLC (acetonitrile: 0.1% aqueous ammonium bicarbonate solution = 5% to 95%) to obtain 116 mg of a white solid with a yield of 53%.

[0656] LCMS: [M+1] + = 464.1.

[0657] 1 1H NMR (400 MHz, CDCl3): δ 8.74 - 8.68 (m, 2H), 8.44 (s, 1H), 7.85 (dd, J1 = 4.8 Hz, J2 = 1.6 Hz, 1H), 7.60 - 7.54 (m, 2H), 7.41 - 7.37 (m, 1H), 7.18 - 7.00 (m, 3H), 6.77 - 6.61 (m, 2H), 4.50 - 4.45 (m, 4H), 3.82 (s, 3H), 1.52 (t, J = 7.2 Hz, 3H).

[0658] Example 20: Synthesis of Compound 41004 - 125 (also known as JBP4 - 018)

[0659] The synthetic route is as follows:

[0660]

[0661] Synthesis of Intermediate JBP4-018.1

[0662]

[0663] To a 100 mL round - bottom flask equipped with a condenser, JBP4 - 014.1.1 (250 mg, 1.76 mmol, 1.0 eq.), 4 - fluoro - 3 - methoxyaniline (250 mg, 1.77 mmol, 1.0 eq.), ACN (30 mL) and potassium carbonate (389 mg, 2.81 mmol, 1.6 eq.) were added in sequence. The temperature was raised to 80 °C and the reaction was stirred for 8 hours.

[0664] After the reaction was completed, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated to obtain the crude product. The crude product was triturated with petroleum ether and filtered to obtain 200 mg of a dark red solid, with a yield of 39%.

[0665] LCMS: [M + 1] + = 264.1.

[0666] Synthesis of Intermediate JBP4-018.2

[0667]

[0668] JBP4 - 018.1 (200 mg, purity 91%, 0.691 mmol, 1.0 eq.) and Fe powder (370 mg, 6.62 mmol, 9.6 eq.) were added to a mixed solution of THF (5 mL) and MeOH (5 mL), and then ammonium chloride (709 mg, 13.3 mmol, 19.2 eq.) was added. The mixture was purged with nitrogen, and the temperature was raised to 65 °C and the reaction was stirred for 2 hours.

[0669] After the reaction was completed, the reaction solution was filtered and concentrated to obtain the crude product. Then, it was subjected to silica gel column chromatography, and the product was eluted with ethyl acetate / petroleum ether = 25 - 40%, to obtain 150 mg of off-white solid with a yield of 87%.

[0670] LCMS: [M+1] + = 234.1

[0671] Synthesis of JBP4-018

[0672]

[0673] JBP4-018.2 (150 mg, 94% purity, 0.605 mmol, 1.3 eq.) and (1H-imidazole-4-carbonyl)glycine (103 mg, 0.470 mmol, 1.0 eq.) were dissolved in DMF (5 mL). The mixture was cooled to 0 °C, and then DIEA (273 mg, 2.11 mmol, 4.5 eq.) and HATU (600 mg, 1.58 mmol, 3.4 eq.) were added successively. Under nitrogen protection, the reaction was stirred at 25 °C for 2 hours.

[0674] After the reaction was completed, water (50 mL) was added and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was washed with brine (80 mL × 2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and dried in vacuo to obtain a brown oil. The crude product was purified by a C18 column (acetonitrile: water = 45 - 70%) to obtain 25.1 mg of off-white solid with a yield of 12%.

[0675] LCMS: [M+1] + = 435.1

[0676] 1 1H NMR (400 MHz, DMSO-d6): δ 13.28 (s, 1H), 9.71 (s, 1H), 9.04 (t, J = 5.2 Hz, 1H), 8.42 (s, 1H), 8.07 - 8.04 (m, 2H), 7.75 - 7.73 (m, 1H), 7.69 - 7.67 (m, 1H), 7.59 - 7.56 (m, 2H), 7.48 - 7.44 (m, 1H), 7.40 - 7.36 (m, 1H), 7.11 - 7.06 (m, 1H), 6.85 - 6.82 (m, 1H), 4.17 - 4.16 (m, 2H), 3.75 (m, 3H).

[0677] Example 21: Synthesis of Compound 41004-126 (also known as JBP4-019)

[0678] The synthetic route is as follows:[[]]

[0679]

[0680] Synthesis of Intermediate JBP4-019.1

[0681]

[0682] Dissolve JBP4-020.4 (1.20 g, purity 100%, 4.83 mmol, 1.0 eq.) in DCM (15 mL), then add manganese dioxide (8.35 g, 96.1 mmol, 19.9 eq.), and stir the reaction at 25 °C for 3 hours.

[0683] After the reaction is completed, filter the reaction solution, and concentrate the filtrate to obtain the crude product. The crude product is purified by silica gel column chromatography, and the product is eluted with petroleum ether:ethyl acetate = 10:1 to obtain 800 mg of yellow solid, with a yield of 60%.

[0684] 1 1H NMR (400 MHz, DMSO-d6) δ 7.90 (t, J = 2.8 Hz, 1H), 7.63 (d, J = 10.4 Hz, 1H), 7.53 - 7.49 (m, 1H), 7.31 (d, J = 2.8 Hz, 2H), 7.30 - 7.27 (m, 1H), 7.19 (s, 2H), 3.87 (s, 3H).

[0685] Synthesis of Intermediate JBP4-019.2

[0686]

[0687] Add JBP4-019.1 (500 mg, purity 90%, 1.83 mmol, 1.0 eq.), DMF (20 mL), HATU (7.70 g, 20.3 mmol, 11.1 eq.), (tert-butoxycarbonyl)glycine (3.56 g, 20.3 mmol, 11.1 eq.) and triethylamine (3.6 mL, 20.3 mmol, 11.1 eq.) into a 50 mL round-bottom flask in sequence. Replace the air with nitrogen, and raise the temperature to 60 °C and stir the reaction for 16 hours.

[0688] After the reaction is completed, pour the reaction solution into water (50 mL), and extract with ethyl acetate (50 mL). Wash the organic phase with brine, dry it over anhydrous sodium sulfate, and filter. Concentrate and dry the filtrate, and then purify it by silica gel column chromatography. The product is eluted with petroleum ether:ethyl acetate = 4:1 to obtain 700 mg of yellow solid, with a yield of 77%.

[0689] LCMS: [M+1] + = 404.3.

[0690] Synthesis of Intermediate JBP4-019.3

[0691]

[0692] JBP4-019.2 (700 mg, purity 90%, 1.56 mmol, 1.0 eq.) was added to HCl / dioxane (5 mL, 4N, 20 mmol, 12.8 eq.), and the mixture was stirred at 25 °C for 1 hour.

[0693] After the reaction was completed, the reaction solution was concentrated under vacuum and dried to obtain 600 mg of a yellow solid with a yield of 99%.

[0694] LCMS: [M+1] + = 304.2.

[0695] Synthesis of JBP4-019

[0696]

[0697] At 0 °C, JBP4-019.3 (200 mg, purity 88%, 0.518 mmol, 1.0 eq.), DMF (5 mL), HATU (291 mg, 0.765 mmol, 1.5 eq.), 1H-indazole-4-carboxylic acid (124 mg, 0.765 mmol, 1.5 eq.) and triethylamine (179 mg, 1.77 mmol, 3.4 eq.) were successively added to a 25 mL round-bottom flask, and then the temperature was raised to 25 °C and the mixture was stirred for 2 hours.

[0698] After the reaction was completed, the reaction solution was poured into water (10 mL) and extracted with ethyl acetate (10 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by pre-HPLC (acetonitrile: 0.1% aqueous ammonium bicarbonate solution = 0% to 90%) to obtain 50 mg of a white solid with a yield of 21%.

[0699] LCMS: [M+1] + = 448.0.

[0700] 11H NMR (400 MHz, DMSO-d6) δ 13.25 (br s, 1H), 10.66 (br s, 1H), 9.02 (t, J = 5.6 Hz, 1H), 8.43 - 8.39 (m, 2H), 8.36 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.65 (t, J = 4.0 Hz, 1H), 7.54 - 7.52 (m, 1H), 7.46 - 7.43 (m, 1H), 7.42 - 7.38 (m, 1H), 7.33 - 7.28 (m, 1H), 4.09 (d, J = 5.6 Hz, 2H), 3.82 (s, 3H).

[0701] Example 22: Synthesis of Compound 41004 - 127 (also known as JBP4 - 020)

[0702] The synthetic route is as follows:

[0703]

[0704] Synthesis of Intermediate JBP4-020.3

[0705]

[0706] Dissolve JBP4 - 020.1 (9.00 g, 38.0 mmol, 1.0 eq.) in toluene (100 mL), and slowly add n - butyllithium (19.8 mL, 2.5 mol / L, 49.4 mmol, 1.3 eq.) dropwise at - 70 °C. The mixture is stirred at - 70 °C for half an hour. Then add JBP4 - 020.2 (7.03 g, 45.6 mmol, 1.2 eq.) dissolved in toluene (50 mL) to the above mixture at - 70 °C. Maintain the temperature and stir the reaction for 2.5 hours.

[0707] After the reaction is completed, quench the reaction with saturated aqueous ammonium chloride solution (100 mL) and extract twice with ethyl acetate (100 mL). The organic phase is washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated, dried, and then purified by silica gel column chromatography. The product is eluted with n - hexane:ethyl acetate = 10:1 to obtain 9.0 g of white solid with a yield of 68%.

[0708] 11H NMR (400 MHz, DMSO-d6) δ 8.59 (dd, J = 4.4, 1.6 Hz, 1H), 8.06 (dd, J = 8.0, 1.2 Hz, 1H), 7.30 - 7.25 (m, 2H), 7.14 - 7.09 (m, 1H), 6.88 - 6.84 (m, 1H), 6.08 (d, J = 6.4 Hz, 1H), 6.01 (d, J = 6.8 Hz, 1H), 3.81 (s, 3H).

[0709] Synthesis of Intermediate JBP4-020.4

[0710]

[0711] At 25 °C, JBP4-020.3 (2.80 g, purity 90%, 8.07 mmol, 1.0 eq.), ammonia water (30 mL) and copper(I) iodide (510 mg, 2.68 mmol, 0.3 eq.) were added to a 100 mL sealed tube, and the temperature was raised to 110 °C and stirred for reaction for 16 hours.

[0712] After the reaction was completed, the reaction solution was cooled to room temperature, poured into water (50 mL), and then extracted twice with ethyl acetate (50 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, dried, and then purified by silica gel column chromatography, eluting the product with n-hexane:ethyl acetate = 6:1 to obtain 1.2 g of a yellow oil, with a yield of 54%.

[0713] 1H NMR (400 MHz, DMSO-d6) δ 7.77 - 7.75 (m, 1H), 7.23 - 7.21 (m, 1H), 7.10 - 7.05 (m, 1H), 7.02 - 6.94 (m, 2H), 6.87 - 6.84 (m, 1H), 6.20 (d, J = 4.8 Hz, 1H), 5.77 (d, J = 4.8 Hz, 1H), 5.22 (s, 2H), 3.78 (s, 3H).

[0714] Synthesis of Intermediate JBP4-020.5

[0715]

[0716] JBP4-0020.4 (400 mg, purity 90%, 1.45 mmol, 1.0 eq.) was dissolved in 2,2-dimethylpropanoic acid (10 mL), and then triethylsilane (5 mL) was added. The reaction solution was heated to 85 °C and stirred for 3 hours.

[0717] After the reaction is completed, the reaction solution is cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product is diluted with a saturated sodium bicarbonate aqueous solution (20 mL) and extracted twice with ethyl acetate (20 mL). The organic phase is washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated and dried, and then passed through a silica gel column. The product is eluted with n-hexane: ethyl acetate = 6:1 to obtain 200 mg of a yellow oil with a yield of 53%.

[0718] 1H NMR (400MHz, DMSO-d6) δ7.73 (t, J=2.8Hz, 1H), 7.12 (dd, J=8.4, 1.2Hz, 1H), 7.05-7.02 ( m, 1H), 6.94 (d, J=2.8Hz, 2H), 6.77-6.75 (m, 1H), 5.10 (s, 2H), 3.95 (s, 2H), 3.78 (s, 3H).

[0719] Synthesis of Intermediate JBP4-020.7

[0720]

[0721] JBP4-020.5 (200 mg, purity 90%, 0.775 mmol, 1.0 eq.) and DMF (5 mL) were added to a 25 mL round-bottom flask, and then HATU (393 mg, 1.03 mmol, 1.3 eq.), JBP4-020.5 (173 mg, 0.988 mmol, 1.3 eq.) and triethylamine (261 mg, 2.58 mmol, 3.3 eq.) were added in sequence at 0° C. The reaction solution was heated to 25° C. and stirred for 2 hours.

[0722] After the reaction was completed, water (10 mL) was added and extracted with ethyl acetate (10 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and dried, and then passed through a silica gel column. The product was eluted with petroleum ether: ethyl acetate = 4:1 to obtain 200 mg of a yellow solid with a yield of 53%.

[0723] 1 H NMR (400MHz, DMSO-d6) δ9.56 (s, 1H), 8.33 (d, J=6.0Hz, 1H), 7.76 (d, J=9.6Hz, 1H), 7.28-7.24 (m, 1H), 7.15-7. 13 (m, 1H), 7.06-6.99 (m, 2H), 6.74-6.71 (m, 1H), 4.08 (s, 2H), 3.77 (s, 3H), 3.75 (d, J=6.0Hz, 2H), 1.39 (s, 9H).

[0724] Synthesis of Intermediate JBP4-020.8

[0725]

[0726] JBP4-020.7 (250 mg, purity 80%, 0.514 mmol, 1.0 eq.) was dissolved in HCl / dioxane (3 mL, 4N, 12 mmol, 23.3 eq.) and stirred at 25°C for 1 hour.

[0727] After the reaction was completed, the reaction solution was concentrated and dried to obtain 150 mg of a yellow solid with a yield of 88%.

[0728] LCMS: [M+1] + =290.2.

[0729] Synthesis of JBP4-020

[0730]

[0731] JBP4-020.8 (150 mg, purity 98%, 0.451 mmol, 1.0 eq.) was dissolved in DMF (5 mL), and HATU (228 mg, 0.600 mmol, 1.3 eq.), 1H-indazole-4-carboxylic acid (97 mg, 0.60 mmol, 1.3 eq.) and triethylamine (140 mg, 1.38 mmol, 3.1 eq.) were added in sequence at 0° C. The mixture was heated to 25° C. and stirred for 2 hours.

[0732] After the reaction was completed, water (10 mL) was added and extracted with ethyl acetate (10 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and dried in vacuo to obtain a crude product, which was purified by prep-HPLC (acetonitrile: 0.1% aqueous ammonium bicarbonate solution = 0 to 90%) to obtain 60 mg of a white solid with a yield of 30%.

[0733] LCMS: [M+1] + =434.0.

[0734] 11H NMR (400 MHz, DMSO-d6) δ 13.26 (s, 1H), 9.77 (s, 1H), 8.90 (t, J = 5.6 Hz, 1H), 8.41 (s, 1H), 8.34 (dd, J = 4.4, 1.2 Hz, 1H), 7.81 - 7.78 (m, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 6.8 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.29 - 7.26 (m, 1H), 7.06 - 6.99 (m, 2H), 6.79 - 6.75 (m, 1H), 4.15 (d, J = 5.6 Hz, 2H), 4.12 (s, 2H), 3.75 (s, 3H).

[0735] Example 23: Synthesis of Compound 41004 - 128 (also known as JBP4 - 021)

[0736] The synthetic route is as follows:

[0737]

[0738] Synthesis of Intermediate JBP4-021.1

[0739]

[0740] Add JBP4 - 014.1 (250 mg, 1.76 mmol, 1.1 eq.), 4 - fluoro - 3 - methoxybenzenethiol (250 mg, 1.58 mmol, 1.0 eq.), ACN (30 mL) and potassium carbonate (389 mg, 2.81 mmol, 1.8 eq.) into a 100 mL round - bottom flask equipped with a condenser. Replace the air with nitrogen three times, and heat to 80 °C and stir for 8 hours.

[0741] After the reaction is completed, filter the reaction solution, and concentrate the filtrate to obtain the crude product. The crude product is purified by trituration with petroleum ether to obtain 300 mg of dark red solid, with a yield of 68%.

[0742] LCMS: [M + 1] + = 281.1.

[0743] Synthesis of Intermediate JBP4-021.2

[0744]

[0745] Add JBP4-021.1 (300 mg, purity 100%, 1.07 mmol, 1.0 eq.), Fe powder (370 mg, 6.63 mmol, 6.2 eq.), THF (50 mL), MeOH (50 mL) and ammonium chloride (709 mg, 13.3 mmol, 12.4 eq.) into a 250 mL round-bottom flask. Replace the air with nitrogen for three times, then heat up to 65 °C and stir the reaction for 2 hours.

[0746] After the reaction is completed, filter and concentrate the reaction solution to obtain a brown solid. Purify the crude product by silica gel column chromatography, elute the product with ethyl acetate / petroleum ether = 25 - 40%, and obtain 250 mg of off-white solid with a yield of 85%.

[0747] LCMS: [M+1] + = 251.3.

[0748] Synthesis of Intermediate JBP4-021.3

[0749]

[0750] Add JBP4-021.2 (250 mg, purity 91%, 0.909 mmol, 1.0 eq.), (tert-butoxycarbonyl) glycine (207 mg, 1.18 mmol, 1.3 eq.) into a 25 mL round-bottom flask and DMF (5 mL). Cool to 0 °C, and then add DIEA (273 mg, 2.11 mmol, 2.3 eq.) and HATU (600 mg, 1.58 mmol, 1.7 eq.) successively. Heat up to 25 °C and stir the reaction for 2 hours.

[0751] After the reaction is completed, pour the reaction solution into water (50 mL), extract with ethyl acetate (30 mL x 3), wash the organic phase with brine (80 mL x 2), dry over anhydrous sodium sulfate, and filter. Concentrate and dry the filtrate, then purify it by C18 column (acetonitrile / water = 45 - 70%) to obtain 280 mg of off-white solid with a yield of 64%.

[0752] LCMS: [M+1] + = 408.2.

[0753] Synthesis of JBP4-021

[0754]

[0755] Dissolve JBP4-021.3 (280 mg, purity 84%, 0.577 mmol, 1.0 eq.) in DCM (5 mL), add 4 M HCl / dioxane (5 mL) at 0 °C, then warm to 25 °C and stir the reaction for 4 hours. After the reaction is completed, concentrate the reaction solution and purify it by trituration with petroleum ether to obtain off-white solid A (250 mg). Dissolve A (250 mg), 1H-indazole-4-carboxylic acid (94 mg, 0.577 mmol, 1.0 eq.), DIEA (273 mg, 2.11 mmol, 3.7 eq.) and HATU (600 mg, 1.58 mmol, 2.7 eq.) in DMF (5 mL), and stir the reaction solution at 25 °C for 2 hours.

[0756] After the reaction is completed, pour the reaction solution into water (50 mL) and extract with ethyl acetate (30 mL x 3). Wash the organic phase with brine (80 mL x 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a brown oil. Purify the crude product by C18 column (acetonitrile / water = 45 - 70%) to obtain 128.3 mg of off-white solid with a yield of 48%.

[0757] LCMS: [M+1] + = 451.9.

[0758] 1 H NMR (400 MHz, DMSO-d6): δ 13.40 - 13.13 (m, 1H), 9.79 (s, 1H), 8.92 (t, J = 5.6 Hz, 1H), 8.45 (s, 1H), 8.23 - 8.22 (m, 1H), 7.90 - 7.88 (m, 1H), 7.75 - 7.67 (m, 2H), 7.47 - 7.43 (m, 1H), 7.28 - 7.18 (m, 3H), 7.01 - 6.97 (m, 1H), 4.20 (d, J = 5.6 Hz, 2H), 3.79 (m, 3H).

[0759] Example 24: Synthesis of Compound 41004-130 (also known as JBP4-023)

[0760] The synthetic route is as follows:

[0761]

[0762] Synthesis of Intermediate JBP4-023.2

[0763]

[0764] To 1,4-dioxane (10 mL), add JBP4-023.1 (500 mg, 1.86 mmol, 1.0 eq.), trimethylcyclotriboroxane (3.5 M in THF, 1.33 mL, 4.66 mmol, 2.5 eq.), Pd(PPh3)4 (215 mg, 0.186 mmol, 0.1 eq.), cesium carbonate (605 mg, 1.86 mmol, 1.0 eq.) and potassium carbonate (513 mg, 3.71 mmol, 2.0 eq.). Under nitrogen protection, heat to 100 °C and stir the reaction overnight.

[0765] After the reaction is completed, concentrate and dry the reaction solution to obtain the crude product. The crude product is purified by silica gel column chromatography, and the product is eluted with petroleum ether:ethyl acetate = 10:1 to obtain 250 mg of yellow solid, with a yield of 53%.

[0766] LCMS: [M+1] + = 205.1.

[0767] Synthesis of Intermediate JBP4-023.3

[0768]

[0769] At 0 °C, dissolve JBP4-023.2 (250 mg, purity 80%, 0.979 mmol, 1.0 eq.) and sodium hydroxide (118 mg, 2.95 mmol, 3.0 eq.) in a mixed solvent of MeOH (1 mL), water (1 mL) and THF (1 mL), and then stir the reaction at 0 °C for 2 hours.

[0770] After the reaction is completed, adjust the pH to 5 with 1 M hydrochloric acid aqueous solution, and then extract three times with ethyl acetate (20 mL). The organic phase is washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and dried to obtain 200 mg of white solid, with a yield of 97%.

[0771] LCMS: [M+1] + = 177.0.

[0772] Synthesis of JBP4-023

[0773]

[0774] JBP4-023.3 (200 mg, purity 84%, 0.954 mmol, 1.0 eq.), JBP4-017.5 (312 mg, purity 100%, 0.952 mmol, 1.0 eq.), HATU (725 mg, 1.91 mmol, 2.0 eq.) and DMF (5 mL) were added to a 25 mL round-bottom flask, cooled to 0 °C, and DIEA (616 mg, 4.77 mmol, 5.0 eq.) was added. The reaction was then stirred at 0 °C for 2 hours.

[0775] After completion of the reaction, the reaction mixture was poured into water (20 mL), extracted with ethyl acetate (30 mL x 2), and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and dried, and then purified by prep-HPLC (acetonitrile: 0.1% aqueous ammonium bicarbonate solution = 0% to 90%) to obtain 70 mg of a white solid with a yield of 16%.

[0776] LCMS: [M+1] + = 449.9.

[0777] 1 1H NMR (400 MHz, DMSO-d6): δ 9.94 (s, 1H), 9.36 (s, 1H), 8.47 (d, J = 7.6 Hz, 1H), 7.84 - 7.83 (m, 1H), 7.66 (d, J = 9.2 Hz, 1H), 7.43 (s, 1H), 7.28 - 7.21 (m, 2H), 7.15 - 7.03 (m, 3H), 6.76 - 6.73 (m, 1H), 4.30 - 4.29 (m, 2H), 3.81 (s, 3H), 2.39 (s, 3H). 19 19F NMR (376 MHz, DMSO-d6): δ -140.23 (s, 1F).

[0778] Example 25: Synthesis of Compound 41004-132 (also known as JBP4-025)

[0779] The synthetic route is as follows:

[0780]

[0781] Synthesis of Intermediate JBP4-025.1

[0782]

[0783] In a 25 mL round-bottom flask equipped with a condenser, 3-chlorophenol (500 mg, 3.89 mmol, 1.0 eq.), JBP4-005.1 (504 mg, 3.89 mmol, 1.0 eq.), potassium carbonate (1.61 g, 11.6 mmol, 3.0 eq.) and DMF (5 mL) were added in sequence. The temperature was raised to 100 °C and the reaction was stirred overnight.

[0784] After the reaction was completed, the reaction solution was cooled to room temperature, water (30 mL) was added and the mixture was extracted twice with ethyl acetate (30 mL). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and dried in vacuo to obtain a crude product, which was purified by prep-HPLC (acetonitrile: 0.1% aqueous ammonium bicarbonate solution = 0% to 90%) to obtain 800 mg of a white solid with a yield of 93%.

[0785] LCMS: [M+1] + = 222.1.

[0786] Synthesis of Intermediate JBP4-025.2

[0787]

[0788] JBP4-025.1 (800 mg, purity 100%, 3.61 mmol, 1.0 eq.) and (tert-butoxycarbonyl)glycine (632 mg, 3.61 mmol, 1.0 eq.) were dissolved in DMF (5 mL). The mixture was cooled to 0 °C, and DIEA (1.46 g, 11.3 mmol, 3.1 eq.) and HATU (2.06 g, 5.42 mmol, 1.5 eq.) were added to the above mixture in sequence. After purging with nitrogen, the reaction was stirred at 25 °C for 2 hours.

[0789] After the reaction was completed, the reaction solution was added to water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (80 mL x 2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and dried to obtain a brown oil. The crude product was purified by a C18 column (acetonitrile / water = 45 - 70%) to obtain 1.0 g of an off-white solid with a yield of 60%.

[0790] LCMS: [M+1] + = 379.2.

[0791] Synthesis of Intermediate JBP4-025.3

[0792]

[0793] At 0 °C, 4 M HCl / dioxane (10 mL) was added to a mixture of JBP4-025.2 (1.00 g, purity 82%, 2.16 mmol, 1.0 eq.) and DCM (10 mL). The reaction was stirred at 25 °C for 4 hours.

[0794] After completion of the reaction, the reaction solution was concentrated and dried in vacuo to obtain the crude product. The crude product was slurried with petroleum ether and filtered to obtain 500 mg of an off-white solid, with a yield of 71%.

[0795] LCMS: [M+1] + = 279.1.

[0796] Synthesis of JBP4-025

[0797]

[0798] JBP4-025.3 (200 mg, purity 97%, 0.616 mmol, 1.0 eq.), 1H-indazole-4-carboxylic acid (113 mg, 0.697 mmol, 1.1 eq.) and DMF (3 mL) were added to a 25 mL three-necked flask. The mixture was cooled to 0 °C, and then DIEA (282 mg, 2.18 mmol, 3.5 eq.) and HATU (397 mg, 1.04 mmol, 1.7 eq.) were added successively. Under nitrogen protection, the reaction was stirred at 25 °C for 2 hours.

[0799] After completion of the reaction, the reaction solution was poured into water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (80 mL x 2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and dried in vacuo to obtain the crude product. The crude product was purified by a C18 column (acetonitrile / water = 45 - 70%) to obtain 27.5 mg of an off-white solid, with a yield of 10%.

[0800] LCMS: [M+1] + = 423.0.

[0801] 1 1H NMR (400 MHz, DMSO-d6): δ 13.27 (s, 1H), 10.16 (s, 1H), 9.31 (s, 1H), 8.91 (t, J = 5.6 Hz, 1H), 8.48 (s, 1H), 8.42 (m, 1H), 7.75 - 7.73 (m, 1H), 7.67 - 7.65 (m, 1H), 7.54 - 7.50 (m, 1H), 7.47 - 7.38 (m, 3H), 7.31 - 7.28 (m, 1H), 4.30 - 4.28 (m, 2H).

[0802] Example 26: Synthesis of Compound 41004-133 (Also Known as JBP4-026)

[0803] The synthesis route is as follows:

[0804]

[0805] Synthesis of Intermediate JBP4-026.2

[0806]

[0807] At 30 °C, JBP4-026.1 (400 mg, 2.12 mmol, 1.0 eq.) and 3-fluoro-5-methoxyphenol (332 mg, 2.34 mmol, 1.1 eq.) were dissolved in acetonitrile (5 mL), and then K2CO3 (586 mg, 4.24 mmol, 2.0 eq.) was added. The temperature was raised to 80 °C and the reaction was stirred overnight.

[0808] After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated and dried to obtain 650 mg of a yellow oil, with a yield of 100%.

[0809] LCMS: [M+1] + = 295.1.

[0810] Synthesis of Intermediate JBP4-026.3

[0811]

[0812] At room temperature, JBP4-026.2 (650 mg, purity 96%, 2.12 mmol, 1.0 eq.), Fe powder (1182 mg, 21.16 mmol, 10.0 eq.) and ammonium chloride (1132 mg, 21.16 mmol, 10.0 eq.) were added to a mixed solvent of MeOH / H2O (6 mL), and then the temperature was raised to 65 °C and the reaction was stirred for 2 hours.

[0813] After the reaction was completed, the reaction solution was filtered, and the filtrate was diluted with ethyl acetate (20 mL) and washed with brine (20 mL). The organic phase was concentrated under reduced pressure to obtain 550 mg of a yellow oil, with a yield of 88%.

[0814] LCMS: [M+1] + = 265.2.

[0815] Synthesis of Intermediate JBP4-026.4

[0816]

[0817] Dissolve (tert-Butoxycarbonyl)glycine (729 mg, 4.16 mmol, 2.2 eq.) and HATU (1583 mg, 4.16 mmol, 2.2 eq.) in DMF (5 mL), then add JBP4-026.3 (550 mg, purity 90%, 1.87 mmol, 1.0 eq.) and DIEA (807 mg, 6.24 mmol, 3.3 eq.). Replace the air with nitrogen and stir the reaction at 30 °C for 3 hours.

[0818] After the reaction is completed, pour the reaction solution into water (50 mL) and extract it three times with ethyl acetate (20 mL). Wash the organic phase with brine (60 mL), dry it over anhydrous sodium sulfate, and filter. Concentrate the filtrate, dry it, and then purify it by silica gel column chromatography. Elute the product with petroleum ether:ethyl acetate = 2:1 to obtain 800 mg of yellow solid, with a yield of 88%.

[0819] LCMS: [M+1] + = 422.2.

[0820] Synthesis of Intermediate JBP4-026.5

[0821]

[0822] Dissolve JBP4-026.4 (800 mg, purity 87%, 1.65 mmol, 1.0 eq.) in DCM (4 mL), add HCl / dioxane (4 mL, 4N, 16 mmol, 9.7 eq.) at 0 °C, and then stir the reaction at 0 °C for 1 hour.

[0823] After the reaction is completed, concentrate the reaction solution under vacuum and dry it to obtain 500 mg of yellow solid, with a yield of 68%.

[0824] LCMS: [M+1] + = 322.2.

[0825] Synthesis of JBP4-026

[0826]

[0827] Add 1H-Indazole-4-carboxylic acid (45 mg, 0.278 mmol, 1.2 eq.), HATU (106 mg, 0.279 mmol, 1.2 eq.) and DMF (4 mL) to a 25 mL round-bottom flask in sequence. After stirring evenly, add JBP4-026.5 (100 mg, purity 81%, 0.226 mmol, 1.0 eq.) and DIEA (144 mg, 1.11 mmol, 4.9 eq.). Protect it with nitrogen and stir the reaction at 30 °C for 2 hours.

[0828] After the reaction was completed, the reaction mixture was poured into water (40 mL) and extracted three times with ethyl acetate (40 mL). The organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by pre-HPLC (acetonitrile: 0.1% aqueous ammonium bicarbonate solution = 0% to 90%) to obtain 46 mg of a bright yellow solid with a yield of 43%.

[0829] LCMS: [M+1] + = 466.1.

[0830] 1 1H NMR (400 MHz, DMSO-d6): δ 13.23 (s, 1H), 9.45 (s, 1H), 8.76 (s, 1H), 8.40 (s, 1H), 7.99 (d, J = 6.0 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.42 (t, J = 7.2 Hz, 1H), 6.72 - 6.69 (m, 1H), 6.58 - 6.52 (m, 3H), 4.13 (d, J = 5.2 Hz, 2H), 3.91 (s, 3H), 3.75 (s, 3H).

[0831] Example 27: Synthesis of Compound 41004-137 (also known as JBP4-030)

[0832] The synthesis route is as follows:

[0833]

[0834] Synthesis of Intermediate JBP4-030.2

[0835]

[0836] At 30 °C, JBP4-030.1 (300 mg, 1.58 mmol, 1.0 eq.) and 4-chlorophenol (214 mg, 1.66 mmol, 1.1 eq.) were dissolved in acetonitrile (5 mL), and then K2CO3 (437 mg, 3.16 mmol, 2.0 eq.) was added. The temperature was raised to 80 °C and the reaction was stirred overnight.

[0837] After the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated and dried to obtain 440 mg of a yellow solid with a yield of 94%.

[0838] LCMS: [M+1] + = 282.1.

[0839] Synthesis of Intermediate JBP4-030.3

[0840]

[0841] At room temperature, JBP4-030.2 (440 mg, purity 95%, 1.48 mmol, 1.0 eq.), Fe powder (826 mg, 14.8 mmol, 10.0 eq.) and ammonium chloride (791 mg, 14.8 mmol, 10.0 eq.) were added to a mixed solvent of MeOH / H2O (6 mL), and then the temperature was raised to 65 °C and stirred for 2 hours.

[0842] After the reaction was completed, the reaction solution was filtered, and the filtrate was diluted with ethyl acetate (20 mL) and washed with brine (20 mL). The organic phase was concentrated under reduced pressure to obtain 260 mg of a yellow solid, with a yield of 61%.

[0843] LCMS: [M+1] + = 252.1.

[0844] Synthesis of Intermediate JBP4-030.4

[0845]

[0846] (tert-Butoxycarbonyl)glycine (175 mg, 0.999 mmol, 1.1 eq.) and HATU (380 mg, 0.999 mmol, 1.1 eq.) were dissolved in DMF (4 mL), and then JBP4-030.3 (260 mg, purity 88%, 0.909 mmol, 1.0 eq.) and DIEA (352 mg, 2.72 mmol, 3.0 eq.) were added. After purging with nitrogen, the reaction was stirred at 30 °C for 4 hours.

[0847] After the reaction was completed, the reaction solution was poured into water (40 mL), and extracted three times with ethyl acetate (20 mL). The organic phase was washed with brine (60 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, dried, and then purified by silica gel column chromatography, eluting the product with petroleum ether:ethyl acetate = 2:1 to obtain 370 mg of a yellow oil, with a yield of 96%.

[0848] LCMS: [M+1] + = 409.2.

[0849] Synthesis of Intermediate JBP4-030.5

[0850]

[0851] JBP4-030.4 (370 mg, purity 96%, 0.869 mmol, 1.0 eq.) was dissolved in DCM (5 mL), TFA (1 mL) was added at 0 °C, and then the reaction was stirred at 0 °C for 2 hours.

[0852] After the reaction was completed, the reaction solution was concentrated under vacuum and dried to obtain 200 mg of a yellow oil, with a yield of 51%.

[0853] LCMS: [M+1] + = 309.1.

[0854] Synthesis of JBP4-030

[0855]

[0856] In a 25 mL round-bottom flask, 1H-indazole-4-carboxylic acid (49 mg, 0.30 mmol, 1.4 eq.), HATU (115 mg, 0.302 mmol, 1.4 eq.) and DMF (4 mL) were added in sequence. After stirring evenly, JBP4-030.5 (100 mg, purity 93%, 0.220 mmol, 1.0 eq.) and DIEA (156 mg, 1.21 mmol, 5.5 eq.) were added. Under nitrogen protection, the reaction was stirred at 30 °C for 2 hours.

[0857] After the reaction was completed, the reaction solution was poured into water (40 mL) and extracted three times with ethyl acetate (40 mL). The organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by pre-HPLC (acetonitrile: 0.1% aqueous ammonium bicarbonate solution = 0% to 90%) to obtain 62.4 mg of a white solid, with a yield of 62%.

[0858] LCMS: [M+1] + = 453.1.

[0859] 1 H NMR (400 MHz, DMSO-d6): δ 13.24 (s, 1H), 9.64 (s, 1H), 8.84 - 8.80 (m, 1H), 8.41 (s, 1H), 8.33 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 6.8 Hz, 1H), 7.49 - 7.46 (m, 2H), 7.45 - 7.41 (m, 1H), 7.18 (d, J = 8.8 Hz, 2H), 4.19 (d, J = 5.6 Hz, 2H), 3.98 (s, 3H).

[0860] Example 28: Synthesis of Compound 41004-138 (also known as JBP4-031)

[0861] The synthesis route is as follows:

[0862]

[0863] Synthesis of Intermediate JBP4-031.2

[0864]

[0865] Dissolve JBP4-031.1 (800 mg, 4.64 mmol, 1.0 eq.), 3-chloro-5-methoxyphenol (735 mg, 4.64 mmol, 1.0 eq.) and K2CO3 (1.28 g, 9.26 mmol, 2.0 eq.) in acetonitrile (20 mL). Heat to 50 °C and stir the reaction overnight.

[0866] After the reaction is completed, concentrate and dry the reaction solution to obtain the crude product. Purify the crude product by silica gel column chromatography, eluting the product with petroleum ether:ethyl acetate = 10:1 to obtain 600 mg of a yellow solid, with a yield of 40%.

[0867] LCMS: [M+1] + = 295.1.

[0868] 1 1H NMR (400 MHz, CDCl3): δ 8.19 - 8.18 (m, 2H), 6.80 - 6.76 (m, 2H), 6.64 - 6.63 (m, 1H), 3.80 (s, 3H), 2.40 (s, 3H).

[0869] Synthesis of Intermediate JBP4-031.3

[0870]

[0871] At room temperature, add JBP4-031.2 (600 mg, purity 90%, 1.83 mmol, 1.0 eq.), Fe powder (511 mg, 9.15 mmol, 5.0 eq.) and ammonium chloride (980 mg, 18.3 mmol, 10.0 eq.) to MeOH (10 mL), then heat to 50 °C and stir the reaction for 4 hours.

[0872] After the reaction is completed, add saturated aqueous sodium bicarbonate solution (30 mL), then filter. Concentrate the filtrate to remove methanol, then extract with ethyl acetate (50 mL) 3 times. Wash the organic phase with brine (30 mL), dry over anhydrous sodium sulfate, and filter. Concentrate and dry the filtrate to obtain 500 mg of a yellow solid, with a yield of 93%.

[0873] LCMS: [M+1] + = 265.1.

[0874] Synthesis of Intermediate JBP4-031.4

[0875]

[0876] JBP4-031.2 (500 mg, purity 90%, 1.70 mmol, 1.0 eq.), (tert-butoxycarbonyl)glycine (595 mg, 3.40 mmol, 2.0 eq.) and HATU (1.29 g, 3.39 mmol, 2.0 eq.) were dissolved in DMF (5 mL). The mixture was cooled to 0 °C, and then DIEA (439 mg, 3.40 mmol, 2.0 eq.) was added. After purging with nitrogen, the reaction was stirred at 0 °C for 2 hours.

[0877] After completion of the reaction, the reaction mixture was poured into water (20 mL), and extracted three times with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and dried, and then purified by a C18 column (acetonitrile: water = 0% to 90%) to obtain 400 mg of a yellow solid with a yield of 53%.

[0878] LCMS: [M+1] + = 422.3.

[0879] 1 1H NMR (400 MHz, CDCl3): δ 8.51 - 8.47 (m, 2H), 7.62 (s, 1H), 6.67 - 6.64 (m, 2H), 6.53 - 6.52 (m, 1H), 5.11 (br s, 1H), 3.88 (d, J = 6.0 Hz, 2H), 3.71 (s, 3H), 2.23 (s, 3H), 1.35 (s, 9H).

[0880] Synthesis of Intermediate JBP4-031.5

[0881]

[0882] JBP4-031.4 (400 mg, purity 95%, 0.901 mmol, 1.0 eq.) was dissolved in DCM (2 mL). HCl / dioxane (1 mL, 4N, 4 mmol, 4.4 eq.) was added at 0 °C, and then the reaction was stirred at 0 °C for 2 hours.

[0883] After completion of the reaction, the reaction mixture was concentrated in vacuo and dried to obtain 300 mg of a yellow solid with a yield of 93%.

[0884] LCMS: [M+1] + = 322.1.

[0885] Synthesis of JBP4-031

[0886]

[0887] In a 25 mL round-bottom flask, JBP4-031.5 (300 mg, purity 100%, 0.837 mmol, 1.0 eq.), 1H-indole-4-carboxylic acid (135 mg, 0.838 mmol, 1.0 eq.), HATU (637 mg, 1.68 mmol, 2.0 eq.) and DMF (5 mL) were added successively. At 0 °C, DIEA (324 mg, 2.51 mmol, 3.0 eq.) was added. Under nitrogen protection, the reaction was stirred at 0 °C for 2 hours.

[0888] After the reaction was completed, the reaction solution was poured into water (20 mL) and extracted twice with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by pre-HPLC (acetonitrile: 0.1% aqueous ammonium bicarbonate solution = 0% to 90%) to obtain 175 mg of a white solid with a yield of 45%.

[0889] LCMS: [M+1] + = 465.1.

[0890] 1 H NMR (400 MHz, CDCl3): δ 8.77 (s, 1H), 8.58 - 8.57 (m, 1H), 8.49 (br s, 1H), 7.70 - 7.69 (m, 1H), 7.56 - 7.54 (m, 2H), 7.29 (t, J = 2.8 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H), 6.98 - 6.97 (m, 2H), 6.71 - 6.69 (m, 2H), 6.58 - 6.57 (m, 1H), 4.41 (d, J = 6.0 Hz, 2H), 3.72 (s, 3H), 2.30 (s, 3H).

[0891] Example 29: Synthesis of Compound 41004-139 (also known as JBP4-032)

[0892] The synthetic route is shown as follows:

[0893]

[0894] Synthesis of Intermediate JBP4-032.2

[0895]

[0896] Dissolve JBP4-032.1 (600 mg, 2.20 mmol, 1.0 eq.), 3-nitrophenol (533 mg, 3.83 mmol, 1.7 eq.), (dimethylamino)acetic acid (45 mg, 0.44 mmol, 0.2 eq.), copper(I) iodide (63 mg, 0.33 mmol, 0.15 eq.) and cesium carbonate (1.25 g, 3.84 mmol, 1.7 eq.) in 1,4-dioxane (3 mL). Replace nitrogen, and react under microwave at 150 °C for 40 minutes.

[0897] After the reaction is completed, cool the reaction solution to room temperature, then pour it into water (20 mL) and extract with ethyl acetate (50 mL) three times. Concentrate the organic phase to obtain the crude product. The crude product is purified by silica gel column chromatography, and elute the product with petroleum ether:ethyl acetate = 1:1 to obtain 400 mg of the target product, with a yield of 75%.

[0898] 1 1H NMR (400 MHz, DMSO-d6): δ 8.04 - 8.01 (m, 1H), 7.91 - 7.90 (m, 1H), 7.70 - 7.66 (m, 1H), 7.62 - 7.59 (m, 1H), 7.38 - 7.36 (m, 1H), 7.14 - 7.12 (m, 1H), 6.98 - 6.94 (m, 1H), 5.38 (s, 2H).

[0899] Synthesis of Intermediate JBP4-032.3

[0900]

[0901] Dissolve (tert-butoxycarbonyl)glycine (869 mg, 4.96 mmol, 3.0 eq.) and HATU (937 mg, 2.46 mmol, 1.5 eq.) in DMF (3 mL), then add JBP4-032.2 (400 mg, purity 95%, 1.64 mmol, 1.0 eq) and DIEA (637 mg, 4.93 mmol, 3.0 eq.). Replace nitrogen, and stir and react at 30 °C for 10 hours.

[0902] After the reaction is completed, pour the reaction solution into water (20 mL) and extract with ethyl acetate (50 mL) three times. Wash the organic phase with brine (10 mL), dry over anhydrous sodium sulfate, and filter. Concentrate and dry the filtrate, then purify it by silica gel column chromatography, and elute the product with petroleum ether:ethyl acetate = 2:1 to obtain 480 mg of a yellow solid, with a yield of 68%.

[0903] 11H NMR (400 MHz, DMSO-d6): δ 9.66 (s, 1H), 8.49 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 8.02 (s, 1H), 7.86 - 7.85 (m, 1H), 7.76 - 7.69 (m, 2H), 7.22 - 7.19 (m, 2H), 3.83 (d, J = 6.0 Hz, 2H), 1.37 (s, 9H).

[0904] Synthesis of JBP4-032

[0905]

[0906] Dissolve JBP4 - 032.3 (480 mg, purity 90%, 1.11 mmol, 1.0 eq.) in DCM (2 mL), add HCl / dioxane (3 mL) at 0 °C, and then stir the reaction at 0 °C for 1 hour. After the reaction is completed, concentrate the reaction solution under vacuum and dry it to obtain intermediate A. Dissolve 1H - indole - 4 - carboxylic acid (180 mg, 1.12 mmol, 1.0 eq.) and HATU (633 mg, 1.66 mmol, 1.5 eq.) in DMF (3 mL), then add intermediate A and DIEA (860 mg, 6.65 mmol, 6.0 eq.), and stir the reaction at 30 °C for 30 minutes.

[0907] After the reaction is completed, pour the reaction solution into water (20 mL) and extract it twice with ethyl acetate (30 mL). Dry the organic phase with anhydrous sodium sulfate, filter it, and concentrate the filtrate to obtain the crude product. The crude product is purified by pre - HPLC (acetonitrile: 0.1% aqueous ammonium bicarbonate solution = 0% to 90%) to obtain 42.5 mg of a white solid with a yield of 8.8%.

[0908] LCMS: [M + 1] + = 431.9.

[0909] 1 1H NMR (400 MHz, DMSO-d6): δ 11.31 (s, 1H), 9.89 (s, 1H), 8.61 - 8.54 (m, 2H), 8.11 - 8.09 (m, 1H), 8.03 (s, 1H), 7.87 - 8.86 (m 1H), 7.74 - 7.67 (m, 2H), 7.56 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.42 - 7.41 (m, 1H), 7.23 - 7.20 (m, 1H), 7.16 - 7.12 (m, 1H), 6.91 (s, 1H), 4.23 (d, J = 6.0 Hz, 2H).

[0910] Example 30: Synthesis of Compound 41004-140 (Also Known as JBP4-033)

[0911] The synthesis route is as follows:

[0912]

[0913] Synthesis of Intermediate JBP4-033.2

[0914]

[0915] At room temperature, JBP4-033.1 (2.00 g, 14.1 mmol, 1.0 eq.) and ethyl 3-hydroxybenzoate (2.46 g, 14.8 mmol, 1.05 eq.) were dissolved in acetonitrile (30 mL), and then potassium carbonate (3.90 g, 28.2 mmol, 2.0 eq.) was added. The temperature was raised to 60 °C and the reaction was stirred for 2 hours.

[0916] After the reaction was completed, the reaction solution was cooled to room temperature and filtered. The filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography. The product was eluted with ethyl acetate / petroleum ether = 5%-10% to obtain 3.5 g of a white solid with a yield of 82%.

[0917] 1 H NMR (400 MHz, CDCl3) δ 8.38 (dd, J = 8.0 and 1.6 Hz, 1H), 8.33 (dd, J = 4.8 and 1.6 Hz, 1H), 7.99-7.96 (m, 1H), 7.87-7.86 (m, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.41-7.38 (m, 1H), 7.18 (dd, J = 8.0 and 4.8 Hz, 1H), 4.38 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 6.8 Hz, 3H).

[0918] Synthesis of Intermediate JBP4-033.3

[0919]

[0920] JBP4-033.2 (3.50 g, purity 95%, 11.5 mmol, 1.0 eq.) was dissolved in a mixed solvent of methanol (32 mL) and water (8 mL), and then iron powder (1.93 g, 34.6 mmol, 3.0 eq.) and ammonium chloride (1.85 g, 34.6 mmol, 3.0 eq.) were added. Nitrogen was displaced, and the reaction was stirred at 70 °C for 10 hours.

[0921] After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was concentrated to remove methanol, and then saturated aqueous sodium bicarbonate (20 mL) was added. The mixture was extracted with ethyl acetate (30 mL × 2). The organic phase was concentrated and dried to obtain 3.0 g of a brown solid with a yield of 91%.

[0922] 1 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.6 Hz, 1H), 7.81 (s, 1H), 7.57 - 7.55 (m, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.36 - 7.34 (m, 1H), 7.08 - 7.05 (m, 1H), 6.87 (dd, J = 7.6 and 4.8 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H).

[0923] Synthesis of Intermediate JBP4-033.4

[0924]

[0925] (tert-Butoxycarbonyl)glycine (2.39 g, 13.6 mmol, 1.3 eq.) was dissolved in DMF (30 mL), and then HATU (5.59 g, 14.7 mmol, 1.4 eq.), JBP4 - 033.3 (3.00 g, purity 90%, 10.5 mmol, 1.0 eq.) and DIEA (4.07 g, 31.5 mmol, 3.0 eq.) were added successively. The reaction system was purged with nitrogen and stirred at 25 °C for 16 hours.

[0926] After the reaction was completed, the reaction mixture was poured into water (50 mL), and the mixture was extracted with ethyl acetate (40 mL × 2). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and dried, and then purified by a C18 column (acetonitrile / water = 5% - 95%) to obtain 3.8 g of a white solid with a yield of 83%.

[0927] 1 1H NMR (400 MHz, CDCl3) δ 8.73 (d, J = 7.2 Hz, 1H), 8.67 (br s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.83 - 7.81 (m, 2H), 7.48 (t, J = 8.0 Hz, 1H), 7.36 - 7.33 (m, 1H), 7.03 (dd, J = 8.0 and 4.8 Hz, 1H), 5.24 (br s, 1H), 4.37 (q, J = 7.2 Hz, 2H), 3.98 (d, J = 6.0 Hz, 2H), 1.40 - 1.36 (m, 12H).

[0928] Synthesis of JBP4-033

[0929]

[0930] Dissolve JBP4-033.4 (200 mg, purity 95%, 0.457 mmol, 1.0 eq.) in DCM (2 mL), add HCl / dioxane (2 mL) at 0 °C, and then stir the reaction at 25 °C for 2 hours. After the reaction is completed, concentrate the reaction solution under vacuum and dry it to obtain intermediate A. Dissolve intermediate A, 1H-indole-4-carboxylic acid (88 mg, 0.55 mmol, 1.2 eq.), DIEA (177 mg, 1.37 mmol, 3.0 eq.) and HATU (225 mg, 0.592 mmol, 1.3 eq.) in DMF (3 mL), and stir the reaction at 25 °C for 2 hours.

[0931] After the reaction is completed, pour the reaction solution into water (10 mL) and extract it with ethyl acetate (10 mL x 2). Wash the organic phase with brine (10 mL), dry it over anhydrous sodium sulfate, filter it, and concentrate the filtrate to obtain the crude product. The crude product is purified by a C18 column (acetonitrile / water = 5%-95%) to obtain 90 mg of a white solid with a yield of 42%.

[0932] LCMS: [M+1] + = 459.1.

[0933] 1 H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 9.85 (s, 1H), 8.59 - 8.52 (m, 2H), 7.84 - 7.81 (m, 2H), 7.69 - 7.68 (m, 1H), 7.60 - 7.55 (m, 2H), 7.50 - 7.46 (m, 2H), 7.41 (t, J = 2.8 Hz, 1H), 7.18 - 7.11 (m, 2H), 6.91 - 6.90 (m, 1H), 4.32 (q, J = 7.2 Hz, 2H), 4.23 (d, J = 5.6 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H).

[0934] Example 31: Synthesis of Compound 41004-141 (also known as JBP4-034)

[0935] The synthetic route is as follows:

[0936]

[0937] Synthesis of Intermediate JBP4-034.2

[0938]

[0939] At room temperature, JBP4-034.1 (2.00 g, 14.1 mmol, 1.0 eq.) and 2,3-dihydro-1,4-benzodioxin-6-ol (2.25 g, 14.8 mmol, 1.05 eq.) were dissolved in acetonitrile (30 mL), and then potassium carbonate (3.90 g, 28.1 mmol, 2.0 eq.) was added. The temperature was raised to 60 °C and the reaction was stirred for 2 hours.

[0940] After the reaction was completed, the reaction solution was cooled to room temperature and filtered. The filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography, and the product was eluted with ethyl acetate / petroleum ether = 5%-10% to obtain 3.4 g of a white solid with a yield of 84%.

[0941] 1 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 8.36 - 8.34 (m, 1H), 7.17 - 7.14 (m, 1H), 6.90 (d, J = 8.8 Hz, 1H), 6.73 (d, J = 2.8 Hz, 1H), 6.66 (dd, J = 8.8 and 2.4 Hz, 1H), 4.27 (s, 4H).

[0942] Synthesis of Intermediate JBP4-034.3

[0943]

[0944] JBP4-034.2 (3.50 g, purity 95%, 12.1 mmol, 1.0 eq.) was dissolved in a mixed solvent of methanol (32 mL) and water (8 mL), and then iron powder (1.93 g, 34.6 mmol, 2.9 eq.) and ammonium chloride (1.85 g, 34.6 mmol, 2.9 eq.) were added. Nitrogen was displaced, and the reaction was stirred at 50 °C for 4 hours.

[0945] After the reaction was completed, the temperature was lowered to room temperature and filtered. The filtrate was concentrated to remove methanol, and then saturated aqueous sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phase was concentrated and dried to obtain 2.9 g of a brown solid with a yield of 88%.

[0946] 1 1H NMR (400 MHz, DMSO-d6) δ 7.27 (d, J = 3.6 Hz, 1H), 7.01 (d, J = 6.8 Hz, 1H), 6.83 - 6.80 (m, 2H), 6.59 - 6.53 (m, 2H), 5.15 (s, 2H), 4.23 (s, 4H).

[0947] Synthesis of Intermediate JBP4-034.4

[0948]

[0949] (tert-Butoxycarbonyl)glycine (2.57 g, 14.7 mmol, 1.4 eq.) was dissolved in DMF (30 mL), and then HATU (6.02 g, 15.8 mmol, 1.5 eq.), JBP4-034.3 (2.90 g, purity 90%, 10.7 mmol, 1.0 eq.), and DIEA (4.38 g, 33.9 mmol, 3.2 eq.) were added successively. After purging with nitrogen, the reaction was stirred at 25 °C for 16 hours.

[0950] After the reaction was completed, the reaction solution was poured into water (50 mL) and extracted with ethyl acetate (40 mL × 2). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and dried, and then purified by a C18 column (acetonitrile / water = 5% - 95%) to obtain 3.9 g of a white solid with a yield of 86%.

[0951] 1 H NMR (400 MHz, CDCl3) δ 8.70 (dd, J = 8.0 and 1.6 Hz, 1H), 8.54 (br s, 1H), 7.85 (dd, J = 4.8 and 1.6 Hz, 1H), 6.99 (dd, J = 8.0 and 4.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 6.68 (d, J = 2.8 Hz, 1H), 6.61 (dd, J = 8.8 and 2.8 Hz, 1H), 5.20 (br s, 1H), 4.27 - 4.25 (m, 4H), 3.98 (d, J = 5.6 Hz, 2H), 1.43 (s, 9H).

[0952] Synthesis of JBP4-034

[0953]

[0954] JBP4-034.4 (200 mg, purity 95%, 0.473 mmol, 1.0 eq.) was dissolved in DCM (2 mL), and HCl / dioxane (2 mL) was added at 0 °C, and then the reaction was stirred at 25 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated in vacuo and dried to obtain Intermediate A. Intermediate A, 1H-indole-4-carboxylic acid (90 mg, 0.56 mmol, 1.2 eq.), DIEA (185 mg, 1.43 mmol, 3.0 eq.), and HATU (235 mg, 0.618 mmol, 1.3 eq.) were dissolved in DMF (3 mL), and the reaction was stirred at 25 °C for 2 hours.

[0955] After the reaction was completed, the reaction solution was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by a C18 column (acetonitrile / water = 5%-95%) to obtain 110 mg of a white solid with a yield of 51%.

[0956] LCMS: [M+1] + = 445.1

[0957] 1 1H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 9.74 (s, 1H), 8.57 (t, J = 6.0 Hz, 1H), 8.49 (dd, J = 7.6 and 1.6 Hz, 1H), 7.79 (dd, J = 4.8 and 1.6 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.48 (dd, J = 7.2 and 0.8 Hz, 1H), 7.42 (t, J = 2.8 Hz, 1H), 7.16 - 7.08 (m, 2H), 6.92 - 6.91 (m, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.68 (d, J = 2.8 Hz, 1H), 6.61 (dd, J = 8.8 and 2.8 Hz, 1H), 4.25 - 4.21 (m, 6H).

[0958] Example 32: Synthesis of Compound 41004-142 (also known as JBP4-035)

[0959] The synthetic route is as follows:

[0960]

[0961] Synthesis of Intermediate JBP4-035.1

[0962]

[0963] JBP4-014.3 (500 mg, purity 88%, 2.03 mmol, 1.0 eq.), (2S)-2-{[(tert-butoxy)carbonyl]amino}-4-(methylthio)butanoic acid (821 mg, 3.29 mmol, 1.6 eq.) and DMF (10 mL) were added to a 50 mL round-bottom flask. At 0 °C, DIEA (1.14 g, 8.82 mmol, 4.3 eq.) and HATU (1.67 g, 4.39 mmol, 2.2 eq.) were added sequentially. The reaction system was purged with nitrogen and stirred at 20 °C for 16 hours.

[0964] After the reaction was completed, the reaction solution was poured into water (40 mL), and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with brine (60 mL x 2), dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated, dried and purified by a C18 column (acetonitrile: water = 45%-70%) to obtain 200 mg of a white solid with a yield of 22%.

[0965] LCMS: [M+1] + = 448.3.

[0966] Synthesis of Intermediate JBP4-035.2

[0967]

[0968] JBP4-035.1 (200 mg, purity 100%, 0.447 mmol, 1.0 eq.) was dissolved in DCM (2 mL), and HCl / dioxane (2.1 mL) was added at 0 °C, then the reaction was stirred at 20 °C for 4 hours.

[0969] After the reaction was completed, the reaction solution was concentrated in vacuo, dried to obtain 150 mg of a white solid with a yield of 86%.

[0970] LCMS: [M+1] + = 348.2.

[0971] Synthesis of JBP4-035

[0972]

[0973] JBP4-035.2 (150 mg, purity 98%, 0.383 mmol, 1.0 eq.), 1H-indazole-4-carboxylic acid (66 mg, 0.41 mmol, 1.1 eq.) and DMF (5 mL) were successively added to a 25 mL round-bottom flask, and DIEA (149 mg, 1.15 mmol, 3.0 eq.) and HATU (264 mg, 0.694 mmol, 1.8 eq.) were added at 0 °C. Under nitrogen protection, the reaction was stirred at 20 °C for 30 minutes.

[0974] After the reaction was completed, the reaction solution was poured into water (20 mL) and extracted three times with ethyl acetate (20 mL). The organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a brown oil. The crude product was purified by pre-HPLC ((XBridge C18 3.5 μm, 50*4.6 mm; 5-95% (v / v) acetonitrile / water (containing 0.05% ammonium bicarbonate))) to obtain 93 mg of a white solid with a yield of 49%.

[0975] LCMS: [M+1] += 492.1。

[0976] 1 1H NMR (400 MHz, DMSO-d6): δ 13.26 (s, 1H), 9.85 (s, 1H), 8.85 (d, J = 7.6 Hz, 1H), 8.46 (dd, J = 8.0 Hz, J = 2.0 Hz, 1H), 8.35 (s, 1H), 7.85 (d, J = 6.4 Hz, 1H), 7.74 - 7.69 (m, 2H), 7.44 - 7.40 (m, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.16 - 7.13 (m, 1H), 6.81 - 6.78 (m, 1H), 6.72 - 6.68 (m, 2H), 4.93 (q, J = 8.0 Hz, 1H), 3.74 (s, 3H), 2.68 - 2.57 (m, 2H), 2.19 - 2.13 (m, 2H), 2.08 (s, 3H).

[0977] Example 33: Synthesis of Compound 41004-143 (also known as JBP4-036) and Compound 41004-144 (also known as JBP4-037)

[0978] The synthetic route is as follows:

[0979]

[0980] Synthesis of Intermediate JBP4-037.1

[0981]

[0982] Add JBP4-014.3 (1.00 g, purity 88%, 4.07 mmol, 1.0 eq.), ((2S)-2-{[(tert-butoxy)carbonyl]amino}-5-methoxy-5-oxopentanoic acid (1.72 g, 6.58 mmol, 1.6 eq.) and DMF (10 mL) into a 50 mL three-necked flask, cool to 0 °C, and then successively add DIEA (2.27 g, 17.6 mmol, 4.3 eq.) and HATU (3.35 g, 8.81 mmol, 2.2 eq.). Protect with nitrogen and stir the reaction at 20 °C for 3 hours.

[0983] After the reaction is completed, pour the reaction solution into water (40 mL) and extract with ethyl acetate (30 mL × 3). Wash the organic phase with brine (60 mL × 2), dry and concentrate to obtain a yellow oil. The crude product is purified by a C18 chromatographic column (acetonitrile / water = 45 - 70%) to obtain 1.2 g of a white solid, with a yield of 58%.

[0984] LCMS: [M+1] + = 460.3.

[0985] Synthesis of Intermediate JBP4-037.2

[0986]

[0987] JBP4-037.1 (1.20 g, 90% purity, 2.35 mmol, 1.0 eq.) and DCM (6 mL) were added to a 50 mL single-necked flask, cooled to 0 °C, and then 4 M hydrochloric acid / dioxane (6.3 mL) was added. Under nitrogen protection, the reaction was stirred at 20 °C for 4 hours.

[0988] After the reaction was completed, the reaction solution was concentrated in vacuo to obtain an off-white solid. The solid was slurried with acetonitrile and filtered to obtain 450 mg of a white solid, with a yield of 48%.

[0989] LCMS: [M+1] + = 360.2.

[0990] Synthesis of Intermediate JBP4-037.3

[0991]

[0992] JBP4-037.2 (200 mg, 100% purity, 0.505 mmol, 1.1 eq.), 1H-indazole-4-carboxylic acid (78 mg, 0.48 mmol, 1.0 eq.) and DMF (5 mL) were added to a 25 mL three-necked flask. The mixture was cooled to 0 °C, and then DIEA (248 mg, 1.92 mmol, 4.0 eq.) and HATU (365 mg, 0.960 mmol, 2.0 eq.) were added successively. Under nitrogen protection, the reaction was stirred at 20 °C for 0.5 hour.

[0993] After the reaction was completed, water (20 mL) was added and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with brine (40 mL × 2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and dried in vacuo to obtain a yellow oil. The crude product was purified by a C18 column (acetonitrile / water = 45 - 70%) to obtain 220 mg of a white solid, with a yield of 79%.

[0994] LCMS: [M+1] + = 504.3.

[0995] Synthesis of JBP4-037

[0996]

[0997] JBP4-037.3 (100 mg, purity 87%, 0.173 mmol, 1.0 eq.) and MeOH (3 mL) were added to a 25 mL round-bottom flask, and the mixture was cooled to 0 °C. LiOH·H2O (23 mg, 0.55 mmol, 3.2 eq.) was dissolved in water (1 mL), and then added to the above mixture. The temperature was raised to 20 °C and the reaction was stirred for 3 hours.

[0998] After the reaction was completed, the reaction solution was acidified with 1 M hydrochloric acid, then extracted with dichloromethane (15 mL × 3). The organic phase was washed with brine (20 mL × 3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and dried in vacuo to obtain a white solid. The crude product was purified by high performance liquid chromatography (column: Xbridge C18 (3.5 μm 50*4.6 mm)), mobile phase A: water (+0.05% FA), mobile phase B: acetonitrile, UV: 214 nm, flow rate: 1.5 mL / min, gradient: 5 - 95% (%B)) to obtain 56.1 mg of a white solid, with a yield of 65%.

[0999] LCMS: [M+1] + = 490.1.

[1000] 1 1H NMR (400 MHz, DMSO-d6): δ 13.25 (brs, 1H), 12.15 (brs, 144H), 9.81 (s, 1H), 8.82 (d, J = 7.2 Hz, 1H), 8.47 (dd, J = 8.0 Hz, J = 1.6 Hz, 1H), 8.35 (s, 1H), 7.84 (dd, J = 4.8 Hz, J = 1.6 Hz, 1H), 7.73 - 7.67 (m, 2H), 7.43 - 7.39 (m, 1H), 7.29 (t, J = 8.4 Hz, 1H), 7.15 - 7.12 (m, 1H), 6.80 - 6.77 (m, 1H), 6.72 - 6.68 (m, 2H), 4.88 - 4.82 (m, 1H), 3.73 (s, 3H), 2.47 - 2.41 (m, 2H), 2.20 - 2.03 (m, 2H).

[1001] Synthesis of JBP4-036

[1002]

[1003] Add JBP4-037 (120 mg, 0.245 mmol), ammonium chloride (24 mg, 0.45 mmol), HATU (168 mg, 0.442 mmol) and DMF (2 mL) into a 25 mL three-necked flask. Cool the mixture to 0 °C, and then add DIEA (143 mg, 1.11 mmol). Protect the reaction under nitrogen and stir at room temperature overnight.

[1004] After the reaction was completed, add water (30 mL) and extract with ethyl acetate (30 mL × 2). Dry the organic phase with anhydrous Na2SO4 and filter. Concentrate and dry the filtrate in vacuo to obtain the crude product. The crude product was purified by a prep-HPLC column (acetonitrile: 0.1% aqueous ammonium bicarbonate solution = 0% to 90%) to obtain 98 mg of a white solid with a yield of 79%.

[1005] LCMS: [M+1] + = 489.1.

[1006] 1 1H NMR (400 MHz, DMSO-d6): δ 13.25 (s, 1H), 9.83 (s, 1H), 8.88 (d, J = 7.2 Hz, 1H), 8.50 (d, J = 8.0 Hz, 1H), 8.37 (s, 1H), 7.84 - 7.82 (m, 1H), 7.73 - 7.67 (m, 2H), 7.43 - 7.27 (m, 3H), 7.15 - 7.11 (m, 1H), 6.86 - 6.70 (m, 4H), 4.83 - 4.78 (m, 1H), 3.73 (s, 3H), 2.34 - 2.29 (m, 2H), 2.16 - 2.05 (m, 2H).

[1007] Example 34. CTG cell proliferation assay

[1008] Cell Seeding on Day 1:

[1009] Collect cells when the density of human colon adenocarcinoma cells RKO cells (or other colon cancer cell lines, liver cancer cell lines, gastric cancer cell lines, breast cancer cell lines, glioma cell lines, etc.) reaches ~50 - 80%.

[1010] Dilute the cells to an appropriate density, and seed 90 μL of cells (200 - 10,000 cells in total, adjusted according to different cells) per well into a cell detection plate (384wp Corning, #3765). Incubate overnight at 37 °C and 5% CO2.

[1011] Drug Treatment on Day 2:

[1012] Dilute the compound to a stock solution of 30 mM; then dilute the stock solution to 300 μM with the culture medium and sequentially dilute it 10-fold for 3 gradients, and transfer the drugs to a drug plate (96wp, Corning, #3357); transfer 10 μL of the compound from the drug plate to a cell detection plate; finally, incubate the cell analysis plate at 37 °C and 5% CO2.

[1013] CTG Reading:

[1014] On the 4th - 6th day (3 - 5 days after treatment), equilibrate the cell plate and CTG reagent in the dark / at room temperature for 30 min, then add CTG to the cell culture plate and shake for 5 min at a rotation speed of 500 rpm; read the detection values with an enzyme-linked immunosorbent assay (ELISA) reader.

[1015] The detection values are based on the culture medium as the background, with the inhibition of cells treated with DMSO being 0%, and the inhibition rate is calculated as:

[1016] Inhibition rate (%) = (DMSO reading - inhibitor reading) / (DMSO reading - culture medium reading) * 100%. The IC50 for cell growth inhibition is obtained by curve fitting of the inhibition rate.

[1017] The results of the cell proliferation experiment are shown below.

[1018] Table 1 Inhibition rate (%) of the compound on RKO cells at different gradients

[1019]

[1020]

[1021] Note: +++ indicates an inhibition rate ≥ 90%, ++ indicates an inhibition rate between 50 - 90%, and + indicates an inhibition rate < 50%.

[1022] As shown in Table 1, compared with AOH1160, the compound of the present application can still exhibit a more excellent inhibition rate at a lower concentration.

[1023] Further, cell growth inhibition IC50 tests were conducted on colorectal cancer cell line RKO, liver cancer cell line JHH-7, gastric cancer cell line AGS, and glioma cell line U87 using several major highly active compounds. The results are shown in Table 2. Compounds 41004-84, 41004-97, 41004-140, and 41004-141 all showed significant cell inhibitory effects. In particular, the IC50 of compound 41004-140 for cell growth inhibition of colorectal cancer cell line RKO, liver cancer cell line JHH-7, gastric cancer cell line AGS, and glioma cell line U87 was significantly increased, significantly better than the control positive drugs AOH1160 and AOH1996, indicating that compound 41004-140 has tumor-killing activity against multiple tumors.

[1024] Table 2 IC50 values of compounds for tumor cell growth inhibition

[1025]

[1026]

[1027] Note: " / " represents not tested.

[1028] Example 35. Surface Plasmon Resonance (SPR) to detect the affinity Kd between protein and inhibitor

[1029] First, the sample includes molecules coupled to the chip surface. Then prepare the buffer, and all buffers are filtered and degassed. If the buffer can tolerate high temperatures, the buffer can be sterilized. This sterilization has the effect of degassing and can also be stored for a longer time. Then, perform molecular coupling. Then dilute the analyte with a suitable buffer and load the sample. Try to make the sample buffer consistent with the system carrier buffer as much as possible. Finally, perform chip regeneration, which means washing off the analyte bound to the chip surface for repeated use of the chip.

[1030] Example 36. Solubility test experiment of PCNA inhibitor

[1031] 1. Preparation of stock solution

[1032] Prepare 10 mM DMSO stock solutions of the test compound and control compounds (progesterone and diclofenac).

[1033] 2. Solubility determination procedure

[1034] Add 15 μL of the stock solution (10 mM) of each sample sequentially into a 96-well plate. Add 485 μL of buffer to each sample. Two wells are used for each sample in this assay. Add a stir bar into each vial and seal it with a molded PTFE / silicone stopper. Then transfer the solubility sample plate to an Eppendorf Thermomixer Comfort plate shaker and shake it at 1100 rpm at 25 °C for 2 hours. After 2 hours, remove the stopper and use a large magnet to remove the stir bar, and transfer the samples from the solubility sample plate to a filter plate. Filter all samples using a vacuum manifold. Take 5 μL aliquots of the supernatant and 5 μL of DMSO, then add 490 μL of a mixture of H2O and acetonitrile (1:1) containing an internal standard. Dilute using a diluent of H2O and acetonitrile (1:1) containing an internal standard. The dilution factor varies according to the solubility value and LC-MS signal response.

[1035] 3. Preparation of 300 μM Standard (STD)

[1036] From the 10 mM DMSO STD plate, transfer 6 μL to the remaining empty plate, then add 194 μL of DMSO to this plate to make the STD concentration 300 μM. From the 300 μM DMSO STD plate, transfer 5 μL of DMSO STD and 5 μL of buffer to the remaining empty plate, then add 490 μL of a mixture of H2O and acetonitrile (1:1) containing an internal standard to this plate to make the final concentration of STD 3 μM. Dilute using a diluent of H2O and acetonitrile (1:1) containing an internal standard. Change the concentration of the standard sample according to the LC-MS signal response.

[1037] 4. Sample Analysis Procedure

[1038] Place the plate into a plate autoinjector. Evaluate the samples by LC-MS / MS analysis.

[1039] 5. Data Analysis

[1040] All calculations are performed using Microsoft Excel.

[1041] Use LC combined with mass spectrometry peak identification and quantification to analyze and quantify the filtrate against standards of known concentration. The solubility values of the test compound and the control compound are calculated as follows

[1042] [Sample] = (Sample area ratio × Sample DF × [STD]) / (STD area ratio)

[1043] DF represents the dilution factor.

[1044] Table 3 Solubility Data (PBS pH 7.4)

[1045] Compound Number Solubility (PBS pH 7.4) (μM) Progesterone (MW314.46) 13.81 Diclofenac (MW296.15) 303.84 41004-120 113.44 41004-140 17.79 41004-141 56.13 41004-84 1.75 41004-97 10.15 AOH1996 0.29

[1046] Note: The upper limit is set at 300 μM. Any value close to or above 300 μM indicates that the solubility of the compound may be 300 μM or higher.

[1047] As shown in Table 3, the solubility of the compounds of the present invention is significantly better than that of the control yangshen AOH1996. In particular, the solubility of compounds 41004-97, 41004-120, 41004-140, and 41004-141 has increased by dozens of times or more.

[1048] All documents mentioned in the present invention are cited herein by reference as if each individual document was specifically and individually cited herein. Further, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims

1. A compound used as a PCNA inhibitor, characterized in that, The compound is a compound of formula (I) as shown below or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound or prodrug thereof: Wherein, Ring A and Ring B are each independently selected from a substituted or unsubstituted 6- to 10-membered aryl group, a substituted or unsubstituted 5- or 6-membered heteroaryl group, a substituted or unsubstituted 6-membered aryl or heteroaryl group and a 5- to 6-membered heteroaryl group, a substituted or unsubstituted 6-membered aryl group and a 5- to 6-membered cycloalkyl or heterocyclic group, a substituted or unsubstituted 5- to 6-membered heteroaryl group and a 5- to 6-membered cycloalkyl or heterocyclic group, a substituted or unsubstituted 5- to 6-membered cycloalkyl or heterocyclic group and a 5- to 6-membered cycloalkyl or heterocyclic group, a substituted or unsubstituted phenyl-heteroaryl group, a substituted or unsubstituted phenyl-phenyl group; Optionally, a substituted or unsubstituted 5- to 6-membered carbocyclic ring, a substituted or unsubstituted 5- to 6-membered heterocyclic ring, a substituted or unsubstituted aryl group, or a substituted or unsubstituted 5- or 6-membered heteroaryl group may be formed by connecting between two adjacent or spaced substituents; The carbocyclic ring or heterocyclic ring may be saturated or partially unsaturated; L is -L1-Y-, -L2-Y-L3- or -L2-CHY-L3-; L1, L2 and L3 are independently selected from -C(O)NR1-, -NR1C(O)-, -C(O)O-, -CO-, -O-, -NR2-, -SO2NR3-, -SO-, -S-, -CF2-, a substituted or unsubstituted 5- or 6-membered heteroaryl group; The substitution of the heteroaryl group means having one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 thioalkyl, C0-C6 alkylthio, C0-C6 alkylhydroxy; R1, R2, and R3 are independently selected from hydrogen, halogen, -CX 1 3, -CHX 1 2, -CH2X 1 , -CN, -COOH, -CONH2, -NO2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted C0-C6 alkylamino, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 thioalkyl; or R1, R2, and R3 may optionally be linked to ring A or ring B to form a substituted or unsubstituted 5-6 membered carbocyclic ring, substituted or unsubstituted 5-6 membered heterocyclic ring, substituted or unsubstituted aryl, or substituted or unsubstituted 5- or 6-membered heteroaryl; the carbocyclic or heterocyclic ring may be saturated or partially unsaturated; X 1 is C1, Br, I, or F; Y is absent or selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C0-C6 alkyl C(O)OC1-C6 alkyl, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted C0-C3 alkylphenyl, substituted or unsubstituted C0-C3 alkyl-benzylindolyl; the substitution of said Y means having one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C0-C6 alkylamino, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 thioalkyl, C0-C6 alkylthio, C0-C6 alkylhydroxy, C0-C6 alkylcarboxy, C0-C6 alkylene-CO-O-C1-C6 alkyl, C0-C6 alkylene-O-CO-C1-C6 alkyl, C0-C6 alkylene-CO-Rx, C0-C6 alkylene-OCO-O-C1-C6 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic group, phenyl, 5-6 membered heteroaryl; wherein, Rx is hydrogen, C1-C6 alkyl, NRaRb, hydroxy, C1-C6 haloalkyl, C1-C6 alkoxy; Ra, Rb are each independently selected from hydrogen, C1-C6 alkyl, halogen, amino, hydroxy; m, n are independently selected from 0, 1, 2, 3, 4 or 5.

2. The compound according to claim 1, wherein The compound has the following formula: Wherein, Ring B is selected from 6-10 membered aryl, 5 membered heteroaryl, 6 membered heteroaryl, 6 membered aryl or heteroaryl and 5-6 membered heteroaryl, 6 membered aryl and 5-6 membered cycloalkyl or heterocyclic group, 5-6 membered heteroaryl and 5-6 membered cycloalkyl or heterocyclic group, 5-6 membered cycloalkyl or heterocyclic group and 5-6 membered cycloalkyl or heterocyclic group, phenyl-5 membered or 6 membered heteroaryl, phenyl-phenyl; R6 is absent or selected from the group consisting of: halogen, -CX 2 3, -CHX 2 2, -CH2X 2 , -CN, -SR 10 , -SOR 10 , -SO2R 10 , -SO3R 10 , -SO4R 10 , -SONR7R8, -SO2NR7R8, -NHNH2, -ONR7R8, -NHC=(O)NHNH2, -NHC=(O)NR7R8, -NO, -NO2, -NR7R8, -C(O)R9, -C(O)-OR9, -Z-C(O)-OR9, -C(O)-Z-OR9, -C(O)NR7R8, -OR 10 , -NR7SO2R 10 , -NR7C=(O)R9, -NR7C(O)-OR9, -NR7OR9, -OCX 2 , -OCHX 2 , -OCH2X 2 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted 5-6 membered heteroaryl; optionally, two adjacent or spaced R6s may be connected by a substituted or unsubstituted 5-6 membered carbocyclic ring, substituted or unsubstituted 5-6 membered heterocyclic ring, substituted or unsubstituted aryl, or substituted or unsubstituted 5- or 6-membered heteroaryl; the carbocyclic or heterocyclic ring may be saturated or partially unsaturated; R8, R9, and R 10 are independently hydrogen, halogen, -CX 3 3, -CHX 3 2, -CH2CN, -COOH, -CONH2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted 5-6 membered heteroaryl; or the R7 and R8 substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted 3-8 membered heterocyclic group, or a substituted or unsubstituted 5-6 membered heteroaryl; Z is -O-, -NH-, or C1-C3 alkylene; X 2 , X 3 is Cl, Br, I or F; b is an integer from 0 to 7; The definitions of ring A, L, m, n are as described in claim 1.

3. The compound according to claim 2, wherein The compound has the following formula: Wherein, Ring A and ring B are each independently selected from phenyl, 5 membered heteroaryl, 6 membered heteroaryl, 6 membered aryl and 5 membered heteroaryl, 6 membered aryl and 5 membered cycloalkyl, 6 membered aryl and 5 membered heterocyclic group, 6 membered heteroaryl and 5 membered heteroaryl, 6 membered heteroaryl and 5 membered cycloalkyl, 6 membered heteroaryl and 5 membered heterocyclic group; Ring C is absent or selected from substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 5-6 membered cycloalkyl, substituted or unsubstituted 5-6 membered heterocyclic group; optionally, two adjacent or alternating substituents can be connected to form a substituted or unsubstituted 5-6 membered carbocyclic ring, a substituted or unsubstituted 5-6 membered heterocyclic ring, a substituted or unsubstituted aryl, or a substituted or unsubstituted 5 membered or 6 membered heteroaryl; the carbocyclic ring or heterocyclic ring can be saturated or partially unsaturated; W is absent or selected from -O-, -NH-, -C1-C3 alkylene-, -CHF-, -CF2-, -OCF2-, -CO-, -S-, -NCH3-, -CH(OH)-, -CHCH3-, -SO-, -SO2-, -SO2NR3-; R4 and R6 are each independently none or selected from the group consisting of: halogen, -CX 2 3, -CHX 2 2, -CH2X 2 , -CN, -SR 10 , -SOR 10 , -SO2R 10 , -SO3R 10 , -SO4R 10 , -SONR7R8, -SO2NR7R8, -NHNH2, -ONR7R8, -NHC=(O)NHNH2, -NHC=(O)NR7R8, -NO, -NO2, -NR7R8, -C(O)R9, -C(O)-OR9, -Z-C(O)-OR9, -C(O)-Z-OR9, -C(O)NR7R8, -OR 10 , -NR7SO2R 10 , -NR7C=(O)R9, -NR7C(O)-OR9, -NR7OR9, -OCX 2 3, -OCHX 2 2, -OCH2X 2 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted 5-6 membered heteroaryl; optionally, two adjacent or spaced R4 or R6 may be connected to form a substituted or unsubstituted 5-6 membered carbocyclic ring, substituted or unsubstituted 5-6 membered heterocyclic ring, substituted or unsubstituted aryl, or substituted or unsubstituted 5- or 6-membered heteroaryl; the carbocyclic or heterocyclic ring may be saturated or partially unsaturated; R4 may be connected to ring C by a chemical bond, or ring A and ring C may be directly connected by a chemical bond; a and b are integers from 0 to 7; X 2 , R8, R9, R 10 , L, m, n, Z are defined as described in claim 2; the definition of R3 is as described in claim 1.

4. The compound according to claim 3, characterized in that, The compound has the following formula: Wherein, Ring A is selected from: substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, or substituted or unsubstituted pyrimidinyl; Ring B is a substituted or unsubstituted group selected from the group consisting of: benzheteroaryl, phenyl-heteroaryl, phenyl-phenyl, or naphthyl; wherein, the heteroaryl (including the heteroaryl in benzheteroaryl) is a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S; Provided that when Ring B is naphthyl, Ring A is substituted or unsubstituted pyridyl, or substituted or unsubstituted pyrimidinyl; Ring C is a substituted or unsubstituted group selected from the group consisting of: phenyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl, 5-6 membered heterocyclic group; Wherein, in Ring A, Ring B and Ring C, the substitution respectively means that Ring A is substituted by one or more R4, Ring B is substituted by one or more R6, and Ring C is substituted by one or more R5; Ry is selected from: hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, wherein, the substituents are deuterium, halogen, hydroxyl, methoxy, methylthio, carboxyl, ester group, amide group, amino, substituted or unsubstituted phenyl, guanidyl, 5-6 membered heteroaryl, benzo 5-6 membered heteroaryl; R4, R5 and R6 are each independently absent, halogen, hydroxyl, sulfonamide group, sulfonyl, or cyano; or are a substituted or unsubstituted group selected from the group consisting of: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylthio, C3-C6 cycloalkoxy, -NR7R8, -C(O)R9, -C(O)-OR9, -Z-C(O)-OR9, -C(O)-Z-OR9, -C(O)NR7R8; Or two adjacent R4 and the ring atoms of Ring A to which they are attached together form a substituted or unsubstituted 4-8 membered heterocyclic ring having 1-3 heteroatoms selected from N, O and S, or a substituted or unsubstituted C4-C8 carbocyclic ring; two adjacent R5 and the ring atoms of Ring C to which they are attached together form a substituted or unsubstituted 4-8 membered heterocyclic ring having 1-3 heteroatoms selected from N, O and S, or a substituted or unsubstituted C4-C8 carbocyclic ring; and / or two adjacent R6 and the ring atoms of Ring B to which they are attached together form a substituted or unsubstituted 4-8 membered heterocyclic ring having 1-3 heteroatoms selected from N, O and S, or a substituted or unsubstituted C4-C8 carbocyclic ring; Z is -O-, -NH-, or C1-C3 alkylene; R7, R8 and R9 are each independently: hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl; or R7, R8 and the adjacent N atom together form a substituted or unsubstituted 4-8 membered heterocyclic ring; W is -O-, -NH-, C1-C3 alkylene, -CHF-, -CF2-, -OCF2-, -CO-, -S-, -NCH3-, -CH(OH)-, -CHCH3-, -SO-, -SO2-, or -SO2NR3-; a, b, and c are each independently an integer from 0 to 7; wherein said substitution means being substituted by one or more substituents selected from the group consisting of deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, phenyl, benzyl, hydroxy, C1-C6 alkoxy.

5. The compound according to claim 4, characterized in that, Said ring B is selected from the group consisting of: Preferably, the ring A is selected from More preferably, the ring C is selected from 6. The compound according to claim 4, wherein Ry is selected from: hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, wherein said substituents are deuterium, halogen, hydroxy, methoxy, methylthio, carboxyl, ester group, amide group, amino, substituted or unsubstituted phenyl, guanidyl, 5-6 membered heteroaryl, benzo 5-6 membered heteroaryl; Preferably, Ry is selected from: hydrogen, C1-C6 alkyl, halo C1-C6 alkyl, or hydroxy-substituted C1-C6 alkyl.

7. The compound according to claim 4, wherein R4 is absent, halogen, or C1-C6 alkyl; preferably C1-C3 alkyl, more preferably methyl.

8. The compound according to claim 4, wherein R5 is absent, halogen, hydroxy, cyano, C1-C6 alkoxy, C1-C6 carboxyl, C2-C6 ester group, or -O-C2-C6 ester group; preferably halogen, C1-C3 alkoxy, or C2-C4 ester group.

9. The compound according to claim 4, wherein R6 is absent, halogen, hydroxy, cyano, C1-C6 alkoxy, C1-C6 carboxyl, C2-C6 ester group, or -O-C2-C6 ester group; preferably halogen, C1-C6 alkyl, or C1-C6 alkoxy.

10. The compound according to any one of claims 1-9, characterized in that, Said compound is selected from the following:

11. A pharmaceutical composition, characterized in that, Said pharmaceutical composition comprises a therapeutically effective amount of the compound according to any one of claims 1-10, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, and a pharmaceutically acceptable carrier.

12. The pharmaceutical composition according to claim 11, characterized in that, Said pharmaceutical composition is a tablet, capsule, granule, syrup, suspension, solution, dispersion, sustained release preparation for oral or non-oral administration, intravenous injection preparation, subcutaneous injection preparation, inhalation preparation, transdermal preparation, rectal or vaginal suppository.

13. Use of a compound according to any one of claims 1-10, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, characterized in that, For preparing a drug of a PCNA inhibitor or a drug for treating PCNA-related diseases.

14. A method for treating and / or preventing PCNA-related diseases, characterized in that, Comprising the step of administering to a subject in need a therapeutically effective amount of the compound according to any one of claims 1-10, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or the pharmaceutical composition according to any one of claims 11-12.

15. The use according to claim 13 or the method according to claim 14, characterized in that, Said PCNA-related diseases are selected from the group consisting of: brain cancer, breast cancer, cervical cancer, colon cancer, rectal cancer, head and neck cancer, leukemia, liver cancer, lung cancer, lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, gastric cancer, thyroid cancer.

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