Polθ inhibitor and use thereof

Abstract

The present application relates to a Polθ inhibitor as shown in formula (Z), the definition of each substituent being as described herein, as well as a composition containing the compound or a salt thereof, and a use thereof in the preparation of medicaments for Polθ-mediated diseases.

Description

A POLθ inhibitor and its use Technical Field

[0001] The present application belongs to the field of medical technology, and specifically relates to a POLθ inhibitor and its use. Background Art

[0002] DNA double strand breaks (DSBs) are one of the most serious DNA damages. In this context, DNA double strand breaks (DSBs) repair plays a key role in cell growth and cancer development. In particular, tumor cells with defects in DNA repair have a selective growth advantage, leading to genetic instability and promoting tumor evolution, but they often over-rely on alternative repair pathways, which represents a tumor cell-specific vulnerability that can be targeted for killing tumor cells (Pilié, PGet al. Nat. Rev. Clin. Oncol. 2019, 16(2), 81-104.). Mammalian cells use four repair pathways to repair highly cytotoxic DNA double strand breaks (DSBs) to maintain genome integrity and cell viability: non-homologous end joining (NHEJ), homologous recombination (HR), single strand annealing (SSA) and alternative end joining (alt-EJ) or microhomology-mediated end joining (MMEJ). There are two different genetic mechanisms of MMEJ, among which DNA polymerase θ (POLθ)-mediated end joining (TMEJ) is the main mechanism (Huang, R. et al. Signal Transduct. Target. Ther. 2021, 6(1), 254.).

[0003] The clinical success of PARPi provides proof of principle for the synthetic lethal approach. Although PARPi has encouraging therapeutic benefits, these drugs have shown some key problems, such as poor clinical efficacy, ineffectiveness against certain DNA repair-deficient cancers, and the development of acquired and innate resistance. The main resistance mechanism observed in preclinical and clinical models is related to the reversal mutation of BRCA2, which allows the correct encoding of functional proteins, thereby restoring the HR pathway. For these reasons, there is an urgent need to identify other synthetic lethal pathways involved in the DNA repair pathway to develop new treatments for BRCA-deficient tumors (Dias, MP et al. Nat. Rev. Clin. Oncol. 2021, 18 (12), 773-791.).

[0004] Among synthetic lethal targets, POLθ (encoded by the PolQ gene) is particularly promising for the treatment of BRCA1-deficient cancers. It is barely expressed in normal tissues but highly expressed in a variety of tumor types (such as breast cancer, ovarian cancer, head and neck squamous cell carcinoma, and lung cancer), and its overexpression is associated with poor prognosis. POLθ belongs to the A family polymerase and is a large (2590 residues in humans) multifunctional protein that contains a superfamily II N-terminal conserved helicase-like domain (called POLθ-hel, residues 32-899) and a C-terminal conserved DNA polymerase domain (called POLθ-pol, residues 1819-2590), connected by an unstructured central region. Both POLθ-hel and POLθ-pol domains are critical for TMEJ activity, and the central portion may have a regulatory role (Black, SJ et al. Nat. Commun. 2019, 10(1), 4423.).

[0005] In summary, POLθ is crucial for cells with homologous recombination defects, and there is currently an unmet market need for the treatment of homologous recombination-deficient tumors. Inhibiting POLθ can inhibit microhomology-mediated end-joining repair in cells. The development of POLθ inhibitors could provide a novel strategy for the targeted treatment of homologous recombination-deficient tumors. Summary of the Invention

[0006] The present application provides a class of compounds having POLθ inhibitory activity.

[0007] The present application relates to a compound of the following formula, its stereoisomers or pharmaceutically acceptable salts, wherein the compound structure is as follows:

[0008] wherein R1 and R2 are each independently selected from H, halogen, amino, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0009] R3 is selected from H, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0010] or said R3 and R1 or R2 and adjacent N and C form a heterocyclic group, said heterocyclic group is optionally substituted by hydrogen, halogen, amino, hydroxy, cyano, carbonyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy;

[0011] R4 is independently selected from hydrogen, hydroxy, halogen, amino, cyano, carboxyl, carbonyl, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0012] R5 is -(CH2) m -C≡CD, wherein D is aryl or heteroaryl, said aryl or heteroaryl being optionally substituted with hydrogen, halogen, amino, carbonyl, sulfone, sulfonyl, alkylsulfonyl, alkylsulfonylalkyl, hydroxy, cyano, carboxyl, alkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0013] B is aryl or heteroaryl, said aryl or heteroaryl being optionally substituted with hydrogen, halogen, amino, hydroxy, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy;

[0014] Ring A is an aryl group or a heteroaryl group;

[0015] m and n are integers of 0-4.

[0016] The present invention also relates to a compound of the following formula Z, its stereoisomers or pharmaceutically acceptable salts thereof:

[0017] wherein R1 and R2 are each independently selected from H, halogen, amino, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0018] R3 is selected from H, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0019] or said R3 and R1 or R2 and adjacent N and C form a heterocyclic group, said heterocyclic group is optionally substituted by hydrogen, halogen, amino, hydroxy, cyano, carbonyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy;

[0020] R4 is independently selected from hydrogen, hydroxy, halogen, amino, cyano, carboxyl, carbonyl, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0021] R5 is -(CH2) m-C≡CD, wherein D is aryl or heteroaryl, said aryl or heteroaryl being optionally substituted with hydrogen, halogen, amino, hydroxy, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0022] B is aryl or heteroaryl, said aryl or heteroaryl being optionally substituted with hydrogen, halogen, amino, hydroxy, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy;

[0023] Ring A is an aryl group or a heteroaryl group;

[0024] m and n are integers of 0-4.

[0025] In some embodiments, Ring A described herein is a 5-10 membered aryl group (preferably a 5-8 membered aryl group, more preferably a 5-6 membered aryl group), or a 5-10 membered heteroaryl group (preferably a 5-9 membered heteroaryl group, more preferably an 8-9 membered heteroaryl group), wherein the heteroaryl group contains 1-3 heteroatoms selected from N, O, and S, and preferably contains 1-2 N.

[0026] In some embodiments, Ring A described herein has the following structure:

[0027] In some embodiments, in the compounds of Formula Z, Formula I, Formula II, and Formula III of the present application, R5 may be -(CH2) m -C≡CD, wherein D is an aryl or heteroaryl group, and the aryl or heteroaryl group is optionally substituted by hydrogen, halogen, amino, carbonyl, sulfone, sulfonyl, alkylsulfonyl, alkylsulfonylalkyl, hydroxyl, cyano, carboxyl, alkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably, D is selected from a 5-6 membered aryl or a 5-6 membered heteroaryl group, and the aryl or heteroaryl group is optionally substituted by hydrogen, hydroxyl, halogen, cyano, carbonyl, sulfone, sulfonyl, alkyl, haloalkyl, alkoxy, alkylsulfonyl, amino The alkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted, preferably optionally substituted by hydrogen, halogen, sulfone, sulfonyl, methylsulfonyl, methylsulfonylmethyl, C1-6 alkyl, -NHC1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl, C5-6 aryl, C5-6 heteroaryl, more preferably optionally substituted by hydrogen, methylsulfonyl, methylsulfonylmethyl, C1-3 alkyl, C1-3 alkoxy, C3-6 cycloalkyl, C3-6 heterocycloalkyl, C5-6 aryl, C5-6 heteroaryl.

[0028] In some embodiments, in the compounds of formula Z, formula I, formula II, and formula III of the present application, B is aryl or heteroaryl, and the aryl or heteroaryl is optionally substituted with hydrogen, halogen, amino, hydroxyl, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, or hydroxyalkoxy, or the aryl or heteroaryl is optionally substituted with hydrogen, halogen, amino, hydroxyl, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0029] In some embodiments, the present application relates to a compound of the following Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0030] wherein R1 and R2 are each independently selected from H, halogen, amino, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0031] R3 is selected from H, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0032] or said R3 and R1 or R2 and adjacent N and C form a heterocyclic group, said heterocyclic group is optionally substituted by hydrogen, halogen, amino, hydroxy, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy;

[0033] R4 is independently selected from hydrogen, hydroxy, halogen, amino, cyano, carboxyl, carbonyl, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0034] R5 is -(CH2) m -C≡CD, wherein D is aryl or heteroaryl, said aryl or heteroaryl being optionally substituted with hydrogen, halogen, amino, hydroxy, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy;

[0035] B is aryl or heteroaryl, said aryl or heteroaryl being optionally substituted with hydrogen, halogen, amino, hydroxy, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy;

[0036] m and n are integers of 0-4.

[0037] In some embodiments, R3 and R1 or R2 and adjacent N and C form a 5-10 membered heterocyclic group, preferably a 5-8 membered heterocyclic group, more preferably a 5-6 membered heterocyclic group, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S, preferably contains 1-2 heteroatoms selected from N and O, and the heterocyclic group is optionally substituted by hydrogen, halogen, amino, hydroxy, cyano, carbonyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, or hydroxyalkoxy, preferably optionally substituted by hydrogen, halogen, amino, hydroxy, cyano, carbonyl, carboxyl, or alkyl, more preferably optionally substituted by hydrogen, hydroxy, or carbonyl.

[0038] In some embodiments, R3 is an aryl group or a heteroaryl group, preferably a 5-10 membered aryl group or a 5-10 membered heteroaryl group, wherein the heteroaryl group contains at least one atom selected from N, O, and S.

[0039] In some embodiments, the present application relates to a compound of the following formula II, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0040] wherein A1, A2, A3, and A4 are each independently selected from CR6, CR6R 6a , NR6, O, S and S(O)2; R6 is independently selected from hydrogen, hydroxy, halogen, alkyl, haloalkyl, alkoxy, amino, aminoalkyl, acyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, or is independently selected from hydrogen, hydroxy, halogen, alkyl, haloalkyl, alkoxy, amino, aminoalkyl, acyl;

[0041] or A1 and A2, A2 and A3 optionally form a substituted or unsubstituted saturated or unsaturated 3-14 membered ring, which may optionally include one or more heteroatoms which may be the same or different and are independently selected from O, N, and S;

[0042] R 6a are independently selected from hydrogen, hydroxy, halogen, alkyl, haloalkyl, alkoxy, amino, aminoalkyl, acyl; or R6 and R 6a together with the carbon atom to which they are attached, form a -C(=S)-, (-C)=O, -C(=NH)- group, or a substituted or unsubstituted saturated or unsaturated 3-14 membered ring, which may optionally include one or more heteroatoms which may be the same or different and are independently selected from O, N, and S;

[0043] B is aryl or heteroaryl, said aryl or heteroaryl being optionally substituted with hydrogen, hydroxy, halogen, haloalkyl, alkoxy, amino, aminoalkyl, acyl, alkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl;

[0044] R4 is independently selected from hydrogen, hydroxy, halogen, amino, cyano, carboxyl, carbonyl, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0045] R5 is -(CH2) m -C≡CD, wherein D is aryl or heteroaryl, said aryl or heteroaryl being optionally substituted with hydrogen, halogen, amino, hydroxy, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy.

[0046] In some embodiments, Selected from:

[0047] Or choose from:

[0048] Preferably selected from

[0049] In some embodiments, the present application relates to a compound of the following formula III, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0050] in:

[0051] A1 is selected from CR6, (-C)=O, S(O)2, R6 is independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl;

[0052] A2 is selected from CR6, NR6, O, R6 is independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl;

[0053] or A1 and A2 form a 5-6 membered aryl or heteroaryl group, wherein the aryl or heteroaryl group is optionally substituted with hydrogen, hydroxy, halogen, haloalkyl, alkoxy, amino, aminoalkyl, acyl, alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl;

[0054] The other substituents are as defined above.

[0055] In some embodiments, A1 is selected from CR6, (-C)=O, R6 is independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, preferably A1 is selected from -CH2-, (-C)=O.

[0056] In some embodiments, A2 is selected from CR6, O, R6 is independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, preferably A2 is selected from -CH2-, -CHOH-, O.

[0057] In some embodiments, B is selected from a 5-6 membered aryl or heteroaryl group, wherein the heteroaryl group may optionally include one or more heteroatoms, which may be the same or different and are independently selected from O, N, and S; the aryl or heteroaryl group is optionally substituted with hydrogen, hydroxyl, halogen, cyano, alkyl, haloalkyl, alkoxy, amino, or aminoalkyl, preferably optionally substituted with hydrogen, hydroxyl, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, amino, or C1-6 aminoalkyl, more preferably optionally substituted with hydrogen, hydroxyl, halogen, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-6 alkoxy, amino, or C1-3 aminoalkyl, further preferably optionally substituted with hydrogen, C1-3 alkyl, or C1-3 haloalkyl.

[0058] In some embodiments, B is selected from:

[0059] in:

[0060] A5, A6, A7, A8 are CR9 or NR9, R9 is independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl;

[0061] R8 is independently selected from hydrogen, hydroxy, halogen, amino, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, or is independently selected from hydrogen, hydroxy, halogen, amino, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy.

[0062] In some embodiments, B is selected from:

[0063] R8 is independently selected from hydrogen, hydroxy, halogen, amino, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, or is independently selected from hydrogen, hydroxy, halogen, amino, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy.

[0064] In some embodiments, D is selected from a 5-6 membered aryl or heteroaryl group, wherein the heteroaryl group may optionally include one or more heteroatoms, which may be the same or different and are independently selected from O, N, and S, and the aryl or heteroaryl group is optionally substituted with hydrogen, hydroxy, halogen, cyano, alkyl, haloalkyl, alkoxy, amino, or aminoalkyl;

[0065] m is an integer from 1 to 3.

[0066] In some embodiments, the present application relates to a compound of the following formula IV or formula V, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0067] A1 is selected from CR6, (-C)=O, S(O)2, R6 is independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl;

[0068] A2 is selected from CR6, NR6, O, R6 is independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl;

[0069] R8 is independently selected from hydrogen, hydroxy, halogen, amino, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, or is independently selected from hydrogen, hydroxy, halogen, amino, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy;

[0070] R4 is independently selected from hydrogen, hydroxy, halogen, amino, cyano, carboxyl, carbonyl, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0071] D is selected from a 5-6 membered aryl or heteroaryl group, wherein the heteroaryl group may optionally include one or more heteroatoms, which may be the same or different and are independently selected from O, N, and S, and the aryl or heteroaryl group is optionally substituted with hydrogen, hydroxy, halogen, cyano, carbonyl, sulfone, sulfonyl, alkyl, haloalkyl, alkoxy, alkylsulfonyl, amino, aminoalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0072] In some embodiments, R8 is selected from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, preferably selected from hydrogen, halogen, C1-3 alkyl, C1-3 haloalkyl, more preferably selected from hydrogen, C1-3 alkyl, C1-3 haloalkyl.

[0073] In some embodiments, R4 is selected from hydrogen, hydroxyl, halogen, amino, carbonyl, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkoxy, C3-6 cycloalkyl, C3-6 heterocyclyl.

[0074] In some preferred embodiments, R4 is selected from hydrogen, halogen, preferably R4 is halogen.

[0075] In some embodiments, D has the structure described below: R7 is selected from hydrogen, halogen, amino, sulfone, sulfonyl, methylsulfonyl, methylsulfonylmethyl, C1-6 alkyl, -NHC1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl, C5-6 aryl, C5-6 heteroaryl, preferably selected from hydrogen, methylsulfonyl, methylsulfonylmethyl, C1-3 alkyl, C1-3 alkoxy, C3-6 cycloalkyl, C3-6 heterocycloalkyl, C5-6 aryl, C5-6 heteroaryl.

[0076] In some embodiments, D has the structure described below: R7 is selected from hydrogen, halogen, amino, sulfone, sulfonyl, methylsulfonyl, methylsulfonylmethyl, C1-6 alkyl, -NHC1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl, C5-6 aryl, C5-6 heteroaryl.

[0077] In some embodiments, D has the structure described below: R7 is selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl.

[0078] In some embodiments, D has the structure described below: R7 is selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl.

[0079] In some embodiments, D has the structure described below: R7 is selected from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl. In some preferred embodiments, R7 is hydrogen.

[0080] In some embodiments, D has the structure described below: R7 is selected from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy. In some preferred embodiments, R7 is -C1-6 alkoxy. In other embodiments, D is

[0081] In some preferred embodiments, the R7 is C3-6 heterocycloalkyl, which includes one or more heteroatoms, which may be the same or different and are independently selected from O, N, and S. In some more preferred embodiments, the R7 is

[0082] In some preferred embodiments, R7 is C5-6 aryl or C5-6 heteroaryl, wherein the heteroaryl includes one or more heteroatoms, which may be the same or different and are independently selected from O, N, and S; preferably, R7 is

[0083] In some preferred embodiments, the compound has the structure shown in Formula VI:

[0084] in,

[0085] A2 is selected from -CH2- or O;

[0086] R8 has 1, 2, 3 or 4, and each is independently selected from hydrogen, hydroxy, halogen, amino, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0087] R4 has 1, 2, 3, 4 or 5, and each is independently selected from hydrogen, hydroxy, halogen, amino, cyano, carboxyl, carbonyl, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0088] R7 is selected from hydrogen, halogen, sulfone, sulfonyl, methylsulfonyl, methylsulfonylmethyl, C1-6 alkyl, -NHC1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl, C5-6 aryl, C5-6 heteroaryl, and the heterocycloalkyl or heteroaryl includes one or more heteroatoms, which may be the same or different and are independently selected from O, N, and S.

[0089] In some preferred embodiments, R7 is selected from hydrogen, halogen, sulfone, sulfonyl, methylsulfonyl, methylsulfonylmethyl, C1-6 alkyl, -NHC1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl, C5-6 aryl, C5-6 heteroaryl, preferably selected from hydrogen, methylsulfonyl, methylsulfonylmethyl, C1-3 alkyl, C1-3 alkoxy, C3-6 cycloalkyl, C3-6 heterocycloalkyl, C5-6 aryl, C5-6 heteroaryl.

[0090] In some preferred embodiments, said R7 is selected from hydrogen, C1-6 alkoxy, More preferably, said R7 is selected from hydrogen, C1-3 alkoxy, More preferably, said R7 is selected from hydrogen, methoxy,

[0091] In some preferred embodiments, the R8 are each independently selected from hydrogen, halogen, cyano, C1-6 alkyl or C1-6 haloalkyl; preferably, R8 are each independently selected from hydrogen, cyano, methyl or halomethyl.

[0092] In some preferred embodiments, the R4 are each independently selected from hydrogen, hydroxyl, halogen, amino, carbonyl, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkoxy, C3-6 cycloalkyl, C3-6 heterocyclyl; preferably R4 is halogen.

[0093] In some preferred embodiments, the compound has a structure as shown in Formula VII:

[0094] A2 is selected from -CH2- or O;

[0095] R 8a 、R 8b Each is independently selected from hydrogen, hydroxy, halogen, amino, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0096] R4 has 1, 2, 3, 4 or 5, and each is independently selected from hydrogen, hydroxy, halogen, amino, cyano, carboxyl, carbonyl, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0097] R7 is selected from hydrogen, halogen, sulfone, sulfonyl, methylsulfonyl, methylsulfonylmethyl, C1-6 alkyl, -NHC1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl, C5-6 aryl, C5-6 heteroaryl, and the heterocycloalkyl or heteroaryl includes one or more heteroatoms, which may be the same or different and are independently selected from O, N, and S.

[0098] In some preferred embodiments, said R7 is selected from hydrogen, C1-6 alkoxy, More preferably, said R7 is selected from hydrogen, C1-3 alkoxy, More preferably, said R7 is selected from hydrogen, methoxy,

[0099] In some preferred embodiments, the R 8a and R 8bEach is independently selected from hydrogen, halogen, C1-6 alkyl or C1-6 haloalkyl; preferably R 8a 、R 8b Each is independently selected from hydrogen, cyano, methyl or halomethyl; preferably R 8a is trifluoromethyl, R 8b It is a methyl group.

[0100] In some preferred embodiments, R4 is independently selected from hydrogen, hydroxyl, halogen, amino, carbonyl, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkoxy, C3-6 cycloalkyl, C3-6 heterocyclyl; preferably R4 is halogen.

[0101] The present application also relates to any combination of the above-mentioned embodiments and preferred embodiments.

[0102] The present application provides a compound having the following structure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0103] The present application provides a compound having the following structure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0104] On the other hand, the present application provides a pharmaceutical composition comprising the above-mentioned compound, its stereoisomers or pharmaceutically acceptable salts and one or more pharmaceutically acceptable carriers or excipients.

[0105] On the other hand, the present application provides the use of the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt, or the above-mentioned pharmaceutical composition in the preparation of a medicament for preventing or treating a Polθ-mediated disease. Alternatively, the present application provides the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt, or the above-mentioned pharmaceutical composition for preventing or treating a Polθ-mediated disease. Alternatively, the present application provides a method for preventing or treating a Polθ-mediated disease, comprising administering a preventive or therapeutically effective amount of the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt, or the above-mentioned pharmaceutical composition to a subject in need.

[0106] In some embodiments, the Pol θ-mediated disease is liver cancer, breast cancer, ovarian cancer, lung cancer, kidney cancer, prostate cancer, skin cancer, bladder cancer, pancreatic cancer, or head and neck cancer.

[0107] Regarding the technical effects achieved by the present application, on the one hand, the compounds of the present application show an inhibitory effect on Polθ, IC 50 Less than 100 nM. In some preferred embodiments, the compounds of the present application show an IC of 0. 50 Less than 50nM. In some preferred embodiments, the compounds of the present application show an IC50 of less than 10nM in terms of the inhibitory effect on Polθ. In some preferred embodiments, some compounds IC 50 In some preferred embodiments, some compounds IC 50 1-50nM; in some preferred embodiments, some compounds have a longer half-life and a lower clearance rate in liver microsomes; in some preferred embodiments, some compounds can maintain a higher blood concentration for a long time; in some preferred embodiments, some compounds can significantly reduce tumor volume, increase drug concentration in tumor tissue, and show excellent anti-tumor effects.

[0108] Terminology

[0109] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0110] In the present application, an alkyl group refers to a saturated aliphatic hydrocarbon group, which is a straight chain or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof.

[0111] More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like.

[0112] The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred in the present application; the hydroxy-substituted alkyl may be 2-hydroxyisopropyl or 1-hydroxyethyl.

[0113] In the present application, the cycloalkyl group refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, and the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and further preferably 3 to 6 carbon atoms. For example, as used herein, the term "C3-6 cycloalkyl" or "3-6 membered cycloalkyl" means a cycloalkyl group containing 3 to 6 carbon atoms.

[0114] Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; and polycyclic cycloalkyls include spirocycloalkyls, fused cycloalkyls, and bridged cycloalkyls.

[0115] In the present application, spiroalkyl refers to a polycyclic group sharing a carbon atom (called spiral atom) between 5 to 20 yuan of monocycles, which can contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiral atoms shared between ring and ring, spiroalkyl is divided into single spiroalkyl, double spiroalkyl or multiple spiroalkyl, preferably single spiroalkyl and double spiroalkyl. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan of single spiroalkyl.

[0116] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0117] In the present application, heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic heterocyclyl containing 3 to 20 ring atoms (i.e., a 3-20 membered heterocyclyl), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, but excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. In this application, the terms "3-12 membered heterocyclyl" and "C3-12 heterocyclyl" can be used interchangeably to refer to a cyclic group containing 3-12 ring atoms and one or more carbon atoms in the ring are replaced by heteroatoms; similarly, "5-10 membered heterocyclyl" and "C5-10 heterocyclyl" can be used interchangeably to refer to a cyclic group containing 5-10 ring atoms and one or more carbon atoms in the ring are replaced by heteroatoms; "5-8 membered heterocyclyl" and "C5-8 heterocyclyl" can be used interchangeably. "3-8 membered heterocyclyl" and "C3-8 heterocyclyl" are used interchangeably to refer to a cyclic group containing 5-8 ring atoms, wherein one or more carbon atoms in the ring are replaced by heteroatoms; "3-8 membered heterocyclyl" and "C3-8 heterocyclyl" are used interchangeably to refer to a cyclic group containing 3-8 ring atoms, wherein one or more carbon atoms in the ring are replaced by heteroatoms; "3-6 membered heterocyclyl" and "C3-6 heterocyclyl" are used interchangeably to refer to a cyclic group containing 3-6 ring atoms, wherein one or more carbon atoms in the ring are replaced by heteroatoms. A heterocyclyl preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contains 3 to 10 ring atoms; and even more preferably contains 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, pyrrolidonyl, piperidin-2-onyl, 3,4-dihydropyridin-2(1H)-onyl, 4,5-dihydropyridazin-3(2H)-onyl, azetidinyl, oxetanyl, oxanyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc.; preferably pyrrolidyl, pyrrolidonyl, piperidin-2-one, 3,4-dihydropyridin-2 (1H) -one, 4,5-dihydropyridazine-3 (2H) -one, azetidinyl, oxetanyl, dihydropyrrolyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, Piperazinyl and pyranyl; more preferably dihydropyrrolyl, pyrrolidinyl, pyrrolidonyl, piperidin-2-onyl, 3,4-dihydropyridin-2 (1H) -onyl, 4,5-dihydropyridazin-3 (2H) -onyl, azetidinyl, oxetanyl, oxanyl, morpholinyl, piperidinyl, piperazinyl,

[0118] , pyranyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged heterocyclic groups; the spirocyclic, fused-ring, and bridged heterocyclic groups involved are optionally connected to other groups through single bonds, or further connected to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups through any two or more atoms on the ring.

[0119] The heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring attached to the parent structure is the heterocyclyl ring.

[0120] The heterocyclic group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate. For example, the heterocyclic group in the definition of R7 encompasses the case where the heterocyclic group is substituted or unsubstituted. When substituted, the heterocyclic group is preferably substituted by one or more groups selected from the following: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0121] In the present application, aryl refers to a 5- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 5- to 10-membered, more preferably 5- to 8-membered, for example, as used herein, the term "C 5-10 "Aryl" or "5- to 10-membered aryl" means an aromatic group containing 5 to 10 carbon atoms, such as phenyl and naphthyl, preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring that is attached to the parent structure is the aryl ring, non-limiting examples of which include:

[0122] The aryl group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0123] In the present application, heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl includes 5- or 6-membered monocyclic compounds, 8- to 10-membered bicyclic groups in which the same or different monocyclic heteroaromatic rings are fused, and 8- to 10-membered bicyclic groups in which a monocyclic heteroaromatic ring is fused to a benzene. In this application, the terms “5-10 membered heteroaryl” and “C5-10 heteroaryl” are used interchangeably to refer to an aryl group containing 5-10 ring atoms and one or more carbon atoms in the ring are replaced by heteroatoms; similarly, “5-9 membered heteroaryl” and “C5-9 heteroaryl” are used interchangeably to refer to an aryl group containing 5-9 ring atoms and one or more carbon atoms in the ring are replaced by heteroatoms; “5-6 membered heteroaryl” and “C5-6 heteroaryl” are used interchangeably to refer to an aryl group containing 5-6 ring atoms and one or more carbon atoms in the ring are replaced by heteroatoms; “8-9 membered heteroaryl” and “C8-9 heteroaryl” are used interchangeably to refer to an aryl group containing 8-9 ring atoms and one or more carbon atoms in the ring are replaced by heteroatoms. The heteroaryl group is preferably 5 to 10 members (e.g., 5 to 9 members), more preferably 5 to 8 members, and most preferably 5 or 6 members, such as pyrazinyl, pyridazinyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, oxadiazole, pyrazinyl, etc., preferably pyrimidinyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazole, pyridine. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0124] Heteroaryl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate. For example, the definition of heteroaryl for R encompasses situations where the heteroaryl is substituted or unsubstituted heteroaryl, and when substituted, the heteroaryl is preferably substituted by one or more groups selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0125] In the application, alkoxy refers to-O-(alkyl) and-O-(non-substituted cycloalkyl), wherein the definition of alkyl is as described above, preferably containing the alkyl of 1 to 8 carbon atoms, more preferably the alkyl of 1 to 6 carbon atoms, most preferably the alkyl of 1 to 3 carbon atoms. The limiting examples of alkoxy include: methoxyl, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or non-substituted, and when substituted, substituent is preferably one or more following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0126] In this application, the term "heterocycloalkyl" refers to a cycloalkyl group in which one or more carbon atoms are replaced by heteroatoms. In this application, the terms "C3-6 heterocycloalkyl" and "3-6 membered heterocycloalkyl" are used interchangeably to refer to a cycloalkyl group containing 3-6 ring atoms and one or more carbon atoms in the ring are replaced by heteroatoms; the terms "C4-6 heterocycloalkyl" and "4-6 membered heterocycloalkyl" are used interchangeably to refer to a cycloalkyl group containing 4-6 ring atoms and one or more carbon atoms in the ring are replaced by heteroatoms.

[0127] As used herein, a haloalkyl group refers to an alkyl group substituted with one or more halogen groups, wherein alkyl is as defined above. Non-limiting examples of haloalkyl groups include trifluoromethyl and trifluoroethyl groups; non-limiting examples of haloalkyl groups also include difluoromethyl, 1,1,2,2-tetrafluoroethyl, and perfluoroethyl groups.

[0128] In the present application, a haloalkoxy group refers to an alkoxy group substituted by one or more halogen groups, wherein the alkoxy group is as defined above; the haloalkoxy group may be fully halogenated or partially halogenated, and the number of halogen groups may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.; the halogen group is preferably F, Cl, Br, or I; for example, it may be trifluoromethoxy, difluoromethoxy, 1,1,2,2-tetrafluoroethoxy, or perfluoroethoxy.

[0129] In the present application, hydroxyalkyl refers to an alkyl group substituted by a hydroxy group, wherein alkyl is as defined above.

[0130] In the present application, alkenyl refers to a chain alkenyl group, also known as an alkene group, preferably an alkenyl group containing 2 to 8 carbon atoms, more preferably an alkenyl group containing 2 to 6 carbon atoms, further preferably an alkenyl group containing 2 to 4 carbon atoms, and most preferably an alkenyl group containing 2 to 3 carbon atoms. Non-limiting examples of alkenyl groups include: vinyl and propenyl. The alkenyl group may be further substituted with other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0131] In the present application, a haloalkyl group refers to an alkyl group substituted by one or more halogens, wherein the alkyl group is as defined above.

[0132] In the present application, a haloalkoxy group refers to an alkoxy group substituted by one or more halogen groups, wherein the alkoxy group is as defined above.

[0133] In the present application, hydroxyalkyl refers to an alkyl group substituted by a hydroxy group, wherein alkyl is as defined above.

[0134] In this application, hydroxyl refers to an -OH group.

[0135] In the present application, halogen refers to fluorine, chlorine, bromine or iodine.

[0136] In the present application, amino refers to -NH2.

[0137] In the present application, cyano refers to -CN.

[0138] In the present application, carboxyl refers to -C(O)OH.

[0139] In the present application, aminoalkyl refers to one or more hydrogen atoms on an amino group being replaced by an alkyl group, such as -NHalkyl or -N(alkyl)2.

[0140] In this application, carbonyl refers to -C(O). When used as a substituent of a cyclic group, "carbonyl" in this application encompasses the case of oxo, that is, the carbon atom in the carbonyl (-C(O)) group can be a ring atom. For example, "cyclic group is substituted with a carbonyl" encompasses the case where the cyclic group is substituted with =O ("oxo"), and the carbon atom in the carbonyl (-C(O)) group is a ring atom, and the cyclic group includes but is not limited to heterocyclic groups, aryls, and heteroaryls.

[0141] The hydrogen atoms described in this application can all be replaced by their isotope deuterium, and any hydrogen atom in the example compounds involved in this application can also be replaced by a deuterium atom.

[0142] In this application, "optional" or "optionally" means that the subsequently described event or circumstances can but need not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group can but need not be present, and the description includes both situations in which the heterocyclic group is substituted with an alkyl group and situations in which the heterocyclic group is not substituted with an alkyl group.

[0143] In this application, "substituted" means that one or more hydrogen atoms (preferably up to 5, more preferably 1 to 3 hydrogen atoms) in a group are independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0144] Those skilled in the art understand that the atoms constituting the compounds and their substituents described in the present application are generally of normal valence. For example, carbon atoms are tetravalent elements and sulfur atoms are hexavalent elements. When the atom is not indicated, such as all four or six atoms connected to a carbon atom or a sulfur atom, the unindicated atom is assumed to be hydrogen.

[0145] In this application, the illustrations of substituents connected to cyclic groups (e.g., aromatic rings, heteroaromatic rings, fused rings, and saturated or unsaturated cycloalkyl or heterocycloalkyl) through bonds between ring atoms are intended to indicate that, unless otherwise indicated, any ring position of the cyclic group or any ring of the fused ring group may be substituted with one or more substituents according to the techniques described in this application or immediately disclosed techniques known in the art. For example, for the cyclic group The general description of the position of the substituent R4 is intended to indicate that one or more hydrogen atoms (preferably up to 5, more preferably 1 to 3 hydrogen atoms) at any substitutable position on ring A can be independently replaced by one or more substituents R4, and when there is more than one R4 substituted on ring A, each R4 can be the same or different. For example, the cyclic group The following non-limiting examples of groups in which the substituent R4 is attached to a specific ring carbon atom are included:

[0146] And when there is more than one R4 substitution on the phenyl ring, each R4 may be the same or different. In some embodiments, similarly, for example, a cyclic group The following non-limiting examples of groups in which the substituent R8 is attached to a specific ring carbon atom are included:

[0147] And when there is more than one R8 substituted on the pyridine ring, each R8 may be the same or different.

[0148] In the present application, any substitution on an aliphatic ring, an aliphatic heterocycle, an aromatic ring, or an aromatic heterocycle means that one or more hydrogen atoms (preferably up to 5, more preferably 1 to 3 hydrogen atoms) at any substitutable position on the aliphatic ring, an aliphatic heterocycle, an aromatic ring, or an aromatic heterocycle are independently replaced by one or more substituents.

[0149] The compounds of this patent application include isotopic derivatives thereof. The term "isotopic derivative" refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of this patent application, but replacing hydrogen with "deuterium" or "tritium", or replacing fluorine with 18F-fluorine labeling (18F isotope), or replacing carbon atoms with 11C-, 13C- or 14C-enriched carbon (11C-, 13C- or 14C-carbon labeling; 11C-, 13C- or 14C-isotope) are within the scope of this patent application. Such compounds can be used as analytical tools or probes in, for example, biological assays, or as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamic, pharmacokinetics or receptor studies. The various deuterated forms of the compounds of this patent application refer to compounds in which each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of compounds with reference to relevant literature. Deuterated forms of the compounds can be prepared using commercially available deuterated starting materials, or they can be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane. Deuterated compounds generally retain comparable activity to the undeuterated compounds, and when deuterated at certain sites, they can achieve improved metabolic stability, thereby conferring certain therapeutic advantages.

[0150] The compounds of this patent application may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers with identical structures but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (such as racemates, mixtures of diastereomers). The substituents in the compounds of this patent application may have additional asymmetric atoms. All of these stereoisomers and their mixtures are included within the scope of this patent application. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers and (D)- and (L)-isomers can be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound of the present patent application can be prepared by asymmetric synthesis or chiral auxiliary, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a diastereomeric salt with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art to obtain the pure isomer. In addition, separation of enantiomers and diastereomers is typically accomplished by chromatography.

[0151] In the chemical structure of the compound described in this patent application, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both Two configurations.

[0152] The compound of this patent application can exist in different tautomeric forms, and all such forms are included in the scope of this patent application.Term " tautomer " or " tautomeric form " refer to the structural isomer that exists in equilibrium and is easily converted into another isomeric form from one isomeric form.It includes all possible tautomers, i.e. exists in the form of a single isomer or in the form of a mixture of any proportions of the tautomer.Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim etc.All tautomeric forms are within the scope of this patent application, and the naming of compound does not exclude any tautomer.

[0153] As used herein, a pharmaceutical composition refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, and other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0154] In the present application, pharmaceutically acceptable salts refer to salts of the compounds of the present application, which are safe and effective when used in mammals and have the desired biological activity.

[0155] With respect to a drug or pharmacologically active agent, the term "prophylactically or therapeutically effective amount" refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect, such as an amount sufficient to prevent, ameliorate, inhibit, delay, or slow the progression of a Pol θ-mediated disease. The determination of a prophylactically or therapeutically effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate prophylactically or therapeutically effective amount in each individual case can be determined by a person skilled in the art through routine testing.

[0156] The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0157] As used herein, the singular form "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0158] In the present application, "plurality" refers to 2 or more, for example, it can be an integer such as 2, 3, 4, 5, 6, 7, 8, etc.

[0159] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given for illustration purposes only and are not limiting.

[0160] The term "subject" encompasses mammals, such as humans, non-human primates (eg, rhesus monkeys), pigs, cows, horses, sheep, dogs, rabbits, mice, etc., preferably humans.

[0161] Unless otherwise specified in the present application, the solution mentioned in the reaction of the present application is an aqueous solution.

[0162] The term "room temperature" in this application refers to a temperature between 10°C and 25°C.

[0163] All patents, patent applications, and other publications are expressly incorporated herein by reference for the purposes of description and disclosure. These publications are provided solely for their disclosure prior to the filing date of the present application. All statements regarding the dates of these documents or the representation of the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. BRIEF DESCRIPTION OF THE DRAWINGS

[0164] Figure 1 is a blood drug concentration-time curve of rats after administration of Example 38 of the present application.

[0165] Figure 2 is a blood drug concentration-time curve of dogs after administration in Example 39 of the present application.

[0166] Figure 3 is a curve diagram of the changes in tumor volume of each group of mice in Example 40 of the present application. Example

[0167] The technical solution of this application is further described in detail below in conjunction with the accompanying drawings and specific implementation examples, but the implementation of this application is not limited to this. Equivalent substitutions, combinations, improvements or modifications of the technical solution of this application made by those skilled in the art based on the description of this application should be included in the scope of protection of this application.

[0168] Unless otherwise specified, the reagents, methods and equipment used in this application are conventional reagents, methods and equipment in this technical field. Unless otherwise specified, the reagents and materials used in the following examples are all commercially available.

[0169] Example 1 Synthesis of Compound KH01

[0170] Compound KH01-2: To a solution of compound KH01-1 (20 g, 81.54 mmol) in DCM (200 mL) at 0°C were added imidazole (8.327 g, 122.31 mmol) and TBS-Cl (14.75 g, 97.85 mmol). The mixture was allowed to react overnight at room temperature. After completion, water (600 mL) was added to quench the reaction mixture. The mixture was then extracted with dichloromethane (200 mL × 3). The organic phase was washed with saturated brine (200 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product, which was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain a colorless oil (28 g, 95.5% yield). 1H NMR (400MHz, DMSO-d6) δ4.44–4.35(m,1H),4.34–4.23(m,1H),3.60(d,J=10.9Hz,3H),3.57–3.47(m,1H),3.15 –3.06(m,1H),2.42–2.27(m,1H),1.95–1.83(m,1H),1.37(d,J=24.9Hz,9H),0.82(s,9H),0.15–-0.08(m,6H).

[0171] Compound KH01-3: To a solution of sodium periodate (57.11 g, 267.01 mmol) and ruthenium oxide (296 mg, 2.23 mmol) in water (240 mL) was added a solution of compound KH01-2 (16 g, 44.50 mmol) in ethyl acetate (120 mL). The mixture was allowed to react overnight at room temperature. After completion of the reaction, the reaction solution was filtered and the filtrate was extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated aqueous sodium bicarbonate (200 mL), 10% aqueous sodium thiosulfate (100 mL × 2), and saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product, which was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain a colorless oil (11.3 g, yield 68.0%). 1 H NMR(400MHz,DMSO-d6)δ4.46(dd,J=14.8,7.8Hz,2H),3.69(s,3H),2.73–2.6 1(m,1H),1.67–1.60(m,1H),1.40(s,9H),0.85(s,9H),0.09(d,J=5.8Hz,6H).

[0172] Compound KH01-4: To a solution of compound KH01-3 (5.5 g, 14.72 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid (5 mL) and the mixture was allowed to react at room temperature for 5 h. After the reaction was complete, the reaction solution was concentrated under vacuum to afford a pale pink oil (4.026 g, 100% yield). LCMS (ESI, m / z): 274.1 [M+H] + .

[0173] Compound KH01-5: To a solution of compound KH01-4 (4.026 g, 14.72 mmol) in 1,4-dioxane (50 mL) were added compound a (5.3 g, 22.08 mmol), RuPhos Pd G2 (572 mg, 0.74 mmol), and potassium phosphate (9.374 g, 44.16 mmol). The mixture was reacted at 100°C overnight under nitrogen. After completion, water (200 mL) was added to the reaction mixture to quench the reaction. The mixture was then extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 30:1) to obtain a yellow oil (4.56 g, yield 71.6%). LCMS (ESI, m / z): 433.1 [M+H]. + . 1 H NMR (400MHz, DMSO-d6) δ8.40(s,1H),7.45(s,1H),4.75(dt,J=66.3,8.0Hz,2H),3.65(s,3H),2.85(d t,J=12.5,7.9Hz,1H),2.46(s,3H),1.78(dt,J=12.5,8.1Hz,1H),0.89(s,9H),0.13(d,J=6.6Hz,6H).

[0174] Compound KH01-6: To a solution of compound KH01-5 (4.5 g, 10.40 mmol) in methanol (40 mL) were added water (8 mL) and lithium hydroxide (498 mg, 20.81 mmol) and allowed to react at room temperature overnight. After completion of the reaction, dilute hydrochloric acid was added to adjust the pH to 5, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by reverse-phase column chromatography (acetonitrile:water = 3:1) to obtain a yellow solid (1.2 g, yield 27.6%). LCMS (ESI, m / z): 419.2 [M+H] + . 1 H NMR (400MHz, DMSO) δ12.89(s,1H),8.37(s,1H),7.44(s,1H),4.72(dt,J=58.2,7.9Hz,2H),2.84(dt ,J=12.5,8.0Hz,1H),2.47(s,3H),1.77(dt,J=12.5,7.9Hz,1H),0.89(s,9H),0.13(d,J=5.9Hz,6H).

[0175] Compound KH01-7: Compound b (366 mg, 3.30 mmol) and T4P (19.8 g, 27.48 mmol) were added to a solution of compound KH01-6 (1.15 g, 2.75 mmol) in pyridine (20 mL) and allowed to react at room temperature for 2 h. After completion, water (100 mL) was added to the reaction mixture to quench the reaction. The mixture was then extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain a brown solid (1.17 g, yield 83.2%). LCMS (ESI, m / z): 512.4 [M+H]. +1 . 1 H NMR (400MHz, DMSO-d6) δ10.45(s,1H),8.39(s,1H),7.59–7.51(m,2H),7.39(s,1H),7.17–7.10(m,2H),4. 91–4.73(m,2H),2.89–2.74(m,1H),2.35(s,3H),1.86–1.76(m,1H),0.90(s,9H),0.15(d,J=10.3Hz,6H).

[0176] Compound KH01-8 (MC23-2321-105): To a solution of compound KH01-7 (500 mg, 0.98 mmol) in DMF (5 mL) were added compound c (233 mg, 1.95 mmol), tetrabutylammonium bromide (63 mg, 0.20 mmol), and potassium carbonate (675 mg, 4.89 mmol), and the mixture was allowed to react at 45°C for 4 h. After completion, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to afford a yellow oil (520 mg, 96.5% yield). LCMS (ESI, m / z): 550 [M+H]. + . 1H NMR (400MHz, DMSO-d6) δ8.37(s,1H),7.81–7.61(m,2H),7.54–7.37(m,3H),4.77–4.51(m,3H),4.16(dd,J=17.5,2.4H z,1H),3.25(t,J=2.4Hz,1H),2.65(s,3H),2.48–2.39(m,1H),1.75–1.60(m,1H),0.88(s,9H),0.10(d,J=13.8Hz,6H).

[0177] Compound KH01-9: Compound d (204 mg, 1.28 mmol), Pd(PPh3)2Cl2 (60 mg, 0.086 mmol), cuprous iodide (33 mg, 0.17 mmol), and DIEA (3 mL) were added to a solution of compound KH01-8 (470 mg, 0.86 mmol) in DMF (9 mL). The mixture was reacted at 70°C for 4 h. After completion, water (50 mL) was added to quench the reaction mixture. The mixture was then extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to afford a yellow solid (320 mg, 59.3% yield). LCMS (ESI, m / z): 628.2 [M+H]. + . 1 H NMR (400MHz, DMSO-d6) δ9.31–9.15(m,1H),8.38(s,1H),7.86–7.70(m,4H),7.52–7.40(m,3H),5.05(d,J=17.8Hz ,1H),4.73–4.51(m,3H),2.59(s,3H),1.81–1.66(m,1H),1.21–1.15(m,1H),0.88(s,9H),0.10(d,J=13.9Hz,6H).

[0178] Compound KH01: To a solution of compound KH01-9 (70 mg, 0.11 mmol) in trifluoroacetic acid (1 mL) was added water (0.3 mL) and the mixture was allowed to react at room temperature for 0.5 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by reverse-phase preparative chromatography to afford KH01 (17.7 mg, 31.3% yield). LCMS (ESI, m / z): 514.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.22(dd,J=4.4,2.3Hz,1H),8.38(s,1H),7.87–7.69(m,4H),7.47(t,J=8.7Hz,2H),7.40(s,1H),5.97(s,1H),5.0 5(d,J=17.8Hz,1H),4.68–4.61(m,1H),4.56(d,J=17.8Hz,1H),4.34(t,J=9.2Hz,1H),2.58(s,3H),2.46–2.36(m,1H),1.78–1.65(m,1H).

[0179] Example 2 Synthesis of Compound KH02

[0180] Compound KH02-1: KH02-0 (5 g, 20.92 mmol) was added to a single-necked flask, followed by 5M sodium hydroxide (8 mL, 40 mmol) and stirring at room temperature for 0.5 hour. The pH was adjusted to 1 with 4M hydrochloric acid, and the aqueous phase was extracted with dimethyltetrahydrofuran (150 mL x 5). The resulting organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The organic phase was then purified using a C18 column [eluent: water-acetonitrile (100:0-70:30)]. The eluate was collected, the acetonitrile was evaporated under reduced pressure, and lyophilized to obtain KH02-1 (2.0 g, yield: 73%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ: 13.20-13.16 (m, 1H), 8.14 (s, 1H), 4.53-4.46 (m, 1H), 4.36-4.28 (m, 2H).

[0181] Compound KH02-2: To a reaction flask, add KH02-1 (2 g, 15.26 mmol) and N,N-dimethylformamide (15 mL), followed by sodium carbonate (809 mg, 7.63 mmol), and stir at room temperature for 4 hours. Dilute with water and extract with dichloromethane. The resulting solution is spin-dried and purified on a silica gel column [eluent: petroleum ether-methyl tert-butyl ether (100:0-10:90)]. The eluate is collected and the solvent is evaporated under reduced pressure to obtain KH02-2 (1.05 g, yield: 31%) as a yellow solid. LCMS (ESI, m / z): 222.2 [M+H] + .

[0182] Compound KH02-3: To a reaction flask, add KH02-2 (1.05 g, 4.75 mmol) and dioxane (20 mL), followed by 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (a) (926 mg, 4.75 mmol), cesium carbonate (2.78 mg, 5.55 mmol), tris(dibenzylideneacetone)dipalladium (217 mg, 0.24 mmol), and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (272 mg, 0.48 mmol). Under nitrogen, heat to 100°C and stir overnight. The reaction mixture was cooled to room temperature, water was added until the cesium carbonate dissolved, and the mixture was extracted with ethyl acetate (100 mL x 3). The resulting solution was purified by silica gel column chromatography [eluent: dichloromethane-methanol (100:0-95:5)]. The eluate was collected and the solvent was evaporated under reduced pressure to obtain a yellow solid KH02-3 (280 mg, yield: 15%). LCMS (ESI, m / z): 381.1 [M+H] + .

[0183] Compound KH02-4: In a reaction flask, add KH02-3 (280 mg, 0.74 mmol) and methanol (4 mL), then add palladium on carbon (28 mg). Ventilate with a hydrogen balloon and stir at room temperature for 2 hours. After the reaction is complete, filter through celite and wash with methanol / dichloromethane until the filtrate shows no UV fluorescence. The filtrate is spin-dried and redissolved in dichloromethane, then dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure to obtain a yellow oil, KH02-4 (100 mg, yield: 98%). LCMS (ESI, m / z): Rt = 0.524 min; MS Calcd.: 290.1; MS Found: 2291.1 [M+H] + .

[0184] Compound KH02-5: KH02-4 (210 mg, 0.72 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (108 mg, 1.08 mmol) was added to the reaction flask, the temperature was lowered to 0°C, and isobutyl chloroformate (118 mg, 0.86 mmol) was added. Under nitrogen protection, the mixture was stirred at room temperature for half an hour. p-Fluoroaniline (104 mg, 0.94 mmol) was added and stirring was continued for 1 hour. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography [eluent: dichloromethane-methanol (100:0-90:10)]. The eluate was collected and the solvent was evaporated under reduced pressure to obtain KH02-5 (200 mg, yield: 72%) as a yellow solid. LCMS (ESI, m / z): 384.1 [M+H] + .

[0185] Compound KH02-6: To a reaction flask, KH02-5 (200 mg, 0.52 mmol), N,N-dimethylformamide (3 mL), and sodium hydroxide (35 mg, 0.79 mmol, 60 wt%) were added sequentially. Under nitrogen, the reaction was stirred at room temperature for 0.5 hour. Propargyl bromide (c) (80 mg, 0.67 mmol) was then added, and the reaction was stirred at room temperature for 1 hour. After completion, the reaction solution was quenched with water and extracted with ethyl acetate (40 mL x 3). The organic phases were combined, washed twice with saturated ammonium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product. The product was purified on a silica gel column [eluent: petroleum ether-methyl tert-butyl ether (100:0-40:60)]. The eluate was collected and the solvent was evaporated under reduced pressure to obtain KH02-6 (90 mg, yield: 40%) as a yellow solid. LCMS (ESI, m / z): 422.1 [M+H] + .

[0186] Compound KH02: To a reaction flask, KH02-6 (90 mg, 0.21 mmol), dioxane (3 mL), 3-bromopyridazine (d) (33 mg, 0.21 mmol), bistriphenylphosphine palladium dichloride (29 mg, 0.04 mmol), cuprous iodide (16 mg, 0.08 mmol), and N,N-diisopropylethylamine (54 mg, 0.42 mmol) were added sequentially. After nitrogen ventilation, the temperature was raised to 70°C and stirred overnight. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. The product was purified by silica gel column chromatography [eluent: dichloromethane-methanol (100:0-90:10)]. The eluate was collected and the solvent was evaporated under reduced pressure to obtain a yellow oil. Purification by preparative HPLC gave KH02 (5.8 mg, yield: 5%). LCMS (ESI, m / z): Rt=1.905min; MS Calcd.: 499.1; MS Found: 500.0[M+H] + . 1 H NMR (400MHz, CD3OD-d6) δ: 9.15 (dd, J=4.8Hz, 2.0Hz, 1H), 8.24 (s, 1H), 7.75-7.68 (m, 4H), 7.36 (t, J=8.8Hz, 2H), 7.22 (s, 1H), 5.16 (dd, J=9.6Hz, 8.4Hz, 1H), 5.04 (d, J=17.6Hz, 1H), 4.67 (d, J=18.0Hz, 1H), 4.52 (dd, J=8.4Hz, 4.4Hz, 1H), 4.38 (t, J=8.8Hz, 1H), 2.59 (s, 3H).

[0187] Example 3 Synthesis of KH03

[0188] Compound KH03-1: To a reaction flask, add KH03-0 (1.2 g, 8.39 mmol) and dioxane (40 mL), followed by 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (a) (1.63 mg, 8.39 mmol), cesium carbonate (4.86 g, 15.10 mmol), tris(dibenzylideneacetone)dipalladium (294 mg, 0.42 mmol), and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (485 mg, 0.84 mmol). Under nitrogen, heat to 100°C and stir overnight. The reaction mixture was cooled to room temperature, water was added until the cesium carbonate dissolved, and the mixture was extracted with ethyl acetate (150 mL x 3). The resulting solution was purified by silica gel column chromatography [eluent: petroleum ether-methyl tert-butyl ether (100:0-70:30)]. The eluate was collected and the solvent was evaporated under reduced pressure to obtain a yellow solid KH03-1 (1.2 g, yield: 47%). LCMS (ESI, m / z): 303.1 [M+H] + . 1 H NMR(400MHz, CDCl3)δ:8.49(s,1H),8.51(s,1H),7.45-7.42(m,2H),7.04(s,1H),7.01(q,J=6.4Hz,2H ),5.13(q,J=6.4Hz,1H),3.08-2.99(m,1H),2.69-2.66(m,1H),2.56-2.51(m,1H),2.38-2.33(m,1H).

[0189] Compound KH03-2: In a reaction flask, add KH03-1 (1.2 g, 3.97 mmol), methanol (12 mL), and deionized water (4 mL), followed by sodium hydroxide (318 mg, 7.95 mmol). Stir at room temperature for 1 hour under nitrogen. Adjust the pH to 5 with 2M hydrochloric acid, and purify the resulting solution via a C18 column [eluent: water-acetonitrile (100:0-40:60)]. The eluate was collected, the acetonitrile was evaporated under reduced pressure, and lyophilized to obtain a yellow solid KH03-2 (1.05 g, yield: 83%). LCMS (ESI, m / z): 289.1 [M+H] + .

[0190] Compound KH03-3: KH03-2 (460 mg, 1.60 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (242 mg, 2.39 mmol) was added to the reaction flask, the temperature was lowered to 0 degrees Celsius, and isobutyl chloroformate (260 mg, 1.91 mmol) was added. Under nitrogen protection, the mixture was stirred at room temperature for half an hour. p-Fluoroaniline (230 mg, 2.07 mmol) was added to the reaction flask and stirring was continued for 1 hour. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified on a silica gel column [eluent: petroleum ether-methyl tert-butyl ether (100:0-50:50)]. The eluate was collected and the solvent was evaporated under reduced pressure to obtain KH03-3 (300 mg, yield: 49%) as a light yellow solid. LCMS (ESI, m / z): 382.1 [M+H] + . 1 H NMR(400MHz, CDCl3)δ:8.59(s,1H),8.51(s,1H),7.45-7.42(m,2H),7.04(s,1H),7.01(q,J=6.4Hz,2H ),5.13(q,J=6.4Hz,1H),3.08-2.99(m,1H),2.69-2.66(m,1H),2.56-2.51(m,1H),2.38-2.33(m,1H).

[0191] Compound KH03-4: To a reaction flask, KH03-3 (300 mg, 0.79 mmol), N,N-dimethylformamide (3 mL), and sodium hydroxide (47 mg, 1.18 mmol, 60 wt%) were added sequentially. Under nitrogen, the reaction was stirred at room temperature for 0.5 hours. Propargyl bromide (c) (120 mg, 1.03 mmol) was then added, and the reaction was stirred at room temperature for another hour. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate (40 mL x 3). The organic phases were combined, washed twice with saturated ammonium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product. The product was purified on a silica gel column using petroleum ether-methyl tert-butyl ether (100:0-70:30) as eluent. The eluate was collected and the solvent was evaporated under reduced pressure to obtain the crude product, a yellow solid (290 mg, yield: 87%). LCMS (ESI, m / z): Rt=0.985min; MS Calcd.: 419.1; MS Found: 420.1[M+H] + . 1H NMR(400MHz, DMSO-d6)δ:8.40(s,1H),7.70-7.67(m,2H),7.47-7.42(m,3H),4.80(dd,J=8.0Hz,4.0Hz,1H),4.67(dd,J=13.6Hz,2.4H z,1H),4.67(dd,J=17.6Hz,2.0Hz,1H),3.26(t,J=2.4Hz,1H),2.68-2.64(m,1H),2.62(s,3H),2.559-2.53(m,1H),2.09-1.99(m,2H).

[0192] Compound KH03: KH03-4 (290 mg, 0.69 mmol), 3-bromopyridazine (d) (109 mg, 0.69 mmol), DIPEA (178 mg, 1.38 mmol), bistriphenylphosphine palladium dichloride (48 mg, 0.07 mmol), cuprous iodide (26 mg, 0.14 mmol), and dioxane (4 mL) were added sequentially to a reaction flask. Under nitrogen, the temperature was raised to 70°C and the reaction was stirred overnight. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified on a silica gel column [eluent: dichloromethane-methanol (100:0-90:10)] to obtain a brown oil. Purification by preparative HPLC gave KH03 (28.95 mg, yield: 7%). LCMS (ESI, m / z): 498.0 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ:9.9.22(dd,J=4.4Hz,2.4Hz,1H),8.40(s,1H),7.79-7.75(m,2H),7.74-7.70(m,2H),7.48(t,J=8.8Hz,2H),7.38(s,1H),5 .04(d,J=18.0Hz,1H),4.85(dd,J=8.8Hz,3.2Hz,1H),4.61(d,J=17.6Hz,1 H),2.69-2.62(m,1H),2.57(s,3H),2.55-2.53(m,1H),2.11-2.05(m,2H).

[0193] Example 4 Synthesis of KH04

[0194] Compound KH04-1: To a reaction flask, add KH04-0 (800 mg, 6.95 mmol) and N,N-dimethylformamide (20 mL), followed by 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (a) (1.36 g, 6.95 mmol) and cesium carbonate (4.1 g, 12.6 mmol). Under nitrogen, heat to 90°C and stir overnight. The reaction solution is cooled to room temperature, water is added until the cesium carbonate dissolves, and the pH is adjusted to 5 with 2 mol / L hydrochloric acid. The resulting solution is purified by C18 reverse-phase column [eluent: deionized water-acetonitrile (100:0-70:30)]. The eluate is collected, the acetonitrile is evaporated under reduced pressure, and the water is lyophilized to obtain a yellow solid KH04-1 (520 mg, yield: 27%). LCMS (ESI, m / z): 275.2 [M+H] + . 1 H NMR (400MHz, CD3OD) δ: 6.66 (s, 1H), 6.47 (s, 1H), 4.57-4.54 (m, 1H), 3.63-3.61 (m, 1H), 3.60-3.46 (m, 1H), 2.39 (s, 3H), 2.36-2.28 (m, 1H), 2.19-2.07 (m, 3H).

[0195] Compound KH04-2: KH04-1 (340 mg, 1.24 mmol) was dissolved in dichloromethane (8 mL). Triethylamine (188 mg, 1.86 mmol) was added to the reaction flask, the temperature was lowered to 0°C, and isobutyl chloroformate (220 mg, 1.61 mmol) was added. Under nitrogen, the mixture was stirred at room temperature for half an hour. p-Fluoroaniline (179 mg, 1.61 mmol) was added to the reaction flask and stirring was continued for 1 hour. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified on a silica gel column [eluent: petroleum ether-methyl tert-butyl ether (100:0-60:40)]. The eluate was collected and the solvent was evaporated under reduced pressure to obtain KH04-2 (335 mg, yield: 73%) as a pale yellow solid. LCMS (ESI, m / z): 368.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ: 10.12-9.96 (m, 1H), 7.46 (s, 2H), 6.98 (t, J=8.4Hz, 2H), 6.75 (s, 1H), 6.56 (s, 1H), 4.92-4. 85 (m, 1H), 3.62 (s, 1H), 3.36 (s, 1H), 2.74-2.54 (m, 4H), 2.37-2.30 (m, 1H), 2.17-2.14 (m, 1H), 2.00-1.92 (m, 1H).

[0196] Compound KH04-3: To a reaction flask, KH04-2 (335 mg, 0.91 mmol), N,N-dimethylformamide (5 mL), and sodium hydroxide (40 mg, 1.0 mmol, 60 wt%) were added sequentially. Under nitrogen, the reaction was stirred at room temperature for 0.5 hour. Propargyl bromide (c) (131 mg, 1.1 mmol) was then added, and the reaction was stirred at room temperature for another hour. After completion, the reaction solution was quenched with water and extracted with ethyl acetate (40 mL x 3). The organic phases were combined, washed twice with saturated ammonium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product. The product was purified on a silica gel column [eluent: petroleum ether-methyl tert-butyl ether (100:0-30:70)]. The eluate was collected and the solvent was evaporated under reduced pressure to obtain KH04-3 (360 mg, yield: 97%) as a yellow solid. LCMS (ESI, m / z): 405.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ: 7.58 (s, 2H), 7.17 (t, J=8.4Hz, 2H), 6.58 (s, 1H), 6.36 (s, 1H), 4.56-4.4 (m, 3H), 4.12(q, J=7.2Hz, 1H), 3.68-3.62(m, 1H), 2.48(s, 3H), 2.26-2.20(m, 2H), 2.04-1.91(m, 3H).

[0197] Compound KH04: KH04-3 (360 mg, 0.89 mmol), 3-bromopyridazine (d) (170 mg, 1.1 mmol), DIPEA (344 mg, 2.67 mmol), bistriphenylphosphine palladium dichloride (124 mg, 0.18 mmol), cuprous iodide (67 mg, 0.35 mmol), and dioxane (5 mL) were added sequentially to a reaction flask. Under nitrogen, the mixture was heated to 100°C and stirred overnight. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain a crude product, which was purified on a silica gel column [eluent: dichloromethane-methanol (100:0-85:15)] to obtain a brown oil. Purification by preparative HPLC gave KH04 (69.56 mg, yield: 16%). LCMS (ESI, m / z): 484.0 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ: 9.13 (dd, J=4.4Hz, 2.0Hz, 1H), 7.78 (s, 2H), 7.73-7 .67(m, 2H), 7.31(t, J=8.4Hz, 2H), 6.61(s, 1H), 6.45(s, 1H), 4.96(d, J=17.6 Hz, 1H), 4.68 (d, J=17.6Hz, 1H), 4.50 (dd, J=7.2Hz, 5.2Hz, 1H), 3.63-3.58 (m , 1H), 3.46-3.30(m, 1H), 2.44(s, 3H), 2.20-2.16(m, 1H), 2.07-1.96(m, 3H).

[0198] Example 5 Synthesis of Compound KH05

[0199] Compound KH05-1: KH02-4 (480 mg, 1.65 mmol), acetonitrile (4 mL), 3-chloro-4-fluoroaniline (240 mg, 1.56 mmol), 1-methylimidazole (511 mg, 6.24 mmol), and N,N,N,N-tetramethylchloroformamidine hexafluorophosphate (874 mg, 3.12 mmol) were added to a reaction flask in sequence. Under nitrogen protection, the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was quenched with water and extracted with dichloromethane. The resulting solution was purified by silica gel column chromatography [eluent: dichloromethane-methanol (100:0-94:6)]. The eluent was collected and the solvent was evaporated under reduced pressure to obtain KH05-1 (580 mg, yield: 83%) as a yellow solid. LCMS (ESI, m / z): 417.8 [M+H] + . 1 H NMR (400MHz, CD3OD) δ: 8.27 (s, 1H), 7.83-7.80 (m, 1H), 7.49-7.45 (s, 1H), 7.24-7.19 (m, 2H), 5.27 ( dd, J = 9.2, 4.4 Hz, 1H), 4.74 (t, J = 7.2 Hz, 1H), 4.49 (dd, J = 9.2, 4.4 Hz, 1H), 2.81 (s, 1H), 2.43 (s, 3H).

[0200] Compound KH05-2: To a reaction flask, KH05-1 (580 mg, 1.39 mmol), N,N-dimethylformamide (5 mL), and sodium hydroxide (83 mg, 2.08 mmol, 60 wt%) were added sequentially. Under nitrogen, the reaction was stirred at room temperature for 0.5 hour. Propargyl bromide (c) (198 mg, 1.67 mmol) was then added, and the reaction was stirred at room temperature for another hour. Upon completion, the reaction solution was quenched with water and extracted with ethyl acetate (80 mL x 3). The combined organic phases were washed twice with saturated ammonium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product. The product was purified on a silica gel column using petroleum ether-methyl tert-butyl ether (100:0-40:60) as eluent. The eluate was collected and the solvent was evaporated under reduced pressure to obtain KH05-2 (340 mg, yield: 53%) as a yellow solid. LCMS (ESI, m / z): 455.8 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ:8.24(s,1H),7.87(s,1H),7.58(s,1H),7.47(t,J=8.8Hz,1H),7.26(s,1H),5.14(dd,J=9.6Hz,4.4Hz,1H),4 .76(dd,J=17.2,2.8Hz,1H),4.46-4.43(m,1H),4.39-4.34(m,1H),4.28(dd,J=17.6,2.4Hz,1H),2.78(t,J=2.8Hz,1H),2.66(s,3H).

[0201] Compound KH05: KH05-2 (340 mg, 0.74 mmol), dioxane (5 mL), 3-bromopyridazine (d) (118 mg, 0.74 mmol), bistriphenylphosphine palladium dichloride (49 mg, 0.07 mmol), cuprous iodide (26 mg, 0.14 mmol), and N,N-diisopropylethylamine (191 mg, 1.48 mmol) were added sequentially to a reaction flask. After nitrogen ventilation, the temperature was raised to 50°C and stirred for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. The product was purified by silica gel column chromatography [eluent: dichloromethane-methanol (100:0-90:10)]. The eluate was collected and the solvent was evaporated under reduced pressure to obtain a yellow oil. Purification by preparative HPLC gave KH05 (135.82 mg, yield: 33%). LCMS (ESI, m / z): 533.9 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ: 9.23 (dd, J=3.6Hz, 2.8Hz, 1H), 8.14 (s, 1H), 7.99 (d, J=7.2Hz, 1H), 7.75-7 .71 (m, 4H), 7.42 (s, 1H), 5.08-5.03 (m, 2H), 4.70-4.63 (m, 2H), 4.36 (t, J=8.8Hz, 1H), 2.57 (s, 3H).

[0202] Example 6 Synthesis of Compound KH06

[0203] Compound KH06-1: KH03-2 (380 mg, 1.32 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (213 mg, 2.11 mmol) was added to the reaction flask, and the temperature was lowered to 0°C. Isobutyl chloroformate (233 mg, 1.72 mmol) was then added. Under nitrogen, the mixture was stirred at room temperature for half an hour. 3-Chloro-4-fluoroaniline (248 mg, 1.72 mmol) was added to the reaction flask and stirring continued for 1 hour. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. The product was purified on a silica gel column using dichloromethane-methyl tert-butyl ether (100:0-93:7) as eluent. The eluate was collected and the solvent was evaporated under reduced pressure to obtain KH06-1 (330 mg, 60% yield) as a purple solid. LCMS (ESI, m / z): 415.8 [M+H]. + .

[0204] Compound KH06-2: To a reaction flask, KH06-1 (330 mg, 0.79 mmol), N,N-dimethylformamide (3 mL), and sodium hydroxide (47 mg, 1.18 mmol, 60 wt%) were added sequentially. Under nitrogen, the reaction was stirred at 0°C for 0.5 hours. Propargyl bromide (c) (120 mg, 1.03 mmol) was then added, and the reaction was stirred at room temperature for 1 hour. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate (40 mL x 3). The organic phases were combined, washed twice with saturated ammonium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product. The product was purified on a silica gel column using petroleum ether-methyl tert-butyl ether (100:0-65:35) as eluent. The eluate was collected and the solvent was evaporated under reduced pressure to obtain the crude product, a yellow solid (190 mg, yield: 53%). LCMS (ESI, m / z): 454.1 [M+H] + .

[0205] Compound KH06: KH06-2 (190 mg, 0.42 mmol), 3-bromopyridazine (d) (66 mg, 0.42 mmol), DIPEA (162 mg, 1.26 mmol), bistriphenylphosphine palladium dichloride (28 mg, 0.04 mmol), cuprous iodide (15 mg, 0.08 mmol), and dioxane (3 mL) were added sequentially to a reaction flask. Under nitrogen, the temperature was raised to 70°C and the reaction was stirred overnight. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified on a silica gel column [eluent: dichloromethane-methanol (100:0-88:12)] to obtain a brown oil. Purification by preparative HPLC gave KH06 (47.46 mg, yield: 21%). LCMS (ESI, m / z): 531.9 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ:9.24-9.22(m,1H),8.41(s,1H),8.05-8.02(m,1H),7.77-7.71(m,4H),7.40(s,1H),5.06(d,J=17.6Hz, 1H),4.88(dd,J=8.8Hz,2.4Hz,1H),4.65(d,J=18Hz,1H),2.68-2.61(m,1H),2.58(s,3H),2.57-2.55(m,1H),2.13-2.07(m,2H).

[0206] Example 7 Synthesis of Compound KH07

[0207] Compound KH07-1: To a reaction flask were added KH04-1 (1.0 g, 3.65 mmol), acetonitrile (10 mL), 3-chloro-4-fluoroaniline (690 mg, 4.74 mmol), 1-methylimidazole (1.2 g, 14.6 mmol), and N,N,N,N-tetramethylchloroformamidine hexafluorophosphate (2.04 g, 7.3 mmol). Stir at room temperature for 1 hour under nitrogen. After completion of the reaction, the mixture was quenched with water and extracted with dichloromethane. The resulting solution was purified by silica gel column chromatography [eluent: petroleum ether-methyl tert-butyl ether (100:0-00:100)]. The eluate was collected and the solvent was evaporated under reduced pressure to obtain KH07-1 (1.0 g, yield: 68%) as a yellow solid. LCMS (ESI, m / z): 401.8 [M+H] + .

[0208] Compound KH07-2: To a reaction flask, KH07-1 (1.0 g, 2.49 mmol), N,N-dimethylformamide (8 mL), and sodium hydroxide (149 mg, 3.73 mmol, 60 wt%) were added sequentially. Under nitrogen, the reaction was stirred at room temperature for 0.5 hour. Propargyl bromide (c) (296 mg, 2.49 mmol) was then added, and the reaction was stirred at room temperature for another hour. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate (60 mL x 3). The combined organic phases were washed twice with saturated ammonium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product. The product was purified on a silica gel column using petroleum ether-methyl tert-butyl ether (100:0-30:70) as eluent. The eluate was collected and the solvent was evaporated under reduced pressure to obtain KH07-2 (860 mg, yield: 78%) as a yellow solid. LCMS (ESI, m / z): 439.8 [M+H] + . 1 H NMR(400MHz,CD3OD)δ:7.94(s,1H),7.62(s,1H),7.43(t,J=8.8Hz,1H),6.66(s,1H),6.46(s,1H),4.68(dd,J=17.2,2.4Hz,1H),4.49-4.45(m,1H ),4.29(dd,J=17.2,2.4Hz,1H),3.61-3.57(m,1H),3.45-3.40(m,1H),2 .72(t,J=2.4Hz,1H),2.52(s,3H),2.19-2.14(m,1H),2.04-1.96(m,3H).

[0209] Compound KH07: KH07-2 (300 mg, 0.68 mmol), 3-bromopyridazine (d) (108 mg, 0.68 mmol), DIPEA (173 mg, 1.34 mmol), bistriphenylphosphine palladium dichloride (49 mg, 0.07 mmol), cuprous iodide (27 mg, 0.14 mmol), and dioxane (5 mL) were added sequentially to a reaction flask. Under nitrogen, the mixture was heated to 70°C and stirred overnight. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified on a silica gel column [eluent: dichloromethane-methanol (100:0-90:10)] to afford a brown oil. Purification by preparative HPLC afforded KH07 (28.9 mg, yield: 8%). LCMS (ESI, m / z): 517.9 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ: 9.14 (dd, J=4.4Hz, 2.0Hz, 1H), 8.02 (d, J=1.6Hz, 1 H), 7.74-7.68 (m, 3H), 7.46 (t, J=8.8Hz, 1H), 6.63 (s, 1H), 6.47 (s, 1H), 5.00 (d, J=18.0Hz, 1H), 4.67 (d, J=18.0Hz, 1H), 4.53-4.50 (m, 1H), 3.63-3.58 (m , 1H), 3.47-3.41(m, 1H), 2.46(s, 3H), 2.23-2.17(m, 1H), 2.09-1.97(m, 3H).

[0210] Example 8 Synthesis of Compound KH08

[0211] KH07-2 (320 mg, 0.73 mmol), 6-bromopyridin-2 (1H) -one (190 mg, 1.09 mmol), DIPEA (188 mg, 1.46 mmol), bistriphenylphosphine palladium dichloride (49 mg, 0.07 mmol), cuprous iodide (27 mg, 0.14 mmol) and dioxane (5 mL) were added to the reaction flask in sequence. Under nitrogen protection, the temperature was raised to 70 ° C. and the reaction was stirred overnight. After the reaction was completed, the reaction solution was evaporated under reduced pressure to remove the solvent to obtain a crude product, which was purified by silica gel column [eluent: dichloromethane-methanol (100:0-90:10)] to obtain a brown oil. Purification by preparative HPLC gave 19 mg of a light yellow solid containing impurities. MS Found: 535.2 [M+H] + Chiral-HPLC chiral separation gave KH08 (28.9 mg, yield: 2.3%). LCMS (ESI, m / z): 532.9 [M+H] + . 1 H NMR (400MHz, CD3OD) δ: 7.97 (br, 1H), 7.67 (d, J=2.4Hz, 1H), 7.52-7.44 (m, 2H), 6.64 (s, 1H), 6.54 (dd, J=9.6, 0.8Hz, 1H), 6.47-6.45 (m, 2 H), 4.94 (d, J = 18.0Hz, 1H), 4.56-4.48 (m, 2H), 3.62-3.67 (m, 1H), 3.47-3.41 (m, 1H), 2.45 (s, 3H), 2.21-2.16 (m, 1H), 2.09-1.97 (m, 3H).

[0212] Example 9 Synthesis of Compound KH09

[0213] Compound KH09-1: Add KH09-0 (50 g, 209 mmol) to a reaction flask. Add aqueous sodium hydroxide (5N, 83.6 mL, 418 mmol) dropwise in an ice-water bath and stir at room temperature for 0.5 hour. Wash once with methyl tert-butyl ether, adjust to acidity with concentrated hydrochloric acid, extract with 2-methyltetrahydrofuran (200 mL x 10), dry over anhydrous sodium sulfate, filter, and evaporate the filtrate to remove the solvent under reduced pressure to obtain crude KH09-1 as a brown oil (14 g, yield: 51%). LCMS: 132.3 [M+H]+, 149.2 [M+NH4]+.

[0214] Compound KH09-2: Dissolve KH09-1 (14 g, 106.80 mmol) and triethylamine (21.57 g, 213.6 mmol) in acetone (100 mL). Add benzyl bromide (18.27 g, 106.80 mmol) in an ice-water bath. Stir under nitrogen overnight at room temperature. After completion of the reaction, evaporate the solvent under reduced pressure to obtain the crude product. Purify the crude product by silica gel column chromatography [petroleum ether:methyl tert-butyl ether (v / v) = (100:0-00:100)] to obtain KH09-2 as a white solid (4.0 g, yield: 16%, purity: >99%). LCMS: 222.2 [M+H] + ,239.2[M+NH4] + .

[0215] Compound KH09-3: To a reaction flask, add KH09-2 (1.50 g, 6.78 mmol), compound a (1.95 g, 8.14 mmol), Pd2(dba)3 (620 mg, 0.67 mmol), Xantphos (785 mg, 1.36 mmol), DOX (40 mL), and K2CO3 (1.22 g, 8.81 mmol). Stir at 85°C under nitrogen for 5 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography [petroleum ether:methyl tert-butyl ether (v / v) = (100:0-50:50)] to obtain KH09-3 as a yellow oil (900 mg, yield: 34%, purity: >99%). LCMS: 381.2 [M+H] + .

[0216] Compound KH09-4: Pd / C (100 mg, 10%) was added to KH09-3 (900 mg, 2.37 mmol) in methanol (40 mL). The mixture was stirred at room temperature overnight under a hydrogen atmosphere. After completion of the reaction, the mixture was filtered and the solvent was evaporated from the filtrate under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-90:10)] to afford KH09-4 as a yellow oil (650 mg, yield: 94%). LCMS: 291.1 [M+H] + .

[0217] Compound KH09-5: In a reaction flask, KH09-4 (240 mg, 0.83 mmol), compound b (144 mg, 0.99 mmol), TCFH (466 mg, 1.66 mmol), NMI (272 mg, 3.32 mmol) and acetonitrile (15 mL) were added. The mixture was protected by nitrogen and reacted at room temperature for 1 hour. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography [dichloromethane: methanol (v / v) = (100:0-95:5)] to give a yellow solid KH09-5 (300 mg, yield: 86%, purity: >99%).

[0218] LCMS: 418.1[M+H] + .

[0219] Compound KH09-6: KH09-5 (300 mg, 0.72 mmol) and DMF (5 mL) were added to a reaction flask under nitrogen protection. NaH (43 mg, 1.08 mmol, 60% in mineral oil) was added to an ice-water bath. Stir at room temperature for 0.5 hour. Propyl bromide c (128 mg, 1.08 mmol) was added under ice-water bath. The ice-water bath was removed and the reaction was stirred at room temperature for 2 hours. The reaction was quenched by adding aqueous ammonium chloride solution and extracted with ethyl acetate (50 mL x 2). The mixture was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure to obtain the crude product. Purification by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-96:4)] afforded KHKH09-6 as a yellow oil (280 mg, yield: 85%, purity: >99%). LCMS: 456.1 [M+H] + .

[0220] Compound KH09: To a reaction flask, KHKH09-6 (130 mg, 0.29 mmol), compound d (81 mg, 0.34 mmol), Pd(PPh3)2Cl2 (41 mg, 0.06 mmol), CuI (11 mg, 0.06 mmol), DOX (10 mL), and DIPEA (112 mg, 0.87 mmol) were added. The mixture was stirred at 60°C under nitrogen for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. The product was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-96:4)] and prep-HPLC. Acetonitrile was evaporated under reduced pressure, and the product was lyophilized to obtain KH09 as a white solid (82.07 mg, yield: 51%, purity: 99.26%). LCMS: 563.8 [M+H] + .HNMR(400MHz,DMSO-d6)δ:8.66(s,2H),8.13(s,1H),7.94(d,J=6.0Hz,1H),7.70(d,J=7.6Hz,2H),7.42(s,1H),5.0 2(dd,J=9.2,3.2Hz,1H),4.95(d,J=17.6Hz,1H),4.65-4.61(m,2H),4.35(t,J=8.8Hz,1H),3.95(s,3H),2.56(s,3H).

[0221] Example 10 Synthesis of Compound KH10

[0222] To a reaction flask, KH09-6 (150 mg, 0.33 mmol), m-fluoroiodobenzene (88 mg, 0.39 mmol), Pd(PPh3)2Cl2 (46 mg, 0.07 mmol), CuI (13 mg, 0.07 mmol), DOX (10 mL), and DIPEA (128 mg, 0.99 mmol) were added and stirred at 60°C under nitrogen for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-95:5)] and prep-HPLC. Acetonitrile was evaporated under reduced pressure, and the product was lyophilized to remove water, yielding KH10 as a white solid (13.11 mg, yield: 7%, purity: 99.49%). LCMS: 549.8 [M+H] +.HNMR(400MHz,DMSO-d6)δ:8.14(s,1H),7.94(dd,J=6.8,2.4Hz,1H),7.74-7.70(m,2H),7.47-7.41(m,2H),7.30-7.25(m,1H),7.22-7.19(m,2H ),5.02(dd,J=9.2,3.2Hz,1H),4.94(d,J=18.0Hz,1H),4.64(dd,J=8.8,3.2Hz,1H),4.58(d,J=18.0Hz,1H),4.35(t,J=8.8Hz,1H),2.55(s,3H).

[0223] Example 11 Synthesis of Compound KH11

[0224] Compound KH11-2: To a reaction flask, add KH11-1 (10.0 g, 52.33 mmol), DMF (0.5 mL), and DCM (200 mL). Add oxalyl chloride (7.31 g, 57.56 mmol) dropwise under an ice-water bath with nitrogen protection. Stir at room temperature for 1 hour, then add MeOH (10 mL). The reaction mixture is evaporated under reduced pressure to remove the solvent, affording the crude product KH11-2 as a light yellow solid (8.0 g, yield: 74%, purity: >99%). LCMS: 206.2 [M+H] + .

[0225] Compound KH11-3: To a reaction flask, add KH11-2 (8.0 g, 39.0 mmol), UHP (7.33 g, 78.0 mmol), and DCM (100 mL). TFAA (16.38 g, 78.0 mmol) was added dropwise in an ice-water bath. Stir overnight at room temperature, then add water (100 mL). The mixture was separated and the organic phase was washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to remove the solvent under reduced pressure to obtain the crude product. Purification by silica gel column chromatography [petroleum ether:methyl tert-butyl ether (v / v) = (100:0-50:50)] afforded KH11-3 as a yellow oil (6.0 g, yield: 66%, purity: 95%). LCMS: 222.1 [M+H] + .

[0226] Compound KH11-4: KH11-3 (6.0 g, 27.13 mmol) and phosphorus oxychloride (50 mL) were added to a reaction flask and stirred overnight at 90°C. The reaction solution was evaporated to remove the solvent under reduced pressure, and the pH was adjusted to alkaline by adding saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to remove the solvent under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography [petroleum ether:methyl tert-butyl ether (v / v) = (100:0-70:30)] to obtain KH11-4 as a yellow oil (6.0 g, yield: 92%, purity: >99%). LCMS: 240.1 [M+H] + .

[0227] Compound KH11-5: To a reaction flask, add KH11-4 (6.0 g, 25.14 mmol), sodium methoxide (136 mg, 2.51 mmol), and MeOH (50 mL). Add sodium borohydride (1.72 g, 45.25 mmol) in steps under an ice-water bath. Stir at room temperature for 2 hours. Evaporate the reaction mixture under reduced pressure to remove the solvent, filter, and evaporate the filtrate under reduced pressure to obtain crude product KH11-5 as a yellow oil (5.1 g, yield: 90%, purity: 95%). LCMS: 211.2 [M+H] + .

[0228] Compound KH11-6: To a reaction flask, KH11-5 (5.1 g, 24.11 mmol) and DCM (200 mL) were added stepwise under an ice-water bath with nitrogen protection. The mixture was stirred at room temperature for 1 hour. A saturated sodium thiosulfate solution and a saturated sodium bicarbonate solution (1:1) (200 mL) were added and stirred at room temperature for 20 minutes. The mixture was extracted with dichloromethane (200 mL x 2) and washed twice with saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure to obtain the crude product. Purification by silica gel column chromatography [petroleum ether:methyl tert-butyl ether (v / v) = (100:0-80:20)] afforded KH11-6 as a yellow oil (5.0 g, yield: 97%, purity: ~98%). HNMR (400MHz, DMSO-d6), δ: 9.96 (s, 1H), 8.39 (s, 1H), 8.21 (s, 1H).

[0229] Compound KH11-7: To a reaction flask, add KH11-6 (550 mg, 2.62 mmol) and DCM (26 mL). Add DAST (632 mg, 3.93 mmol) dropwise under ice-water bath. Stir at room temperature for 1 hour. Quench the reaction by adding a solution of sodium bicarbonate (136 mg, 1.62 mmol) dissolved in water (2 mL) under ice-water bath. Extract quickly with dichloromethane (20 mL x 2). The organic phase is dried over anhydrous sodium sulfate and filtered. The filtrate is evaporated under reduced pressure at 30°C to remove the solvent, yielding crude KH11-7 as a yellow liquid (500 mg, yield: 78%, purity: ~95%). H NMR (400 MHz, DMSO-d6), δ: 8.29 (s, 1H), 8.12 (s, 1H), 7.10 (t, J = 54.0 Hz, 1H).

[0230] Compound KH11-9: To a reaction flask, add KH11-8 (6.0 g, 41.2 mmol), K2CO3 (6.8 g, 49.5 mmol), and DMF (100 mL). Under nitrogen, add propargyl bromide c (5.9 g, 49.5 mmol) at room temperature. Stir overnight at room temperature until the reaction is complete. The reaction mixture is quenched with water and extracted with ethyl acetate (50 mL x 2). The organic phase is washed twice with saturated sodium chloride. The organic phase is dried over anhydrous sodium sulfate and filtered. The solvent is evaporated from the filtrate under reduced pressure to obtain the crude product. Purification by silica gel column chromatography [petroleum ether:methyl tert-butyl ether (v / v) = (100:0-95:5)] affords KH11-9 as a pale yellow oil (5.0 g, yield: 66%, purity: >99%). HNMR (400MHz, DMSO-d6), δ: 7.15 (t, J=9.2Hz, 1H), 6.74 (dd, J=6.4, 2.8Hz, 1H), 6.62-6 .58(m,1H),6.18(t,J=6.4Hz,1H),3.86(dd,J=6.0,2.4Hz,2H),3.09(t,J=2.8Hz,1H).

[0231] Compound KH11-10: To a reaction flask, add KH11-9 (350 mg, 1.91 mmol), compound e (471 mg, 2.29 mmol), Pd(PPh3)2Cl2 (268 mg, 0.38 mmol), CuI (72 mg, 0.38 mmol), DOX (15 mL), and DIPEA (739 mg, 5.73 mmol). Stir at 60°C under nitrogen for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography [petroleum ether:methyl tert-butyl ether (v / v) = (100:0-35:65)] afforded KH11-10 as a brown solid (180 mg, yield: 22%, purity: 61%). LCMS: 262.1 [M+H]+ .

[0232] Compound KH11-11: To a reaction flask, add KH09-1 (100 mg, 0.76 mmol) and DCM (5 mL). Under nitrogen, place in an ice-water bath, add Ghosez reagent (306 mg, 2.28 mmol), and stir in the ice-water bath for 0.5 hour. Then, add KH11-10 (200 mg, 0.76 mmol) and pyridine (300 mg, 3.80 mmol). The reaction was allowed to react at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-96:4)] afforded KH11-11 as a yellow oil (100 mg, yield: 27%, purity: 80%). LCMS: 375.1 [M+H] + .

[0233] Compound KH11: To a reaction flask, KH11-11 (100 mg, 0.27 mmol), KH11-7 (74 mg, 0.32 mmol), Pd2(dba)3 (25 mg, 0.03 mmol), Xantphos (31 mg, 0.05 mmol), DOX (10 mL), and K2CO3 (48 mg, 0.35 mmol) were added. The mixture was stirred at 85°C under nitrogen for 3 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-96:4)] and prep-HPLC. The acetonitrile was evaporated under reduced pressure, and the product was lyophilized to obtain KH11 as a white solid (8.44 mg, yield: 5%, purity: 99.12%). LCMS: 569.8 [M+H] + .HNMR(400MHz,DMSO-d6)δ:9.22(dd,J=4.4,2.0Hz,1H),8.51(s,1H),7.95(d,J=6.8Hz,1H),7.82(s,1H),7.76-7.72(m,2H),7.70- 7.68(m,2H),7.10(t,J=14.4Hz,1H),5.06(dd,J=9.6,3.6Hz,1H),4.97(d,J=18.0Hz,1H),4.75-4.71(m,2H),4.38(t,J=9.2Hz,1H).

[0234] Example 12 Synthesis of Compound KH12

[0235] To a reaction flask, KH09-6 (150 mg, 0.33 mmol), p-fluoroiodobenzene (84 mg, 0.38 mmol), Pd(PPh3)2Cl2 (41 mg, 0.06 mmol), CuI (11 mg, 0.06 mmol), DOX (10 mL), and DIPEA (127 mg, 0.99 mmol) were added and stirred at 60°C under nitrogen for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-94:6)] and prep-HPLC. Acetonitrile was evaporated under reduced pressure, and the product was lyophilized to remove water, yielding KH12 as a white solid (42.04 mg, yield: 23%, purity: 99.79%). LCMS: 549.8 [M+H] + .HNMR(400MHz,DMSO-d6)δ:8.14(s,1H),7.94(dd,J=6.8,2.4Hz,1H),7.72-7.69(m,2H),7.43-7.39(m,3H),7.26-7.21(m,2H),5.02( dd,J=9.2,3.2Hz,1H),4.94(d,J=17.6Hz,1H),4.63(dd,J=8.8,3.2Hz,1H),4.55(d,J=17.6Hz,1H),4.35(t,J=9.2,1H),2.54(s,3H).

[0236] Example 13 Synthesis of Compound KH13

[0237] Compound KH13-1: To a reaction flask, KH09-4 (200 mg, 0.69 mmol), 2,4-difluoro-5-chloroaniline f (136 mg, 0.83 mmol), TCFH (387 mg, 1.38 mmol), NMI (226 mg, 2.76 mmol), and acetonitrile (10 mL) were added. The mixture was reacted at room temperature under nitrogen for 1 hour. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography [PE:MTBE (v / v) = (100:0-63:37)] afforded KH13-1 as a white solid (200 mg, yield: 66%, purity: >70%). LCMS: 436.1 [M+H] + .

[0238] Compound KH13-2: To a reaction flask, add KH13-1 (200 mg, 0.50 mmol) and DMF (5 mL). Under nitrogen, place in an ice-water bath and add NaH (30 mg, 0.75 mmol, 60% in mineral oil). Stir at room temperature for 0.5 hour. Add propargyl bromide c (90 mg, 0.76 mmol) in an ice-water bath, remove the ice-water bath, and stir at room temperature for 2 hours. The reaction is complete. Ammonium chloride aqueous solution is added to quench the reaction solution, which is extracted with ethyl acetate (10 mL x 3), washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is evaporated to remove the solvent under reduced pressure to obtain the crude product. Purification by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-95:5)] affords KH13-2 as a yellow oil (190 mg, yield: 87%, purity: >99%). LCMS: 474.1 [M+H]. + .

[0239] Compound KH13: To a reaction flask, KH13-2 (190 mg, 0.40 mmol), 2-bromo-6-hydroxypyridine (104 mg, 0.60 mmol), Pd(PPh3)2Cl2 (55 mg, 0.08 mmol), CuI (14 mg, 0.08 mmol), DOX (8 mL), and DIPEA (129 mg, 1 mmol) were added. The mixture was stirred at 70°C under nitrogen for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. The product was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-95:5)] and prep-HPLC. Acetonitrile was evaporated under reduced pressure, and the product was lyophilized to obtain KH13 as a white solid (12.68 mg, yield: 6%, purity: 99.00%). LCMS: 566.8 [M+H] + .HNMR(400MHz,DMSO-d6)δ:11.95(s,1H),8.16-8.14(m,1H),8.06(dd,J=14.8,7.6Hz,1H),7.85(dd,J=16.8,8.4Hz,1H),7.4 2-7.36(m,2H),6.45-6.35(m,2H),5.16-5.13(m,1H),4.87-4.72(m,2H),4.68-4.48(m,1H),4.40-4.31(m,1H),2.59(s,3H).

[0240] Example 14 Synthesis of Compound KH14

[0241] To a reaction flask, KH13-2 (160 mg, 0.34 mmol), 3-bromopyridazine (80 mg, 0.51 mmol), Pd(PPh3)2Cl2 (41 mg, 0.06 mmol), CuI (11 mg, 0.06 mmol), DOX (9 mL), and DIPEA (112 mg, 0.87 mmol) were added. The mixture was stirred at 70°C for 2 hours under nitrogen. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. The product was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-95:5)] and prep-HPLC. The acetonitrile was evaporated under reduced pressure, and the product was lyophilized to obtain KH14 as a white solid (14.08 mg, yield: 8%, purity: 99.13%). LCMS: 551.8 [M+H] + .HNMR(400MHz,CD3OD)δ:9.15-9.14(m,1H),8.26-8.23(m,1H),8.19-7.93(m,1H),7.71-7.70(m,2H),7.54(dd,J=18,8.4Hz,1H),7. 23-7.21(m,1H),5.23-5.17(m,1H),5.08-4.96(m,1H),4.77-4.63(m,1H),4.61-4.48(m,1H),4.41-4.40(m,1H),2.61-2.51(m,3H).

[0242] Example 15 Synthesis of Compound KH15

[0243] Compound KH15-1: To a reaction flask, add KH15-0 (6.0 g, 41.2 mmol), K2CO3 (6.8 g, 49.5 mmol), and DMF (100 mL). Under nitrogen, add propargyl bromide (5.9 g, 49.5 mmol) at room temperature. Stir overnight at room temperature until the reaction is complete. The reaction mixture is quenched with water and extracted with ethyl acetate (50 mL x 2). The organic phase is washed twice with saturated sodium chloride. The organic phase is dried over anhydrous sodium sulfate and filtered. The solvent is evaporated from the filtrate under reduced pressure to obtain the crude product. Purification by silica gel column chromatography [petroleum ether:methyl tert-butyl ether (v / v) = (100:0-95:5)] affords KH15-1 as a pale yellow oil (5.0 g, yield: 66%, purity: >99%). HNMR (400MHz, DMSO-d6), δ: 7.15 (t, J=9.2Hz, 1H), 6.74 (dd, J=6.4, 2.8Hz, 1H), 6.62-6 .58(m,1H),6.18(t,J=6.4Hz,1H),3.86(dd,J=6.0,2.4Hz,2H),3.09(t,J=2.8Hz,1H).

[0244] Compound KH15-2: To a reaction flask, add KH15-1 (400 mg, 2.18 mmol), compound d (617 mg, 2.61 mmol), Pd(PPh3)2Cl2 (306 mg, 0.44 mmol), CuI (83 mg, 0.44 mmol), DOX (15 mL), and DIPEA (844 mg, 6.54 mmol). Stir at 60°C under nitrogen for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography [petroleum ether:methyl tert-butyl ether (v / v) = (100:0-35:65)] afforded KHKH15-2 as a brown solid (250 mg, yield: 36%, purity: 92%). LCMS: 292.1 [M+H] + .

[0245] Compound KH15-3: To a reaction flask, add KH15-2a (80 mg, 0.62 mmol) and DCM (5 mL). Under nitrogen, place in an ice-water bath, add Ghosez reagent (249 mg, 1.86 mmol), and stir in the ice-water bath for 0.5 hour. Then, add KH15-2 (181 mg, 0.62 mmol) and pyridine (245 mg, 3.10 mmol). The reaction was allowed to react at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-97:3)] afforded KH15-3 as a yellow oil (180 mg, yield: 70%, purity: 98%). LCMS: 403.1 [M+H] + .

[0246] Compound KH15: To a reaction flask, KH15-3 (180 mg, 0.45 mmol), compound h (129 mg, 0.54 mmol), Pd2(dba)3 (41 mg, 0.04 mmol), Xantphos (52 mg, 0.09 mmol), DOX (10 mL), and CS2CO3 (440 mg, 1.35 mmol) were added. The mixture was stirred at 85°C overnight under nitrogen. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. The product was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-96:4)] and prep-HPLC. Acetonitrile was evaporated under reduced pressure, and the product was lyophilized to obtain KH15 as a white solid (113.46 mg, yield: 43%, purity: 97.21%). LCMS: 561.8 [M+H] +.HNMR(400MHz, DMSO-d6)δ:8.65(s,2H),8.41(s,1H),7.99(dd,J=6.8,2.4Hz,1H),7.78-7.75(m,1H),7.70(t,J=8.8Hz,1H),7.40(s, 1H), 4.96 (d, J = 18.0Hz, 1H), 4.87 (dd, J = 8.8, 3.2Hz, 1H), 4.59 (d, J = 17.6Hz, 1H), 3.95 (s, 3H), 2.71-2.62 (m, 5H), 2.16-2.03 (m, 2H).

[0247] Example 16 Synthesis of Compound KH16

[0248] Compound KH16-1: To a reaction flask, add KH16-0 (5.0 g, 45.0 mmol), K2CO3 (7.45 g, 54.0 mmol), and DMF (100 mL). Under nitrogen, add propargyl bromide (6.42 g, 54.0 mmol) at room temperature. Stir overnight at room temperature until the reaction is complete. The reaction mixture is quenched with water and extracted with ethyl acetate (50 mL x 2). The organic phase is washed twice with saturated sodium chloride. The organic phase is dried over anhydrous sodium sulfate and filtered. The solvent is evaporated from the filtrate under reduced pressure to obtain the crude product. Purification by silica gel column chromatography [petroleum ether:methyl tert-butyl ether (v / v) = (100:0-95:5)] affords KH16-1 as a yellow oil (3.0 g, yield: 42%, purity: ~95%). HNMR (400MHz, DMSO-d6), δ: 6.97-6.92(m,2H), 6.64-6.60(m,2H), 5.88(t,J=6.0Hz,1H), 3.83(dd,J=6.4,2.4Hz,2H), 3.04(t,J=2.4Hz,1H).

[0249] Compound KH16-2: To a reaction flask, add KH16-1 (700 mg, 4.69 mmol), compound d (1.33 g, 5.63 mmol), Pd(PPh3)2Cl2 (658 mg, 0.94 mmol), CuI (179 mg, 0.94 mmol), DOX (20 mL), and DIPEA (1.82 g, 14.07 mmol). Stir at 60°C under nitrogen for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography [petroleum ether:methyl tert-butyl ether (v / v) = (100:0-40:60)] afforded KH16-2 as a yellow-brown solid (550 mg, yield: 40%, purity: 88%). LCMS: 258.1 [M+H] + .

[0250] Compound KH16-3: To a reaction flask, add KH15-2a (80 mg, 0.62 mmol) and DCM (5 mL). Under nitrogen, place in an ice-water bath, add Ghosez reagent (249 mg, 1.86 mmol), and stir in the ice-water bath for 0.5 hour. Then, add KH16-2 (159 mg, 0.62 mmol) and pyridine (245 mg, 3.10 mmol). The reaction was allowed to react at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-96:4)] afforded KH16-3 as a yellow oil (180 mg, yield: 74%, purity: 94%).

[0251] Compound KH16: To a reaction flask, KH16-3 (180 mg, 0.49 mmol), compound h (141 mg, 0.59 mmol), Pd2(dba)3 (45 mg, 0.05 mmol), Xantphos (57 mg, 0.10 mmol), DOX (10 mL), and Cs2CO3 (479 mg, 1.47 mmol) were added. The mixture was stirred at 85°C overnight under nitrogen. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. The product was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-96:4)] and prep-HPLC. Acetonitrile was evaporated under reduced pressure, and the product was lyophilized to obtain KH16 as a white solid (113.06 mg, yield: 42%, purity: 96.84%). LCMS: 528.0 [M+H] + .HNMR(400MHz,DMSO-d6)δ:8.65(s,2H),8.40(s,1H),7.75(dd,J=8.4,5.2Hz,2H),7.47(t,J=8.4Hz,2H),7.39(s,1H),4.96 (d,J=17.6Hz,1H),4.82(dd,J=8.8,3.6Hz,1H),4.54(d,J=17.6Hz,1H),3.95(s,3H),2.71-2.53(m,5H),2.10-2.00(m,2H).

[0252] Example 17 Synthesis of Compound KH17

[0253] Compound KH17-1: To a reaction flask, add KH09-1 (80 mg, 0.61 mmol) and DCM (5 mL). Under nitrogen, place in an ice-water bath, add Ghosez reagent (245 mg, 1.83 mmol), and stir in the ice-water bath for 0.5 hour. Then, add KH16-2 (157 mg, 0.61 mmol) and pyridine (241 mg, 3.05 mmol). React at room temperature for 2 hours. After completion of the reaction, evaporate the solvent under reduced pressure to obtain the crude product. Purify by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-96:4)] to obtain KH17-1 as a yellow oil (180 mg, yield: 73%, purity: 92%). LCMS: 371.2 [M+H] + .

[0254] Compound KH17: To a reaction flask, add KH17-1 (180 mg, 0.48 mmol), compound h (140 mg, 0.58 mmol), Pd2(dba)3 (44 mg, 0.05 mmol), Xantphos (56 mg, 0.10 mmol), DOX (10 mL), and K2CO3 (132 mg, 0.96 mmol). Stir at 85°C under nitrogen for 5 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. This was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-96:4)] and prep-HPLC. Acetonitrile was evaporated under reduced pressure, and the product was lyophilized to obtain KH17 as a white solid (68.31 mg, yield: 26%, purity: 98.80%). LCMS: 529.9 [M+H] + .HNMR(400MHz,DMSO-d6)δ:8.66(s,2H),8.13(s,1H),7.71-7.68(m,2H),7.47(t,J=8.8Hz,2H),7.40(s,1H),4.98- 4.93(m,2H),4.59(dd,J=8.8,3.6Hz,1H),4.55(d,J=17.6Hz,1H),4.33(t,J=8.0Hz,1H),3.95(s,3H),2.56(s,3H).

[0255] Example 18 Synthesis of Compound KH18

[0256] Compound KH18-1: To a reaction flask, add KH18-0 (5.0 g, 30.57 mmol), K2CO3 (5.06 g, 36.69 mmol), and DMF (100 mL). Under nitrogen, add propargyl bromide (4.36 g, 36.69 mmol) at room temperature. Stir overnight at room temperature until the reaction is complete. The reaction mixture is quenched with water and extracted with ethyl acetate (50 mL x 2). The organic phase is washed twice with saturated sodium chloride. The organic phase is dried over anhydrous sodium sulfate and filtered. The solvent is evaporated from the filtrate under reduced pressure to obtain the crude product. Purification by silica gel column chromatography [petroleum ether:methyl tert-butyl ether (v / v) = (100:0-90:10)] affords KH18-1 as a yellow oil (3.0 g, yield: 43%, purity: ~90%). HNMR (400MHz, DMSO-d6), δ: 7.38 (dd, J=11.2, 9.2Hz, 1H), 6.93 (dd, J=8.8, 7.6 Hz,1H),6.12(dd,J=6.4,5.2Hz,1H),3.98-3.93(m,2H),3.11(t,J=2.0Hz,1H).

[0257] Compound KH18-2: To a reaction flask, add KH18-1 (700 mg, 3.47 mmol), compound d (983 mg, 4.17 mmol), Pd(PPh3)2Cl2 (487 mg, 0.69 mmol), CuI (132 mg, 0.69 mmol), DOX (20 mL), and DIPEA (1.34 g, 10.41 mmol). Stir at 60°C under nitrogen for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography [petroleum ether:methyl tert-butyl ether (v / v) = (100:0-50:50)] afforded KH18-2 as a yellow-brown solid (700 mg, yield: 60%, purity: 93%). LCMS: 310.1 [M+H] + .

[0258] Compound KH18-3: To a reaction flask, add KH09-1 (80 mg, 0.61 mmol) and DCM (5 mL). Under nitrogen, place in an ice-water bath, add Ghosez reagent (245 mg, 1.83 mmol), and stir in the ice-water bath for 0.5 hour. Then, add KH18-2 (189 mg, 0.61 mmol) and pyridine (241 mg, 3.05 mmol). The reaction was allowed to react at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-96:4)] afforded KH18-3 as a yellow oil (180 mg, yield: 52%, purity: 75%). LCMS: 423.1 [M+H] + .

[0259] Compound KH18: To a reaction flask, KH18-3 (180 mg, 0.43 mmol), compound h (123 mg, 0.51 mmol), Pd2(dba)3 (39 mg, 0.05 mmol), Xantphos (50 mg, 0.09 mmol), DOX (10 mL), and K2CO3 (119 mg, 0.86 mmol) were added. The mixture was stirred at 85°C under nitrogen for 5 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. The product was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-96:4)] and prep-HPLC. Acetonitrile was evaporated under reduced pressure, and the product was lyophilized to remove water, yielding KH18 as a white solid (82.06 mg, yield: 33%, purity: 99.83%). LCMS: 581.8 [M+H] + .HNMR(400MHz,DMSO-d6)δ:8.72-8.61(m,2H),8.16-8.09(m,2H),7.98-7.92(m,1H),7.45-7.41(m,1H),5.15-5. 07(m,1H),4.84(s,1H),4.75-4.48(m,2H),4.36-4.31(m,1H),3.96-3.94(m,3H),2.58(s,1H),2.50-2.49(m,2H).

[0260] Example 19 Synthesis of Compound KH19

[0261] Compound KH19-1: To a reaction flask, add KH15-2a (80 mg, 0.62 mmol) and DCM (5 mL). Under nitrogen, place in an ice-water bath, add Ghosez reagent (249 mg, 1.86 mmol), and stir in the ice-water bath for 0.5 hour. Then, add KH18-2 (192 mg, 0.62 mmol) and pyridine (245 mg, 3.10 mmol). The reaction was allowed to react at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-96:4)] afforded KH19-1 as a yellow oil (180 mg, yield: 64%, purity: 94%). LCMS: 421.1 [M+H] + .

[0262] Compound KH19: To a reaction flask, KH19-1 (180 mg, 0.43 mmol), compound h (123 mg, 0.51 mmol), Pd2(dba)3 (39 mg, 0.04 mmol), Xantphos (50 mg, 0.09 mmol), DOX (10 mL), and Cs2CO3 (420 mg, 1.29 mmol) were added and stirred overnight at 85°C under nitrogen. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-96:4)] and prep-HPLC. Acetonitrile was evaporated under reduced pressure and the product was lyophilized to obtain KH19 as a white solid (69.63 mg, yield: 26%, purity: 95.79%). LCMS: 579.8 [M+H]. + .HNMR(400MHz,DMSO-d6)δ:8.70-8.62(m,2H),8.42-8.40(m,1H),8.20-8.07(m,1H),7.99-7.93(m,1H),7.43-7.38(m,1H),4.97-4.89(m,2 H),4.75-4.4.66(m,1H),3.95-3.94(m,3H),2.72-2.67(m,1H),2.59- 2.57(m,2H),2.57-2.55(m,1H),2.48-2.45(m,1H),2.27-1.88(m,2H).

[0263] Example 20 Synthesis of Compound KH2O

[0264] Synthesis of compound KH20-1: In a single-necked reaction flask, KH20-0 (700 mg, 5.42 mmol), 3-bromopropyne (774 mg, 6.51 mmol), and potassium carbonate (1.12 g, 8.13 mmol) were dissolved in DMF (18 mL). The reaction was stirred at room temperature overnight under nitrogen. After completion, saturated aqueous ammonium chloride (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:methyl tert-butyl ether (v / v) = (100:0-70:30)) to obtain KH20-1 as a pale yellow liquid (500 mg, yield: 55%, purity: >95%). 1HNMR(400MHz,DMSO-d6)δ:7.15(q,J=10.4Hz,1H),6.63-6.57(m,1H),6.42-6.40( m, 1H), 6.18 (t, J = 6.0Hz, 1H), 3.85 (dd, J = 6.0, 2.0Hz, 2H), 3.08 (t, J = 2.0Hz, 1H).

[0265] Synthesis of compound KH20-2: To a single-necked reaction flask, KH20-1 (700 mg, 4.19 mmol), 5-iodo-2-methoxypyrimidine (KH20-1a) (1.19 g, 5.03 mmol), Pd(PPh3)2Cl2 (294 mg, 0.42 mmol), CuI (159 mg, 0.84 mmol), DIPEA (1.62 g, 12.57 mmol), and 1,4-dioxane (20 mL) were added. The reaction was stirred at 60°C under nitrogen for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography [petroleum ether:ethyl acetate (v / v) = (100:0-40:60)] to obtain KH20-2 as a yellow-brown solid (700 mg, yield: 44%, purity: 73%).

[0266] LCMS: MS Calcd.:275.1; MS Found:276.3[M+H] + .

[0267] Synthesis of compound KH20-3: In a single-necked reaction flask, L-pyroglutamic acid (KH20-2a) (55 mg, 0.43 mmol) was dissolved in dichloromethane (5 mL). The mixture was cooled in an ice-water bath, followed by the addition of 1-chloro-N,N,2-trimethylpropyleneamine (173 mg, 1.29 mmol). The mixture was stirred for 1 hour. KH20-2 (130 mg, 0.47 mmol) and pyridine (170 mg, 2.15 mmol) were then added sequentially to the reaction mixture. Under nitrogen, the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography (dichloromethane:methanol (v / v) = (100:0-96:4)) to afford KH20-3 as a yellow oil (160 mg, yield: 75%, purity: 77.87%).

[0268] LCMS:MS Calcd.:386.1; MS Found:387.2[M+H] + .

[0269] Synthesis of compound KH20: In a single-necked reaction flask, KH20-3 (145 mg, 0.38 mmol), 2-bromo-6-methyl-4-trifluoromethylpyridine (KH20-3a) (108 mg, 0.45 mmol), Pd2(dba)3 (34 mg, 0.04 mmol), Xant-phos (43 mg, 0.08 mmol) and cesium carbonate (367 mg, 1.12 mmol) were added to 1,4-dioxane (10 mL). Under nitrogen protection, the reaction was stirred at 85 ° C overnight. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-96:4)] to obtain crude KH2O as a yellow solid. The crude product was purified by prep-HPLC, acetonitrile was evaporated under reduced pressure, and the product was lyophilized to remove water to obtain 61.63 mg of KH2O as a white solid (yield: 30%, purity: 99.61%). LCMS: MS Calcd.: 545.1; MS Found: 545.9 [M+H] + .HNMR(400MHz,DMSO-d6)δ:8.65(s,2H),8.40(s,1H),7.85-7.81(m,1H),7.74-7.69(m,1H),7.62-7.60(m,1H),7.40(s,1H),4.95(d, J=17.6Hz,1H),4.87(dd,J=8.8,3.2Hz,1H),4.58(d,J=18.0Hz,1H),3.95(s,3H),2.68-2.62(m,2H),2.56(s,3H),2.13-2.07(m,2H).

[0270] Example 21 Synthesis of Compound KH21

[0271] Synthesis of Compound KH21-1: Add KH21-0 (50 g, 209 mmol) to a reaction flask. Add aqueous sodium hydroxide (5N, 83.6 mL, 418 mmol) dropwise in an ice-water bath and stir at room temperature for 0.5 hour. Wash once with methyl tert-butyl ether, adjust to acidity with concentrated hydrochloric acid, extract with 2-methyltetrahydrofuran (200 mL x 10), dry over anhydrous sodium sulfate, filter, and evaporate the filtrate to remove the solvent under reduced pressure to obtain crude KH21-1 as a brown oil (14 g, yield: 51%). LCMS: MS Calcd.: 131.0; MS Found: 132.3 [M+H] + ,149.2[M+NH4] + .

[0272] Synthesis of compound KH21-2: Dissolve KH21-1 (14 g, 106.80 mmol) and triethylamine (21.57 g, 213.6 mmol) in acetone (100 mL). Add benzyl bromide (18.27 g, 106.80 mmol) in an ice-water bath. Stir under nitrogen overnight at room temperature. After completion of the reaction, evaporate the solvent under reduced pressure to obtain the crude product. Purify the crude product by silica gel column chromatography [petroleum ether:methyl tert-butyl ether (v / v) = (100:0-00:100)] to obtain KH21-2 as a white solid (4.0 g, yield: 16%, purity: >99%). LCMS: MS Calcd.: 221.1; MS Found: 222.2 [M+H] + ,239.2[M+NH4] + .

[0273] Synthesis of compound KH21-1: Pd / C (60 mg, 10%) was added to KH21-2 (500 mg, 2.26 mmol) in methanol (10 mL). The mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. After completion of the reaction, the mixture was filtered and the solvent was evaporated under reduced pressure to obtain a yellow oil (250 mg, yield: 84%). LCMS: MS Found: 132.3 [M+H] + ,149.2[M+NH4] + ,285.1[2M+Na] + .

[0274] Synthesis of compound KH21-3: To a reaction flask, add KH21-1 (45 mg, 0.34 mmol) and DCM (5 mL). Under nitrogen, place in an ice-water bath, add Ghosez reagent (137 mg, 1.02 mmol), and stir in the ice-water bath for 0.5 hour. Then, add KH20-2 (95 mg, 0.34 mmol) and pyridine (133 mg, 1.70 mmol). The reaction was allowed to react at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-96:4)] afforded KH21-3 as a yellow oil (70 mg, yield: 34%, purity: 65%).

[0275] LCMS: MS Calcd.:388.1; MS Found:389.2[M+H] + .

[0276] Synthesis of Compound KH21: To a reaction flask, KH21-3 (70 mg, 0.18 mmol), KH20-3a (43 mg, 0.18 mmol), Pd2(dba)3 (16 mg, 0.02 mmol), Xantphos (21 mg, 0.04 mmol), DOX (5 mL), and K2CO3 (50 mg, 0.36 mmol) were added. The mixture was stirred at 85°C under nitrogen for 5 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product. The product was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-96:4)] and prep-HPLC. Acetonitrile was evaporated under reduced pressure, and the product was lyophilized to obtain KH21 as a white solid (9.63 mg, yield: 9%, purity: 98.61%). LCMS: MS Calcd.: 547.1; MS Found: 547.8 [M+H] + .HNMR(400MHz,DMSO-d6)δ:8.66(s,2H),8.13(s,1H),7.80-7.70(m,2H),7.56-7.54(m,1H),7.4 1(s,1H),5.03-4.93(m,2H),4.63-4.57(m,2H),4.37(t,J=8.8Hz,1H),3.95(s,3H),2.55(s,3H).

[0277] Example 22 Synthesis of Compound KH22

[0278] Synthesis of compound KH22-1: In a single-necked reaction flask, KH22-0 (5.00 g, 25.38 mmol) was added to DMF (50 mL), cooled in an ice-water bath, and sodium hydride (1.32 g, 32.97 mmol, 60 wt%) was added. Under nitrogen protection, the reaction was stirred at 5°C for half an hour, followed by the addition of 4-methoxybenzyl chloride (5.17 g, 32.97 mmol). Under nitrogen protection, the reaction was stirred at 5°C for 2 hours. After completion of the reaction, saturated aqueous ammonium chloride (80 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (60 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to remove the solvent under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography [petroleum ether:methyl tert-butyl ether (v / v) = (100:0-90:10)] to obtain KH22-1 as a colorless oil (5.60 g, yield: 70%, purity: 72.42%). LCMS: MS Calcd.: 316.0; MS Found: 317.2 [M+H] + .

[0279] Synthesis of compound KH22-2: In a single-necked reaction flask, KH22-1 (5.60 g, 17.66 mmol) was dissolved in DMF (60 mL) and acetonitrile (20 mL). The mixture was cooled in an ice-water bath, followed by the addition of a selective fluorine reagent (5.00 g, 14.13 mmol). The reaction was stirred at 0°C for 2 hours under nitrogen. After completion, the reaction was quenched with saturated aqueous sodium bicarbonate (80 mL) and extracted with ethyl acetate (60 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:methyl tert-butyl ether (v / v) = (100:0-80:20)) to afford KH22-2 as a colorless oil (2.00 g, yield: 34%, purity: 56.15%). LCMS:MS Calcd.:334.0;MS Found:335.1[M+H] + .

[0280] Synthesis of compound KH22-3: In a single-necked reaction flask, KH22-2 (2.00 g, 5.97 mmol), benzophenone imine (1.30 g, 7.16 mmol), Pd2(dba)3 (550 mg, 0.60 mmol), Xant-phos (694 mg, 1.20 mmol), and cesium carbonate (3.91 g, 12.00 mmol) were added to 1,4-dioxane (60 mL). Under nitrogen, the reaction was stirred at 100°C for 5 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether:methyl tert-butyl ether (v / v) = (100:0-74:26)) to afford KH22-3 as a colorless oil (2.20 g, yield: 85%, purity: 45.97%). LCMS:MS Calcd.:435.2; MS Found:436.2[M+H] + .

[0281] Synthesis of compound KH22-4: In a single-necked reaction flask, KH22-3 (2.20 g, 5.05 mmol) was dissolved in tetrahydrofuran (24 mL) and 4 mol / L hydrochloric acid (8 mL). The reaction was stirred at room temperature under nitrogen for 0.5 hours. After completion, saturated aqueous potassium carbonate was added to adjust the pH to 8-9, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to remove the solvent under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography [petroleum ether:methyl tert-butyl ether (v / v) = (100:0-54:46)] to obtain KH22-4 as a white solid (1.00 g, yield: 73%, purity: >99%). LCMS: MS Calcd.: 271.1; MS Found: 272.2 [M+H] + .

[0282] Synthesis of compound KH22-5: In a single-necked reaction flask, KH22-4 (1.00 g, 3.69 mmol), 3-bromopropyne (877 mg, 7.37 mmol), and potassium carbonate (1.02 g, 7.37 mmol) were dissolved in DMF (20 mL). The reaction was stirred at room temperature overnight under nitrogen. After completion, saturated aqueous ammonium chloride (30 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:methyl tert-butyl ether (v / v) = (100:0-74:26)) to afford KH22-5 as a colorless oil (700 mg, yield: 61%, purity: >99%). LCMS: MS Calcd.: 309.1; MS Found: 310.1 [M+H] + .

[0283] Synthesis of compound KH22-6: In a single-necked reaction flask, KH22-5 (400 mg, 1.29 mmol), 5-iodo-2-methoxypyrimidine (KH20-1a) (458 mg, 1.94 mmol), Pd(dppf)Cl2 (95 mg, 0.13 mmol), cuprous iodide (25 mg, 0.13 mmol), and N,N-diisopropylethylamine (333 mg, 2.58 mmol) were added to 1,4-dioxane (20 mL). Under nitrogen, the reaction mixture was stirred at 60°C for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = (100:0-40:60)) to afford KH22-6 as a colorless oil (280 mg, yield: 52%, purity: 74.88%). LCMS:MS Calcd.:417.2;MS Found:418.1[M+H] + .

[0284] Synthesis of compound KH22-7: In a single-necked reaction flask, L-pyroglutamic acid (95 mg, 0.74 mmol) was dissolved in dichloromethane (15 mL). The mixture was cooled in an ice-water bath, followed by the addition of 1-chloro-N,N,2-trimethylpropyleneamine (197 mg, 1.48 mmol). The mixture was stirred for 1 hour, followed by the addition of KH22-6 (280 mg, 0.67 mmol) and pyridine (176 mg, 2.22 mmol). Under nitrogen, the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography (dichloromethane:methanol (v / v) = (100:0-96:4)) to afford KH22-7 (280 mg, yield: 79%, purity: 68.19%) as a colorless oil. LCMS:MS Calcd.:528.2;MS Found:559.3[M+H] + .

[0285] Synthesis of compound KH22-8: In a single-necked reaction flask, KH22-7 (280 mg, 0.53 mmol), 2-bromo-6-methyl-4-trifluoromethylpyridine (165 mg, 0.69 mmol), Pd2(dba)3 (47 mg, 0.05 mmol), Xant-phos (59 mg, 0.10 mmol), and cesium carbonate (346 mg, 1.06 mmol) were added to 1,4-dioxane (20 mL). Under nitrogen, the reaction was stirred at 85°C overnight. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = (100:0-94:6)) to afford KH22-8 as a colorless oil (200 mg, yield: 55%, purity: 76.34%). LCMS:MS Calcd.:687.2;MS Found:688.2[M+H] + .

[0286] Synthesis of compound KH22: In a single-necked reaction flask, KH22-8 (200 mg, 0.29 mmol) was dissolved in trifluoroacetic acid (15 mL). The reaction was stirred at 70°C overnight under nitrogen. After completion, the solvent was evaporated under reduced pressure, and the reaction was quenched by the addition of saturated aqueous sodium bicarbonate (15 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure to obtain the crude product. Purification by prep-HPLC yielded KH22 as a white solid (37.52 mg, yield: 23%, purity: 97.76%). LCMS: MS Calcd.: 567.2; MS Found: 568.3 [M+H] + . 1 HNMR(400MHz,CD3OD)δ:11.73(d,J=8.8Hz,1H),8.56(d,J=10.4Hz,2H),8.36( s,1H),8.28(d,J=8.4Hz,1H),7.59(s,1H),7.55(d,J=8.8Hz,1H),7.33(s,1H), 6.55(s,1H),5.03(d,J=17.2Hz,1H),4.92(s,1H),4.74(d,J=17.6Hz,1H),3.93 (s,3H),2.78-2.69(m,1H),2.67-2.57(m,1H),2.51(s,3H),2.29-2.22(m,2H).

[0287] Example 23 Synthesis of Compound KH23

[0288] Synthesis of compound KH23-2: In a single-necked reaction flask, KH23-1 (2.00 g, 6.31 mmol), benzophenone imine (1.48 g, 8.20 mmol), Pd2(dba)3 (578 mg, 0.63 mmol), Xant-phos (729 mg, 1.26 mmol), and cesium carbonate (4.11 g, 12.62 mmol) were added to 1,4-dioxane (63 mL). Under nitrogen, the reaction was stirred at 110°C for 4 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether:methyl tert-butyl ether (v / v) = (100:0-82:18)) to afford KH23-2 as a colorless oil (2.00 g, yield: 76%, purity: 80.69%). LCMS: MS Calcd.:417.2; MS Found:418.3[M+H] + .

[0289] Synthesis of compound KH23-3: In a single-necked reaction flask, KH23-2 (2.00 g, 4.79 mmol) was dissolved in tetrahydrofuran (24 mL) and 4 mol / L hydrochloric acid (8 mL). The reaction was stirred at room temperature under nitrogen for 2 hours. After completion, saturated aqueous potassium carbonate was added to adjust the pH to 8-9, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to remove the solvent under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography [petroleum ether:methyl tert-butyl ether (v / v) = (100:0-60:40)] to obtain KH23-3 as a white solid (900 mg, yield: 74%, purity: >99%). LCMS: MS Calcd.: 253.1; MS Found: 254.2 [M+H] + .

[0290] Synthesis of compound KH23-4: In a single-necked reaction flask, KH23-3 (900 mg, 3.55 mmol), 3-bromopropyne (634 mg, 5.33 mmol), and potassium carbonate (980 mg, 7.10 mmol) were dissolved in DMF (15 mL). The reaction was stirred at room temperature overnight under nitrogen. After completion, the reaction was quenched with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by silica gel column chromatography [petroleum ether:methyl tert-butyl ether (v / v) = (100:0-70:30)] to afford KH23-4 as a colorless oil (300 mg, yield: 29%, purity: >99%). LCMS: MS Calcd.: 291.1; MS Found: 292.1 [M+H] +.

[0291] Synthesis of compound KH23-5: In a single-necked reaction flask, KH23-4 (300 mg, 1.03 mmol), 5-iodo-2-methoxypyrimidine (364 mg, 1.54 mmol), Pd(dppf)Cl2 (74 mg, 0.10 mmol), cuprous iodide (20 mg, 0.10 mmol), and N,N-diisopropylethylamine (266 mg, 2.06 mmol) were added to 1,4-dioxane (15 mL). Under nitrogen, the reaction mixture was stirred at 60°C for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = (100:0-40:60)) to afford KH23-5 as a colorless oil (400 mg, yield: 73%, purity: 74.88%). LCMS:MS Calcd.:399.2;MS Found:400.3[M+H] + .

[0292] Synthesis of compound KH23-6: In a single-necked reaction flask, L-pyroglutamic acid (81 mg, 0.63 mmol) was dissolved in dichloromethane (10 mL). The mixture was cooled in an ice-water bath, followed by the addition of 1-chloro-N,N,2-trimethylpropyleneamine (168 mg, 1.26 mmol). The mixture was stirred for 1 hour. KH23-5 (250 mg, 0.63 mmol) and pyridine (150 mg, 1.89 mmol) were then added to the reaction mixture. Under nitrogen, the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography (dichloromethane:methanol (v / v) = (100:0-96:4)) to afford KH23-6 as a colorless oil (150 mg, yield: 47%, purity: 68.19%). LCMS:MS Calcd.:510.2;MS Found:511.2[M+H] + .

[0293] Synthesis of compound KH23-7: In a single-necked reaction flask, KH23-6 (150 mg, 0.29 mmol), 2-bromo-6-methyl-4-trifluoromethylpyridine (106 mg, 0.44 mmol), Pd2(dba)3 (28 mg, 0.03 mmol), Xant-phos (35 mg, 0.06 mmol), and cesium carbonate (189 mg, 0.58 mmol) were added to 1,4-dioxane (15 mL). Under nitrogen, the reaction was stirred at 85°C overnight. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = (100:0-94:6)) to afford KH23-7 (150 mg, yield: 76%, purity: 80.24%) as a colorless oil. LCMS:MS Calcd.:669.2; MS Found:670.3[M+H] + .

[0294] Synthesis of compound KH23: In a single-necked reaction flask, KH23-7 (90 mg, 0.13 mmol) was dissolved in trifluoroacetic acid (8 mL). Under nitrogen, the reaction was stirred at 60°C for two days. After completion, the solvent was evaporated under reduced pressure, and the reaction was quenched by the addition of saturated aqueous sodium bicarbonate (10 mL). The mixture was extracted with ethyl acetate (15 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure to obtain the crude product. Purification by prep-HPLC yielded KH23 as a white solid (12.46 mg, yield: 17%, purity: 96.84%). LCMS: MS Calcd.: 549.2; MS Found: 550.2 [M+H] + . 1 HNMR(400MHz,CD3OD)δ:11.88(s,1H),8.57(s,2H),8.36(s,1H),8.21(d,J=8.0Hz,1H),7.59(s,1H),7.48(d,J=8.4Hz,1H),7.34(s,1H),6.55( s,1H),5.03(d,J=18.0Hz,1H),4.92(t,J=6.0Hz,1H),4.73(d,J=17.6H z,1H),3.93(s,3H),2.74-2.58(m,2H),2.56(s,3H),2.28-2.23(m,2H).

[0295] Example 24 Synthesis of Compound KH24

[0296] Synthesis of compound KH24-1: Zinc powder (4.11 g, 63.18 mmol) was added to a three-necked reaction flask equipped with a thermometer. Under nitrogen protection, the mixture was heated in an oil bath, raised to 200°C, stirred for 15 minutes, and then cooled to room temperature. This was repeated three times. When the zinc powder cooled to room temperature, anhydrous DMF (8 mL) and 1,2-dibromoethane (196 mg, 1.05 mmol) were added, followed by stirring at 90°C for 30 minutes. When the reaction solution cooled to room temperature, trimethylsilyl chloride (59 mg, 0.53 mmol) was added and stirred at room temperature for 30 minutes. A solution of 1-Boc-3-iodoazetidine (2.98 g, 10.53 mmol) in DMF (10 mL) was then added to the reaction solution. The reaction was stirred at 60°C for 2 hours under nitrogen protection. In another three-necked reaction flask equipped with a thermometer, 5-bromo-2-iodopyrimidine (KH24-0, 3.00 g, 10.53 mmol) and bistriphenylphosphine palladium dichloride (731 mg, 1.05 mmol) were dissolved in DMF (15 mL). The zinc reagent prepared in the previous step was added to the reaction mixture, and the reaction was stirred at 80°C under nitrogen for 2 hours. After completion of the reaction, aqueous ammonium chloride (50 mL) was added to quench the reaction, filtered through celite, and extracted with ethyl acetate (40 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography [petroleum ether:methyl tert-butyl ether (v / v) = (100:0-84:16)] to obtain KH24-1 as a colorless oil (1.40 g, yield: 42%, purity: 82.30%). LCMS:MS Calcd.:313.0;MS Found:258.1[M-56+H] + .

[0297] Synthesis of compound KH24-2: In a single-necked reaction flask, KH24-1 (1.00 g, 3.18 mmol), KH20-1 (532 mg, 3.18 mmol), Pd(dppf)Cl2 (234 mg, 0.32 mmol), cuprous iodide (61 mg, 0.32 mmol), and N,N-diisopropylethylamine (1.23 g, 9.54 mmol) were added to 1,4-dioxane (15 mL). Under nitrogen, the reaction was stirred in a microwave oven at 100°C for 1 hour. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = (100:0-50:50)) to afford KH24-2 as a yellow solid (500 mg, yield: 39%, purity: 53.14%). LCMS:MS Calcd.:400.2;MS Found:345.2[M-56+H] + .

[0298] Synthesis of compound KH24-3: In a single-necked reaction flask, L-pyroglutamic acid (97 mg, 0.75 mmol) was dissolved in dichloromethane (10 mL). The mixture was cooled in an ice-water bath, followed by the addition of 1-chloro-N,N,2-trimethylpropyleneamine (202 mg, 1.50 mmol). The mixture was stirred for 1 hour. KH24-2 (300 mg, 0.75 mmol) and pyridine (237 mg, 3.00 mmol) were then added to the reaction mixture. Under nitrogen, the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (dichloromethane:methanol (v / v) = (100:0-93:7)) to afford KH24-3 as a yellow solid (200 mg, yield: 65%, purity: 79.70%). LCMS:MS Calcd.:511.2;MS Found:412.3[M-Boc+H] + .

[0299] Synthesis of compound KH24-4: In a single-necked reaction flask, KH24-3 (200 mg, 0.49 mmol), 2-bromo-6-methyl-4-trifluoromethylpyridine (140 mg, 0.58 mmol), Pd2(dba)3 (48 mg, 0.05 mmol), Xant-phos (58 mg, 0.10 mmol), and cesium carbonate (319 mg, 0.98 mmol) were added to 1,4-dioxane (12 mL). Under nitrogen, the reaction was stirred at 85°C overnight. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-92:8)] to afford KH24-4 as a yellow solid (200 mg, yield: 61%, purity: 80%). LCMS:MS Calcd.:670.2;MS Found:615.3[M-56+H] + .

[0300] Synthesis of compound KH24: In a single-necked reaction flask, KH24-4 (200 mg, 0.30 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (2 mL). The reaction was stirred at room temperature under nitrogen for 2 hours. After completion, the solvent was evaporated under reduced pressure, and the reaction was quenched by the addition of saturated aqueous sodium bicarbonate (8 mL). The mixture was extracted with ethyl acetate (15 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure to obtain the crude product, which was purified by prep-HPLC to obtain KH24 as a white solid (27.47 mg, yield: 16%, purity: 97.74%). LCMS: MS Calcd.: 570.2; MS Found: 571.3 [M+H] + . 1HNMR(400MHz,CD3OD)δ:8.79(s,2H),8.40(s,1H),7.87-7.81(m,1H),7.74-7. 69(m,1H),7.63-7.61(m,1H),7.40(s,1H),4.97(d,J=17.6Hz,1H),4.88(dd,J= 8.8,3.2Hz,1H),4.63(d,J=18.0Hz,1H),4.12-4.08(m,2H),3.85(t,J=7.2Hz, 2H),3.70(t,J=7.6Hz,2H),2.68-2.62(m,2H),2.57(s,3H),2.14-2.07(m,2H).

[0301] Example 25 Synthesis of Compound KH25

[0302] Synthesis of compound KH25-1a: In a single-necked reaction flask, p-fluoroaniline (6.0 g, 54.0 mmol), 3-bromopropyne (7.72 g, 64.86 mmol), and potassium carbonate (8.95 g, 64.86 mmol) were dissolved in DMF (108 mL). The reaction was stirred at room temperature overnight under nitrogen. After completion, the reaction was quenched with saturated aqueous ammonium chloride (200 mL) and extracted with ethyl acetate (200 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:methyl tert-butyl ether (v / v) = (100:0-70:30)) to afford KH25-1a as a pale yellow liquid (3.5 g, yield: 43%, purity: >95%). 1 HNMR(400MHz, DMSO-d6)δ:6.97-6.92(m,2H),6.64-6.60(m,2H),5.88(t,J=6.4Hz,1H),3.83(dd,J=6.4,2.4Hz,2H),3.04(t,J=2.4Hz,1H).

[0303] Synthesis of compound KH25-1: In a single-necked reaction flask, KH25-0 (3.00 g, 15.46 mmol), N-BOC-3-bromocyclobutane (4.38 g, 18.56 mmol), and potassium carbonate (3.20 g, 23.19 mmol) were added sequentially to DMF (35 mL). The reaction was stirred at 80°C overnight under nitrogen. After completion, the reaction was quenched with aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = (100:0-98:2)) to afford KH25-1 as a white solid (4.0 g, yield: 54%, purity: 72.42%). LCMS: MS Calcd.:349.0; MS Found:294.0[M-56+H] + .

[0304] Synthesis of compound KH25-2: In a single-necked reaction flask, KH25-1 (1.18 g, 2.45 mmol), KH25-1a (367 mg, 2.46 mmol), Pd(dppf)Cl2 (180 mg, 0.25 mmol), cuprous iodide (48 mg, 0.25 mmol), and N,N-diisopropylethylamine (953 mg, 7.39 mmol) were added to 1,4-dioxane (24 mL). The atmosphere was replaced with nitrogen three times. Under nitrogen, the reaction was stirred at 50°C for 1 hour. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography [petroleum ether:ethyl acetate (v / v) = (100:0-50:50)] to afford KH25-2 as a yellow solid (315 mg, yield: 35%, purity: 96.10%). LCMS: MS Calcd.:370.2; MS Found:315.2[M-56+H] + .

[0305] Synthesis of compound KH25-3: In a single-necked reaction flask, L-pyroglutamic acid (72 mg, 0.56 mmol) was dissolved in dichloromethane (10 mL). The mixture was cooled in an ice-water bath, followed by the addition of 1-chloro-N,N,2-trimethylpropyleneamine (234 mg, 1.75 mmol). The mixture was stirred for 1 hour. KH25-2 (280 mg, 0.73 mmol) and pyridine (216 mg, 2.73 mmol) were then added to the reaction mixture. Under nitrogen, the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = (100:0-97:3)) to afford KH25-3 as a yellow solid (230 mg, yield: 66%, purity: 91.15%). LCMS: MS Calcd.:481.2; MS Found:382.2[M-Boc+H] + .

[0306] Synthesis of compound KH25-4: In a single-necked reaction flask, KH25-3 (230 mg, 0.48 mmol), 2-bromo-6-methyl-4-trifluoromethylpyridine (171 mg, 0.72 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), Xant-phos (58 mg, 0.1 mmol), and cesium carbonate (489 mg, 1.50 mmol) were added to 1,4-dioxane (10 mL). The atmosphere was replaced with nitrogen three times. Under nitrogen, the reaction was stirred at 85°C for 6 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = (100:0-94:6)) to afford KH25-4 as a yellow solid (270 mg, yield: 79%, purity: 89.97%). LCMS: MS Calcd.:640.2; MS Found:641.2[M+H] + .

[0307] Synthesis of compound KH25-5: In a single-necked reaction flask, KH25-4 (160 mg, 0.11 mmol) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (2 mL). The reaction was stirred at room temperature under nitrogen for 1 hour. After completion, the solvent was evaporated under reduced pressure, and the reaction was quenched by the addition of saturated aqueous sodium bicarbonate (10 mL). The mixture was extracted with ethyl acetate (15 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure to obtain the crude product. Purification by prep-HPLC afforded KH25 as a white solid (53.59 mg, yield: 48%, purity: 98.48%). LCMS: MS Calcd.: 540.3; MS Found: 541.3 [M+H] +. 1 HNMR(400MHz,CD3OD)δ:8.40(s,1H),8.08(s,1H),7.72-7.68(m,2H),7.60( s,1H),7.45(t,J=8.4Hz,2H),7.39(s,1H),5.16-5.12(m,1H),4.90(d,J=17 .6Hz,1H),4.82-4.78(m,1H),4.41(d,J=17.6Hz,1H),3.85(t,J=8.4Hz,2H) ,3.69(t,J=8.0Hz,2H),2.67-2.55(m,2H),2.58(s,3H),2.07-2.02(m,2H).

[0308] Example 26 Synthesis of Compound KH26

[0309] Synthesis of Compound KH26-1: In a single-necked reaction flask, 4-iodopyrazole (2.00 g, 10.31 mmol) was dissolved in DMF (35 mL). The mixture was cooled in an ice-water bath, followed by the addition of sodium hydride (619 mg, 15.47 mmol, 60 wt%). Under nitrogen, the reaction was stirred at 0°C for 0.5 hours, followed by the addition of 3-iodooxetane (2.85 g, 15.47 mmol). The reaction was stirred at 65°C overnight under nitrogen. After completion of the reaction, aqueous ammonium chloride (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to remove the solvent under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography [petroleum ether:methyl tert-butyl ether (v / v) = (100:0-64:36)] to obtain KH26-1 as a colorless oil (2.00 g, yield: 78%, purity: 87.04%). LCMS: MS Calcd.: 250.0; MS Found: 251.1 [M+H] + .

[0310] Synthesis of compound KH26-2: In a single-necked reaction flask, KH26-1 (1.00 g, 4.00 mmol), KH20-1 (669 mg, 4.00 mmol), Pd(dppf)Cl2 (293 mg, 0.40 mmol), cuprous iodide (76 mg, 0.40 mmol), and N,N-diisopropylethylamine (1.54 g, 12.00 mmol) were added to 1,4-dioxane (30 mL). Under nitrogen, the reaction mixture was stirred at 50°C for 45 minutes. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = (100:0-40:60)) to afford KH26-2 as a yellow solid (500 mg, yield: 43%, purity: 86.84%). LCMS: MS Calcd.:289.1; MS Found:290.2[M+H] + .

[0311] Synthesis of compound KH26-3: In a single-necked reaction flask, L-pyroglutamic acid (90 mg, 0.69 mmol) was dissolved in dichloromethane (10 mL). The mixture was cooled in an ice-water bath, followed by the addition of 1-chloro-N,N,2-trimethylpropyleneamine (186 mg, 1.38 mmol). The mixture was stirred for 1 hour. KH26-2 (200 mg, 0.69 mmol) and pyridine (164 mg, 2.07 mmol) were then added to the reaction mixture. Under nitrogen, the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = (100:0-93:7)) to afford KH26-3 as a yellow solid (100 mg, yield: 36%, purity: 72.76%). :LCMS:MS Calcd.:400.1;MS Found:401.2[M+H] + .

[0312] Synthesis of compound KH26: In a single-necked reaction flask, KH26-3 (90 mg, 0.22 mmol), 2-bromo-6-methyl-4-trifluoromethylpyridine (69 mg, 0.29 mmol), Pd2(dba)3 (19 mg, 0.02 mmol), Xant-phos (23 mg, 0.04 mmol), and cesium carbonate (63 mg, 0.44 mmol) were added to 1,4-dioxane (8 mL). Under nitrogen, the reaction was stirred at 85°C for 6 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-92:8)] to obtain crude KH26 as a yellow solid. The crude product was purified by prep-HPLC to obtain KH26 as a white solid (51.70 mg, yield: 41%, purity: 99.68%).

[0313] LCMS: MS Calcd.:559.2; MS Found:560.3[M+H] + . 1 HNMR(400MHz,CD3OD)δ:8.40(s,1H),8.12(s,1H),7.91-7.67(m,3H),7.58-7.55(m,1H),7.40(s,1H),5.57-5. 52(m,1H),4.94-4.83(m,6H),4.44(d,J=17.6Hz,1H),2.70-2.61(m,1H),2.57-2.50(m,4H),2.10-2.03(m,2H).

[0314] Example 27 Synthesis of Compound KH27

[0315] Synthesis of compound KH27-1: In a single-necked reaction flask, KH27-0 (3 g, 15.46 mmol), N-BOC-3-bromocyclobutane (4.38 g, 18.56 mmol), and potassium carbonate (3.20 g, 23.19 mmol) were added sequentially to DMF (35 mL). The reaction was stirred at 80°C overnight under nitrogen. After completion, the reaction was quenched with aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = (100:0-98:2)) to afford KH27-1 as a white solid (4.0 g, yield: 54%, purity: 72.42%). LCMS: MS Calcd.:349.0; MS Found:294.0[M-56+H] + .

[0316] Synthesis of compound KH27-2: To a single-necked reaction flask, add KH27-1 (2.36 g, 4.82 mmol), KH20-1 (820 mg, 4.82 mmol), Pd(dppf)Cl2 (350 mg, 0.48 mmol), cuprous iodide (182 mg, 0.96 mmol), DIPEA (1.9 g, 14.8 mmol), and 1,4-dioxane (30 mL). Under nitrogen, the reaction mixture was stirred at 50°C for 1 hour. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = (100:0-98:2)) to afford KH27-2 as a yellow solid (562 mg, yield: 27%, purity: 88.98%). :LCMS:MS Calcd.:388.2;MS Found:333.1[M-56+H] + .

[0317] Synthesis of compound KH27-3: In a single-necked reaction flask, L-pyroglutamic acid (103 mg, 0.80 mmol) was dissolved in DCM (4 mL). The mixture was cooled in an ice-water bath, and Ghosez reagent (234 mg, 2.40 mmol) was added. The mixture was stirred for 1 hour. KH27-2 (436 mg, 1 mmol) and pyridine (316 mg, 4.0 mmol) were then added sequentially to the reaction mixture. Under nitrogen, the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-93:7)] to obtain KH27-3 as a yellow solid (430 mg, yield: 65%, purity: 75.53%). LCMS: MS Calcd.: 499.2; MS Found: 400.3 [M-Boc+H] + .

[0318] Synthesis of compound KH27-4: To a single-necked reaction flask, KH27-3 (172 mg, 0.26 mmol), 2-bromo-6-methyl-4-trifluoromethylpyridine (94 mg, 0.39 mmol), Pd2(dba)3 (24 mg, 0.026 mmol), Xant-phos (30 mg, 0.052 mmol), cesium carbonate (254 mg, 0.78 mmol), and 1,4-dioxane (8 mL) were added sequentially. Under nitrogen, the reaction mixture was stirred at 85°C overnight. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = (100:0-94:6)) to afford KH27-4 as a yellow solid (187 mg, yield: 82%, purity: 74.86%). :LCMS:MS Calcd.:658.2;MS Found:559.2[M-Boc+H] + .

[0319] Synthesis of Compound KH27: In a single-necked reaction flask, KH27-4 (187 mg, 0.21 mmol) was dissolved in DCM (4 mL) and TFA (2 mL). The reaction was stirred at room temperature under nitrogen for 1 hour. After completion, the pH of the reaction mixture was adjusted to 9 with saturated sodium bicarbonate solution, followed by extraction with DCM (10 mL x 3). The organic phase was evaporated under reduced pressure to remove the solvent, and the crude product was purified by prep-HPLC to yield KH27 as a white solid (68.74 mg, 56% yield, 97.54% purity).

[0320] LCMS: MS Calcd.:558.2; MS Found:559.3[M+H] + . 1 HNMR(400MHz,DMSO-d6)δ:8.40(s,1H),8.09(s,1H),7.82-7.77(m,1H),7.76-7.67(m,1 H),7.61(s,1H),7.57(d,J=8.8Hz,1H),7.41(s,1H),5.17-5.12(m,1H),4.92(d,J=17.6H z,1H),4.85(dd,J=8.4,4.0Hz,1H),4.43(d,J=17.6Hz,1H),3.85(t,J=7.6Hz,2H),3.69 (t,J=8.0Hz,2H),2.67-2.58(m,2H),2.57(s,3H),2.56-2.52(m,1H),2.10-2.05(m,2H).

[0321] Example 28 Synthesis of Compound KH28

[0322] In a single-necked reaction flask, KH27 (17 mg, 0.03 mmol), aqueous formaldehyde (5 mg, 0.06 mmol, 37 wt%), and acetic acid (1 drop) were added sequentially to methanol (1 mL). The mixture was stirred at room temperature for 10 minutes, followed by the addition of sodium cyanoborohydride (4 mg, 0.06 mmol). Under nitrogen, the reaction was stirred at room temperature for 2 hours. After completion, the reaction was quenched with saturated aqueous sodium bicarbonate solution, and the solvent was evaporated under reduced pressure. The crude product was purified by prep-HPLC to yield KH28 as a white solid (3.22 mg, yield: 18%, purity: >99%). LCMS: MS Calcd.: 572.2; MS Found: 572.9 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ:8.40(s,1H),8.09(s,1H),7.81-7.76(m,1H),7.74-7 .67(m,1H),7.60(s,1H),7.56(d,J=8.8Hz,1H),7.40(s,1H),4.95-4.88(m,2H), 4.86(dd,J=8.0,4.0Hz,1H),4.43(d,J=17.6Hz,1H),3.65(t,J=8.0Hz,2H),2.6 9-2.59(m,2H),2.56(s,3H),2.55-2.52(m,2H),2.30(s,3H),2.10-2.03(m,2H).

[0323] Example 29 Synthesis of Compound KH29

[0324] Synthesis of compound KH29-1: In a single-necked reaction flask, 4-iodopyrazole (3.00 g, 15.47 mmol) was dissolved in DMF (50 mL). The mixture was cooled in an ice-water bath, followed by the addition of sodium hydride (743 mg, 18.56 mmol, 60 wt%). The reaction was stirred at 0°C under nitrogen for 0.5 hours, followed by the addition of chloromethyl methyl sulfide (1.79 g, 18.56 mmol). The reaction was stirred at 0°C under nitrogen for 1 hour. After completion of the reaction, aqueous ammonium chloride (80 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to remove the solvent under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography [petroleum ether:methyl tert-butyl ether (v / v) = (100:0-70:30)] to obtain KH29-1 as a colorless oil (3.00 g, yield: 76%, purity: >99.9%). LCMS: MS Calcd.: 253.9; MS Found: 255.0 [M+H] + .

[0325] Synthesis of compound KH29-2: In a single-necked reaction flask, KH29-1 (700 mg, 2.75 mmol) was dissolved in dichloromethane (28 mL), cooled in an ice-water bath, and then m-chloroperbenzoic acid (1.90 g, 11.00 mmol, 85 wt%) was added. Under nitrogen protection, the reaction was stirred at room temperature overnight, and then the temperature was raised to 40°C and stirred overnight. After completion of the reaction, saturated aqueous sodium sulfite (20 mL) and saturated aqueous sodium bicarbonate (20 mL) were added to quench the reaction, and the mixture was extracted with dichloromethane (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to remove the solvent to obtain a crude product. The crude product was purified by silica gel column chromatography [petroleum ether:methyl tert-butyl ether (v / v) = (100:0-54:46)] to obtain KH29-2 as a colorless oil (600 mg, yield: 76%, purity: 56.85%). LCMS: MS Calcd.: 285.9; MS Found: 287.0 [M+H] + .

[0326] Synthesis of compound KH29-3: In a single-necked reaction flask, KH29-2 (200 mg, 0.70 mmol), KH25-1a (104 mg, 0.70 mmol), Pd(dppf)Cl2 (51 mg, 0.07 mmol), cuprous iodide (27 mg, 0.17 mmol), and N,N-diisopropylethylamine (271 mg, 2.10 mmol) were added to 1,4-dioxane (8 mL). Under nitrogen, the reaction was stirred at 50°C for 1 hour. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = (100:0-40:60)) to afford KH29-3 as a yellow solid (150 mg, yield: 70%, purity: >95%). LCMS: MS Calcd.:307.1; MS Found:308.2[M+H] + .

[0327] Synthesis of compound KH29-4: In a single-necked reaction flask, L-pyroglutamic acid (50 mg, 0.39 mmol) was dissolved in dichloromethane (8 mL). The mixture was cooled in an ice-water bath, followed by the addition of 1-chloro-N,N,2-trimethylpropyleneamine (106 mg, 0.78 mmol). The mixture was stirred for 1 hour. KH29-3 (150 mg, 0.49 mmol) and pyridine (93 mg, 1.17 mmol) were then added to the reaction mixture. Under nitrogen, the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = (100:0-87:13)) to afford KH29-4 as a yellow solid (130 mg, yield: 78%, purity: 77.69%). LCMS: MS Calcd.:418.1; MS Found:419.2[M+H] + .

[0328] Synthesis of compound KH29: In a single-necked reaction flask, KH29-4 (130 mg, 0.31 mmol), 2-bromo-6-methyl-4-trifluoromethylpyridine (90 mg, 0.37 mmol), Pd2(dba)3 (28 mg, 0.03 mmol), Xant-phos (35 mg, 0.06 mmol), and cesium carbonate (202 mg, 0.62 mmol) were added to 1,4-dioxane (8 mL). Under nitrogen, the reaction was stirred at 85°C for 4 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by prep-HPLC to obtain KH29 as a white solid (108.10 mg, 60% yield, 95.97% purity).

[0329] LCMS: MS Calcd.:577.1; MS Found:577.8[M+H] + . 1 HNMR(400MHz,CD3OD)δ:8.40(s,1H),8.07(s,1H),7.75(s,1H),7.72(dd,J=8.4,5.2Hz,2H),7.45(t,J=8.4Hz,2H),7.37(s,1H),5.73( s,2H),4.92(d,J=17.2Hz,1H),4.81(dd,J=8.4,3.6Hz,1H),4.43(d,J=17.2Hz,1H),3.03(s,3H),2.67-2.53(m,5H),2.07-2.03(m,2H).

[0330] Example 30 Synthesis of Compound KH30

[0331] Synthesis of compound KH30-2: In a single-necked reaction flask, KH30-0 (2.00 g, 12.69 mmol) was dissolved in THF (50 mL). The mixture was cooled in an ice-water bath, followed by the addition of oxalyl chloride (6.45 g, 50.76 mmol) and DMF (0.2 mL). The reaction was stirred at room temperature under nitrogen for 2 hours. After completion of the reaction as monitored by TLC, the solvent was evaporated under reduced pressure to yield the crude product. The crude product, KH30-1, was directly used for the next reaction. In a single-necked reaction flask, acetic hydrazide (1.60 g, 21.57 mmol) and N,N-diisopropylethylamine (9.82 g, 76.14 mmol) were added to THF (30 mL). The mixture was cooled in an ice-water bath, followed by the addition of a THF solution of KH30-1 (15 mL). The reaction was stirred at room temperature under nitrogen for 1 hour. After completion of the reaction, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to remove the solvent under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography [petroleum ether:ethyl acetate (v / v) = (100:0-20:80] to obtain KH30-2 as a pale yellow oil (3.01 g, yield: 91%, purity: 81.59%). LCMS: MS Calcd.: 213.0; MS Found: 214.1 [M+H] + .

[0332] Synthesis of compound KH30-3: In a single-necked reaction flask, KH30-2 (3.01 g, 11.53 mmol) was dissolved in phosphorus oxychloride (20 mL). Under nitrogen, the reaction was stirred at 110°C overnight. After completion, the reaction solution was poured into ice water to quench, and then saturated aqueous potassium carbonate solution was slowly added dropwise until the pH of the reaction solution reached 8. The mixture was then extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to remove the solvent under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography [petroleum ether:ethyl acetate (v / v) = (100:0-90:10)] to obtain KH30-3 as a white solid (1.05 g, yield: 45%, purity: >95%). LCMS: MS Calcd.: 195.0; MS Found: 196.1 [M+H] + .

[0333] Synthesis of compound KH30-4: In a single-necked reaction flask, KH30-3 (1.01 g, 5.18 mmol), KH20-1 (863 mg, 5.17 mmol), Pd(dppf)Cl2 (365 mg, 0.52 mmol), cuprous iodide (198 mg, 1.04 mmol), and N,N-diisopropylethylamine (2.00 g, 15.51 mmol) were added to 1,4-dioxane (30 mL). Under nitrogen, the reaction mixture was stirred at 50°C for 1 hour. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = (100:0-40:60)) to afford KH30-4 as a yellow solid (820 mg, yield: 46%, purity: 94.42%). LCMS:MS Calcd.:326.1; MS Found:327.1[M+H] + .

[0334] Synthesis of compound KH30-5: In a single-necked reaction flask, L-pyroglutamic acid (103 mg, 0.80 mmol) was dissolved in dichloromethane (2 mL). The mixture was cooled in an ice-water bath, followed by the addition of 1-chloro-N,N,2-trimethylpropyleneamine (214 mg, 1.60 mmol). The mixture was stirred for 1 hour. KH30-4 (345 mg, 1.00 mmol) and pyridine (221 mg, 2.80 mmol) were then added to the reaction mixture. Under nitrogen, the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-93:7)] to obtain KH30-5 as a yellow solid (250 mg, yield: 47%, purity: 81.78%). LCMS:MS Calcd.:437.1; MS Found:438.2[M+H]+ .

[0335] Synthesis of compound KH30: In a single-necked reaction flask, KH30-5 (150 mg, 0.28 mmol), 2-bromo-6-methyl-4-trifluoromethylpyridine (100 mg, 0.42 mmol), Pd2(dba)3 (27 mg, 0.028 mmol), Xant-phos (32 mg, 0.056 mmol), and potassium carbonate (116 mg, 0.84 mmol) were added to 1,4-dioxane (2 mL). Under nitrogen protection, the reaction was stirred in a microwave at 80°C for 5 hours. After completion of the reaction, the reaction solution was evaporated to remove the solvent under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-92:8)] to obtain crude KH30 as a yellow solid. The crude product was purified by prep-HPLC to obtain KH30 as a white solid (54.95 mg, yield: 33%, purity: >95%).

[0336] LCMS:MS Calcd.:596.2;MS Found:596.8[M+H] + . 1 HNMR(400MHz,DMSO-d6)δ:9.10(d,J=1.6Hz,1H),8.41(s,1H),8.34(dd,J=8.0 ,2.4Hz,1H),7.89-7.83(m,1H),7.74(q,J=19.2,8.8Hz,1H),7.65-7.60(m,2H ),7.39(s,1H),5.03(d,J=18.0Hz,1H),4.90(dd,J=8.8,3.2Hz,1H),4.61(d,J =17.6Hz,1H),2.67-2.62(m,2H),2.61(s,3H),2.58(s,3H),2.14-2.08(m,2H).

[0337] Example 31 Synthesis of Compound KH31

[0338] Synthesis of compound KH31-1: In a single-necked reaction flask, KH21-1 (70 mg, 0.53 mmol) was dissolved in dichloromethane (5 mL). The mixture was cooled in an ice-water bath, followed by the addition of 1-chloro-N,N,2-trimethylpropyleneamine (146 mg, 1.06 mmol). The mixture was stirred for 1 hour, followed by the addition of KH30-4 (192 mg, 0.58 mmol) and pyridine (126 mg, 1.59 mmol). Under nitrogen, the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (dichloromethane:methanol (v / v) = (100:0-89:11)) to afford KH31-1 as a yellow solid (150 mg, yield: 64%, purity: >95%). LCMS:MS Calcd.:439.1; MS Found:440.1[M+H] + .

[0339] Synthesis of compound KH31: In a single-necked reaction flask, KH31-1 (90 mg, 0.20 mmol), 2-bromo-6-methyl-4-trifluoromethylpyridine (64 mg, 0.27 mmol), Pd2(dba)3 (18 mg, 0.02 mmol), Xant-phos (23 mg, 0.04 mmol), and potassium carbonate (83 mg, 0.60 mmol) were added to 1,4-dioxane (5 mL). Under nitrogen, the reaction was stirred in a microwave oven at 80°C for 3.5 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography [dichloromethane:methanol (v / v) = (100:0-99:11)] to obtain crude KH31 as a pale yellow solid. The crude product was then purified by prep-HPLC to obtain KH31 as a white solid (37.19 mg, yield: 30%, purity: >95%).

[0340] LCMS:MS Calcd.:598.1; MS Found:598.8[M+H] + . 1 HNMR(400MHz, DMSO-d6)δ:9.10(d,J=1.2Hz,1H),8.34(dd,J=8.4,2.4Hz,1H),8.14(s,1H),7.80-7.34(m,2H),7.65(d,J=8.0H z,1H),7.59-7.57(m,1H),7.41(s,1H),5.06-5.00(m,2H),4.65-4.61(m,2H),4.38(t,J=9.2Hz,1H),2.61(s,3H),2.57(s,3H).

[0341] Example 32 Synthesis of Compound KH32

[0342] In a single-necked reaction flask, KH24 (150 mg, 0.26 mmol) and aqueous formaldehyde (42 mg, 0.52 mmol, 37 wt%) were dissolved in methanol (3 mL). The mixture was cooled in an ice-water bath, and then 1 drop of glacial acetic acid was added dropwise to the reaction mixture. After stirring for 10 minutes, NaBH3CN (26 mg, 0.39 mmol) was added. The reaction was stirred at room temperature for 1 hour under nitrogen. After completion of the reaction, saturated NaHCO3 solution (3 mL) was added to quench the reaction. The methanol solvent was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate (6 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by prep-HPLC, acetonitrile was evaporated under reduced pressure, and the water was lyophilized to obtain KH32 as a white solid (72.64 mg, yield: 47%, purity: 96.71%). LCMS: MS Calcd.: 584.2; MS Found: 585.0 [M+H] + . 1 HNMR(400MHz,CD3OD)δ:8.81(s,2H),8.43(s,1H),7.88-7.84(m,1H),7.76-7.71(m,1 H),7.65-7.63(m,1H),7.42(s,1H),5.23(s,1H),5.00(d,J=18.0Hz,1H),4.91(dd,J= 8.4,2.8Hz,1H),4.65(d,J=18.0Hz,1H),3.91-3.87(m,1H),3.69(t,J=7.6Hz,2H),3. 40(t,J=7.2Hz,2H),2.71-2.64(m,1H),2.59(s,3H),2.31(s,3H),2.16-2.07(m,2H).

[0343] Example 33 Synthesis of Compound KH33

[0344] In a single-necked reaction flask, KH25 (80 mg, 0.15 mmol) and formaldehyde solution (25 mg, 0.30 mmol, 37 wt%) were dissolved in methanol (3 mL). The mixture was cooled in an ice-water bath, and then 1 drop of glacial acetic acid was added dropwise to the reaction mixture. After stirring for 10 minutes, NaBH3CN (16 mg, 0.23 mmol) was added. The reaction was stirred at room temperature for 1 hour under nitrogen. After completion of the reaction, saturated NaHCO3 solution (3 mL) was added to quench the reaction. The methanol solvent was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate (6 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by prep-HPLC, acetonitrile was evaporated under reduced pressure, and the water was lyophilized to obtain KH33 as a white solid (36.23 mg, yield: 44%, purity: 97.94%). LCMS: MS Calcd.: 554.2; MS Found: 555.0 [M+H] + . 1 HNMR(400MHz,CD3OD)δ:8.42(s,1H),8.11(s,1H),7.73-7.71(m,2H),7.63(s ,1H),7.47(t,J=8.4Hz,2H),7.41(s,1H),4.96-4.90(m,2H),4.84-4.81(m,1 H),4.44(d,J=17.6Hz,1H),3.69(t,J=6.4Hz,2H),3.37-3.69(m,2H),2.72-2 .65(m,1H),2.63(s,3H),2.60-2.56(m,1H),2.33(s,3H),2.08-2.02(m,2H).

[0345] Example 34 Synthesis of Compound KH34

[0346] Synthesis of compound KH34-1: In a single-necked reaction flask, KH26-1 (1.00 g, 4.00 mmol), KH25-1a (597 mg, 4.00 mmol), Pd(dppf)Cl2 (293 mg, 0.40 mmol), cuprous iodide (76 mg, 0.40 mmol), and N,N-diisopropylethylamine (1.54 g, 12.00 mmol) were added to 1,4-dioxane (30 mL). Under nitrogen, the reaction mixture was stirred at 50°C for 45 minutes. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = (100:0-40:60)) to afford KH34-1 as a yellow solid (500 mg, yield: 46%, purity: 89.36%). LCMS:MS Calcd.:271.1;MS Found:272.2[M+H] + .

[0347] Synthesis of compound KH34-2: In a single-necked reaction flask, L-pyroglutamic acid (114 mg, 0.88 mmol) was dissolved in dichloromethane (10 mL). The mixture was cooled in an ice-water bath, followed by the addition of 1-chloro-N,N,2-trimethylpropyleneamine (186 mg, 1.38 mmol). The mixture was stirred for 1 hour, followed by the addition of KH34-1 (300 mg, 1.11 mmol) and pyridine (209 mg, 2.64 mmol). Under nitrogen, the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography (dichloromethane:methanol (v / v) = (100:0-93:7)) to afford KH34-2 as a yellow solid (250 mg, yield: 74%, purity: 81.28%). LCMS:MS Calcd.:382.1;MS Found:383.2[M+H] + .

[0348] Synthesis of compound KH34: In a single-necked reaction flask, KH34-2 (250 mg, 0.65 mmol), 2-bromo-6-methyl-4-trifluoromethylpyridine (187 mg, 0.78 mmol), Pd2(dba)3 (55 mg, 0.06 mmol), Xant-phos (35 mg, 0.06 mmol), and cesium carbonate (318 mg, 0.97 mmol) were added to 1,4-dioxane (10 mL). Under nitrogen, the reaction was stirred at 85°C for 5 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by prep-HPLC to obtain KH34 as a white solid (110.95 mg, yield: 31%, purity: 99.08%). LCMS: MS Calcd.: 541.2; MS Found: 542.0 [M+H] + . 1 HNMR(400MHz,CD3OD)δ:8.40(s,1H),8.11(s,1H),7.72-7.68(m,3H),7.44(t,J=8.8Hz,2H),7.39(s,1H ),5.56-5.30(m,1H),4.92-4.79(m,6H),4.42(d,J=19.2Hz,1H),2.67-2.54(m,5H),2.07-2.02(m,2H).

[0349] Example 35 Synthesis of Compound KH35

[0350] Synthesis of KH35-1: In a single-necked reaction flask, KH35-0 (0.25 g, 2.17 mmol) and 2-chloro-6-methyl-4-trifluoromethylnicotinonitrile (527 mg, 2.39 mmol) were added to DMF (20 mL), followed by the addition of cesium carbonate (1.06 g, 3.26 mmol). Under nitrogen, the reaction was stirred at 90°C for 2 hours and then at room temperature overnight. After completion, the reaction was quenched with aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to remove the solvent under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography [petroleum ether:ethyl acetate (v / v) = (100:0-20:80)] to afford KH35-1 as a white solid (0.4 g, yield: 36%, purity: 90%). LCMS MS Calcd.:299.1; MS Found:300.2[M+H]+.

[0351] Synthesis of KH35-2: In a single-necked reaction flask, KH35-1 (0.21 g, 0.70 mmol), p-fluoroaniline (86 mg, 0.77 mmol), TCFH (393 mg, 1.40 mmol), and NMI (230 mg, 2.80 mmol) were added to DMF (5 mL). The reaction was stirred at room temperature under nitrogen for 2 hours. After completion, water (20 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to remove the solvent under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography [petroleum ether:ethyl acetate (v / v) = (100:0-30:70)] to obtain KH35-2 as a yellow solid (150 mg, yield: 45%, purity: 84.11%). :LCMS:MS Calcd.:392.1;MS Found:393.3[M+H]+.

[0352] Synthesis of KH35-3: In a single-necked reaction flask, KH35-2 (150 mg, 0.38 mmol) was dissolved in DMF (3 mL). The mixture was cooled in an ice-water bath, followed by the addition of NaH (23 mg, 0.57 mmol, 60 wt%). After stirring for 0.5 hours, propargyl bromide (68 mg, 0.57 mmol) was added to the reaction mixture. Under nitrogen, the reaction mixture was stirred at room temperature for 2 hours. After completion, the reaction was quenched with aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to remove the solvent under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography [petroleum ether:ethyl acetate (v / v) = (100:0-30:70)] to afford KH35-3 as a yellow solid (100 mg, yield: 52%, purity: 85.78%). LCMS: MS Calcd.:430.1; MS Found:431.2[M+H]+.

[0353] Synthesis of KH35: In a single-necked reaction flask, KH672C-3 (100 mg, 0.23 mmol), 3-chloro-6-iodopyridazine (56 mg, 0.23 mmol), Pd(PPh3)3Cl2 (16 mg, 0.023 mmol), cuprous iodide (5 mg, 0.023 mmol), and cesium carbonate (225 mg, 0.69 mmol) were added to 1,4-dioxane (6 mL). The atmosphere was then flushed with nitrogen three times. The reaction was stirred at 50°C under nitrogen for 1 hour. After completion of the reaction, the reaction solution was evaporated to remove the solvent under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography [petroleum ether:ethyl acetate (v / v) = (100:0-50:50)] to obtain crude KH672C as a yellow solid. Purification by prep-HPLC gave KH672C as a white solid (29.27 mg, yield: 23%, purity: 96.36%).

[0354] LCMS: MS Calcd.:542.1; MS Found:543.1[M+H]+.

[0355] 1HNMR (400MHz, DMSO-d6)δ:7.98(d,J=8.8Hz,1H),7.85(d,J=8.8Hz,1H),7.71(t,J=5.2Hz,2H),7.44(t,J=8.4Hz,2H),7.06(s,1H),5.04 (d,J=18.0Hz,1H),4.56(d,J=18.0Hz,1H),4.48(d,J=6.4Hz,1H),3.93-3.91(m,2H),3.34(s,3H),2.08-2.03(m,1H),1.94-1.86(m,3H).

[0356] Example 36 In vitro activity assay of the compound

[0357] Experimental reagents and consumables

[0358] Table 1

[0359] Sample solution preparation

[0360] Compounds were serially diluted with DMSO in a 384PP plate. Using an Echo, 0.15 μL of compound was transferred to a 384-well microplate (Greiner 784075), ensuring a final DMSO content of 1% (in duplicate). The control compound, ART558 (CAS No. 2603528-97-6), was commercially available. The preparation method for ART812 (CAS No. 2607138-82-7) is described in Example 65 of Chinese Patent No. CN114667167A. The structures of ART558 and ART812 are as follows:

[0361] Experimental procedures

[0362] Add 5 μL of 3X POLQ-C enzyme solution to each well of a 384-well microplate containing compound samples and incubate at 25°C for 10 minutes. Wells containing DMSO and POLQ-C enzyme serve as high controls, while wells containing DMSO and assay buffer serve as low controls. Add 5 μL of 3X FITC-dATP, dsDNA, and a mixed solution of dCTP, dGTP, and dTTP to each well. Finally, add 5 μL of Streptavidin-Tb cryptate solution to each well and incubate at 25°C for 60 minutes. (Final concentrations: 5 nM POLQ-C, 10 nM dsDNA, 10 μM dCTP, dGTP, and dTTP, 0.1 μM FITC-dATP, 1X Streptavidin-Tb cryptate). The 490 nm and 520 nm signals were read on a BMG (PHERAstar FSX) microplate reader and the ratio was calculated (Ratio: 520 / 490*10 4 The percentage inhibition of compound-treated wells was normalized between High Control and Low Control (% Inhibition = (AVE High Control -Ratio 化合物读值 ) / (AVE High Control -AVE Low Control )*100). Then, the four-parameter IC was fitted by XLfit 5.5.0. 50 Curve and analysis, IC 50 The results show that the IC of the compounds described in this application is 50%. 50 In the range of 1-50 nM, especially the IC of compound KH25 50 Reached 1.89 nM, as shown in Table 2.

[0363] Table 2 In vitro activity detection experimental results

[0364] Example 37 Liver microsome stability test

[0365] Material

[0366] Liver microsomes: Human liver microsomes were purchased from Corning, and rat liver microsomes were purchased from RILD and stored in a -80°C freezer.

[0367] Reduced Nicotinamide Adenine Dinucleotide Phosphate (NADPH), Supplier: BONTAC, Catalog Number: BT04

[0368] Control compounds: testosterone, diclofenac, propafenone

[0369] Experimental procedures

[0370] Preparation of working fluid

[0371] Stock solution: 10 mM DMSO solution

[0372] Working concentration preparation: dilute to 100 μM in 100% acetonitrile (organic phase content: 99% ACN, 1% DMSO)

[0373] operate

[0374] Prepare two 96-well incubation plates, named T60 incubation plate and NCF60 incubation plate respectively.

[0375] 445 μL of microsomal working solution (liver microsomal protein concentration is 0.56 mg / mL) was added to the T60 incubation plate and the NCF60 incubation plate, respectively, and then the above incubation plates were placed in a 37° C. water bath for pre-incubation for about 10 minutes.

[0376] After pre-incubation, add 5 μL of the test sample or control compound working solution to each well of the T60 incubation plate and the NCF60 incubation plate and mix well. Initiate the reaction by adding 50 μL of potassium phosphate buffer to each well of the NCF60 incubation plate.

[0377] To the T0 stop plate, add 180 μL of stop solution (200 ng / mL tolbutamide and 200 ng / mL labetalol in acetonitrile) and 6 μL of NADPH regeneration system working solution. Remove 54 μL of sample from the T60 incubation plate and transfer it to the T0 stop plate (T0 sample generation). To the blank plate, add only 54 μL of microsome working solution, 6 μL of NADPH regeneration system working solution, and 180 μL of stop solution.

[0378] The reaction was initiated by adding 44 μL of NADPH regeneration system working solution to each well of a T60 incubation plate. Therefore, in the test or control compound samples, the final reaction concentration of the compound, testosterone, diclofenac, and propafenone was 1 μM, the concentration of liver microsomes was 0.5 mg / mL, and the final concentrations of DMSO and acetonitrile in the reaction system were 0.01% (v / v) and 0.99% (v / v), respectively.

[0379] After incubation for an appropriate time (e.g., 5, 15, 30, 45, and 60 minutes), 180 μL of stop solution (an acetonitrile solution containing 250 nM tolbutamide and 250 nM labetalol) was added to the sample wells of each stop plate, and then 60 μL of sample was removed from the T60 incubation plate or NCF60 incubation plate to terminate the reaction.

[0380] All sample plates were shaken and centrifuged at 3220 × g for 20 min at 4°C, and then 80 μL of supernatant from each well was diluted into 240 μL of pure water for liquid chromatography tandem mass spectrometry analysis.

[0381] Liquid chromatography tandem mass spectrometry

[0382] All samples were injected and analyzed.

[0383] Sample analysis

[0384] In this study, the sample analysis of the test and reference compounds testosterone, diclofenac, and propafenone was performed using liquid chromatography-tandem mass spectrometry (LC-MS / MS).

[0385] Data Analysis

[0386] The in vitro elimination rate constant k of the test and control compounds was calculated by converting the ratio of the compound to the internal standard peak area into the residual percentage in the following formula: e :

[0387] when

[0388] By k e Calculation of in vitro liver microsomal intrinsic clearance (CL int(mic) ) and hepatic intrinsic clearance (CL int(liver) )

[0389] CL int(mic) =0.693 / T 1 / 2 / Microsomal protein content (microsomal concentration during incubation mg / mL)

[0390] CL int(liver) =CL int(mic)× amount of microsomal protein in the liver (mg / g) × liver weight to body weight ratio

[0391] The parameters used in the formula are shown in Table 3 below.

[0392] Table 3

[0393] Table 4-1 Results of human liver microsome stability test

[0394] Table 4-2 Results of rat liver microsome stability test

[0395] Example 38 Pharmacokinetic Evaluation of Compound

[0396] Experimental purpose: To study the pharmacokinetics of the compound in SD rats

[0397] Experimental materials: SD rats (male, 6-9 weeks old)

[0398] Experimental methods:

[0399] The pharmacokinetic characteristics of the compounds following oral administration in rodents were tested using a standard protocol. The compounds were prepared as clear solutions and administered orally to rats as a single dose. The positive control group received ART812, while the other groups received the test compounds in a 10% DMSO / 80% PEG400 / 10% water vehicle. Male Sprague-Dawley rats were administered a 10 mg / kg oral gavage. Plasma was collected at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after dosing. Plasma concentrations were quantified using LC-MS / MS analysis, and plasma concentration-time curves were plotted. The results are shown in Figure 1.

[0400] Example 39 Pharmacokinetic Evaluation of Compound

[0401] Experimental purpose: To study the pharmacokinetics of the compound in Beagle dogs

[0402] Experimental materials: Beagle dogs (male, 7-9 kg)

[0403] Experimental methods:

[0404] The pharmacokinetic characteristics of the compounds following oral administration were tested in Beagle dogs using a standard protocol. The compounds were prepared as clear solutions and administered orally to Beagle dogs as a single dose. The positive control group received ART812, while the other groups received the test compounds in a 10% DMSO / 80% PEG400 / 10% water vehicle. Male Beagle dogs were administered a 3 mg / kg oral gavage. Plasma was collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after dosing. Plasma concentrations were quantified using LC-MS / MS, and plasma concentration-time curves were plotted. The results are shown in Figure 2.

[0405] The above results indicate that the exemplary compounds of the present application can maintain a high blood concentration for a long time after oral administration.

[0406] Example 40 Animal Efficacy Study

[0407] Objective: To study the in vivo pharmacodynamics of the compound in a female BALB / c Nude mouse model bearing subcutaneous xenografts of human colon cancer DLD-1BRCA2- / - cells.

[0408] Experimental Materials:

[0409] Cell Culture: Human colon cancer DLD-1BRCA2- / - cells were cultured as monolayers in RPMI1640 medium supplemented with 2 mM L-glutamine, 25 mM sodium bicarbonate, 10% fetal bovine serum, and 1% penicillin-streptomycin solution at 37°C in a 5% CO incubator. Cells were routinely digested and passaged twice weekly using trypsin-EDTA. When cell saturation reached 80%-90% and the desired number of cells was reached, cells were harvested, counted, and plated.

[0410] Animals: BALB / c nude mice, female, 6-8 weeks old, weighing 18-20 g.

[0411] Experimental methods and results:

[0412] Tumor inoculation: 0.2 mL (5 x 10 DLD-1BRCA2- / - cells plus PBS:Matrigel = 1:1) was subcutaneously inoculated on the right back near the upper limb of each mouse, and the average tumor volume reached about 100-150 mm 3 The drug efficacy test grouping and drug administration were started at around 9:00 a.m. The experimental grouping and drug administration schedule are shown in Table 5.

[0413] Table 5 Animal experimental groups and dosing regimens

[0414] Animals were weighed and tumor volumes were measured before administration, and tumor volumes were measured twice a week after administration.

[0415] Tumor volume measurement method: Use a vernier caliper to measure the tumor diameter. The formula for calculating tumor volume is: V = 0.5 x ax b2,

[0416] a and b represent the long and short diameters of the tumor, respectively.

[0417] The curves of tumor volume changes in each group are shown in Figure 3.

[0418] The above results indicate that the exemplary compounds of the present application can significantly reduce tumor volume when used in combination with Niraparib.

[0419] On day 28 of administration, tumors were removed from mice in each group, and 10 volumes of homogenate (15 mM PBS: MeOH = 2:1) were added to the tumor samples for homogenization. The dilution factor was 11. After homogenization, the concentration of the homogenate was quantitatively analyzed by LC-MS / MS analysis. The concentration of the test substance in the tumor sample was calculated by the dilution factor. The results are shown in Tables 6 and 7.

[0420] Table 6 Drug concentrations in tumor homogenates

[0421] Table 7 Niraparib concentration in tumor homogenate

[0422] The above results indicate that the exemplary compounds of the present application, when used in combination with Niraparib, can increase the drug concentration in tumor tissue.

[0423] For the purposes of description and disclosure, all patents, patent applications, and other publications are expressly incorporated herein by reference. These publications are provided solely because their disclosure predates the filing date of the present application. All statements regarding the dates of these documents or the representations of their contents are based on information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Furthermore, any citation of these publications herein does not constitute an admission that such publications become part of the common general knowledge in the art in any country.

[0424] Those skilled in the art will recognize that the scope of the present application is not limited to the various specific implementation modes and examples described above, but that various modifications, replacements, or recombinations can be made without departing from the spirit of the present application, which all fall within the scope of protection of the present application.

Claims

1. A compound of the formula: The compound structure is as follows: wherein R1 and R2 are each independently selected from H, halogen, amino, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R3 is selected from H, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl; or said R3 and R1 or R2 and adjacent N and C form a heterocyclic group, said heterocyclic group is optionally substituted by hydrogen, halogen, amino, hydroxy, cyano, carbonyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy; R4 is independently selected from hydrogen, hydroxy, halogen, amino, cyano, carboxyl, carbonyl, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl; R5 is -(CH2) m -C≡CD, wherein D is aryl or heteroaryl, said aryl or heteroaryl being optionally substituted with hydrogen, halogen, amino, carbonyl, sulfone, sulfonyl, alkylsulfonyl, alkylsulfonylalkyl, hydroxy, cyano, carboxyl, alkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; B is aryl or heteroaryl, said aryl or heteroaryl being optionally substituted with hydrogen, halogen, amino, hydroxy, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy; Ring A is an aryl group or a heteroaryl group; m and n are integers of 0-4.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The compound structure is as follows: wherein R1 and R2 are each independently selected from H, halogen, amino, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R3 is selected from H, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl; or said R3 and R1 or R2 and adjacent N and C form a heterocyclic group, said heterocyclic group is optionally substituted by hydrogen, halogen, amino, hydroxy, cyano, carbonyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy; R4 is independently selected from hydrogen, hydroxy, halogen, amino, cyano, carboxyl, carbonyl, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl; R5 is -(CH2) m -C≡CD, wherein D is aryl or heteroaryl, said aryl or heteroaryl being optionally substituted with hydrogen, halogen, amino, hydroxy, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; B is aryl or heteroaryl, said aryl or heteroaryl being optionally substituted with hydrogen, halogen, amino, hydroxy, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy; Ring A is an aryl group or a heteroaryl group; m and n are integers of 0-4.

3. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The ring A is a 5-10 membered aryl group or a 5-10 membered heteroaryl group, preferably having the following structure:

4. The compound according to any one of claims 1 to 3, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The compound structure is as follows: wherein R1 and R2 are each independently selected from H, halogen, amino, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R3 is selected from H, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl; or said R3 and R1 or R2 and adjacent N and C form a heterocyclic group, said heterocyclic group is optionally substituted by hydrogen, halogen, amino, hydroxy, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy; R4 is independently selected from hydrogen, hydroxy, halogen, amino, cyano, carboxyl, carbonyl, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl; R5 is -(CH2) m -C≡CD, wherein D is aryl or heteroaryl, said aryl or heteroaryl being optionally substituted with hydrogen, halogen, amino, hydroxy, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy; B is aryl or heteroaryl, said aryl or heteroaryl being optionally substituted with hydrogen, halogen, amino, hydroxy, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy; m and n are integers of 0-4.

5. A compound according to any one of the preceding claims, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein R3 and R1 or R2 and adjacent N and C form a 5-10 membered heterocyclic group, preferably a 5-8 membered heterocyclic group, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S, and the heterocyclic group is optionally substituted by hydrogen, halogen, amino, hydroxy, cyano, carbonyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, or hydroxyalkoxy; Alternatively, R3 is an aryl group or a heteroaryl group, wherein the heteroaryl group contains at least one atom selected from N, O, and S.

6. A compound according to any one of the preceding claims, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: The compound has the structure shown in Formula II: wherein A1, A2, A3, and A4 are each independently selected from CR6, CR6R 6a , NR6, O, S and S(O)2; R6 is independently selected from hydrogen, hydroxy, halogen, alkyl, haloalkyl, alkoxy, amino, aminoalkyl, acyl, cycloalkyl, aryl, heterocyclyl and heteroaryl; or A1 and A2, A2 and A3 optionally form a substituted or unsubstituted saturated or unsaturated 3-14 membered ring, which may optionally include one or more heteroatoms which may be the same or different and are independently selected from O, N, and S; R 6a are independently selected from hydrogen, hydroxy, halogen, alkyl, haloalkyl, alkoxy, amino, aminoalkyl, acyl; or R6 and R 6a together with the carbon atom to which they are attached, form a -C(=S)-, (-C)=O, -C(=NH)- group, or a substituted or unsubstituted saturated or unsaturated 3-14 membered ring, which may optionally include one or more heteroatoms which may be the same or different and are independently selected from O, N, and S; B is aryl or heteroaryl, said aryl or heteroaryl being optionally substituted with hydrogen, hydroxy, halogen, haloalkyl, alkoxy, amino, aminoalkyl, acyl, alkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl; R4 is independently selected from hydrogen, hydroxy, halogen, amino, cyano, carboxyl, carbonyl, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl; R5 is -(CH2) m -C≡CD, wherein D is aryl or heteroaryl, said aryl or heteroaryl being optionally substituted with hydrogen, halogen, amino, hydroxy, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy.

7. A compound according to any one of the preceding claims, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: The compound has a structure as shown in Formula III: in: A1 is selected from CR6, (-C)=O, S(O)2, R6 is independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl; A2 is selected from CR6, NR6, O, R6 is independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl; or A1 and A2 form a 5-6 membered aryl or heteroaryl group, wherein the aryl or heteroaryl group is optionally substituted with hydrogen, hydroxy, halogen, haloalkyl, alkoxy, amino, aminoalkyl, acyl, alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl; The other substituents are as defined in claim 6.

8. A compound according to any one of the preceding claims, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: Selected from:

9. A compound according to any one of the preceding claims, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: B is selected from a 5-6 membered aryl or heteroaryl group, wherein the heteroaryl group may optionally include one or more heteroatoms, which may be the same or different and are independently selected from O, N, and S, and the aryl or heteroaryl group is optionally substituted with hydrogen, hydroxyl, halogen, cyano, alkyl, haloalkyl, alkoxy, amino, or aminoalkyl.

10. A compound according to any one of the preceding claims, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: B is selected from: in: A5, A6, A7, A8 are CR9 or NR9, R9 is independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl; R8 is independently selected from hydrogen, hydroxy, halogen, amino, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl; Preferably, B is selected from: R8 is independently selected from hydrogen, hydroxy, halogen, amino, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl.

11. A compound according to any one of the preceding claims, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: D is selected from a 5-6 membered aryl or heteroaryl group, wherein the heteroaryl group may optionally include one or more heteroatoms, which may be the same or different and are independently selected from O, N, and S, and the aryl or heteroaryl group is optionally substituted with hydrogen, hydroxy, halogen, cyano, alkyl, haloalkyl, alkoxy, amino, or aminoalkyl; m is an integer from 1 to 3.

12. A compound according to any one of the preceding claims, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: The compound has a structure as shown in Formula IV or Formula V: A1 is selected from CR6, (-C)=O, S(O)2, R6 is independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl; A2 is selected from CR6, NR6, O, R6 is independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl; R8 is independently selected from hydrogen, hydroxy, halogen, amino, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl; R4 is independently selected from hydrogen, hydroxy, halogen, amino, cyano, carboxyl, carbonyl, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl; D is selected from a 5-6 membered aryl or heteroaryl group, wherein the heteroaryl group may optionally include one or more heteroatoms, which may be the same or different and are independently selected from O, N, and S, and the aryl or heteroaryl group is optionally substituted with hydrogen, hydroxy, halogen, cyano, carbonyl, sulfone, sulfonyl, alkyl, haloalkyl, alkoxy, alkylsulfonyl, amino, aminoalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

13. A compound according to any one of the preceding claims, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: R8 is selected from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl; Preferably, R4 is selected from hydrogen, hydroxyl, halogen, amino, carbonyl, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkoxy, C3-6 cycloalkyl, C3-6 heterocyclyl; more preferably, R4 is halogen.

14. A compound according to any one of the preceding claims, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: The D has the following structure: R7 is selected from hydrogen, halogen, amino, sulfone, sulfonyl, methylsulfonyl, methylsulfonylmethyl, C1-6 alkyl, -NHC1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl, C5-6 aryl, C5-6 heteroaryl.

15. A compound according to any one of the preceding claims, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: The D has the following structure: R7 is selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl.

16. A compound according to any one of the preceding claims, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: The D has the following structure: R7 is selected from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl; preferably, R7 is hydrogen.

17. A compound according to any one of the preceding claims, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: The D has the following structure: R7 is selected from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy; preferably, R7 is -C1-6 alkoxy; more preferably, D is 18. A compound according to any one of the preceding claims, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: Said R7 is a C3-6 heterocyclic group, said heterocyclic group includes one or more heteroatoms, said heteroatoms may be the same or different and are independently selected from O, N, and S; preferably, said R7 is 19. A compound according to any one of the preceding claims, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: Said R7 is C5-6 aryl or C5-6 heteroaryl, said heteroaryl includes one or more heteroatoms, said heteroatoms may be the same or different and are independently selected from O, N, and S; preferably, said R7 is 20. A compound according to any one of the preceding claims, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: The compound has the structure shown in Formula VI: in, A2 is selected from -CH2- or O; R8 has 1, 2, 3 or 4, and each is independently selected from hydrogen, hydroxy, halogen, amino, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl; R4 has 1, 2, 3, 4 or 5, and each is independently selected from hydrogen, hydroxy, halogen, amino, cyano, carboxyl, carbonyl, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl; R7 is selected from hydrogen, halogen, sulfone, sulfonyl, methylsulfonyl, methylsulfonylmethyl, C1-6 alkyl, -NHC1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl, C5-6 aryl, C5-6 heteroaryl, and the heterocycloalkyl or heteroaryl includes one or more heteroatoms, which may be the same or different and are independently selected from O, N, and S.

21. A compound according to any one of the preceding claims, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: R7 is selected from hydrogen, C1-6 alkoxy, Preferably, hydrogen, methoxy, 22. A compound according to any one of the preceding claims, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: R8 is each independently selected from hydrogen, halogen, cyano, C1-6 alkyl or C1-6 haloalkyl; preferably R8 is each independently selected from hydrogen, cyano, methyl or halomethyl.

23. A compound according to any one of the preceding claims, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: R4 is independently selected from hydrogen, hydroxyl, halogen, amino, carbonyl, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkoxy, C3-6 cycloalkyl, C3-6 heterocyclyl; preferably R4 is halogen.

24. A compound according to any one of the preceding claims, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: The compound has the structure shown in Formula VII: A2 is selected from -CH2- or O; R 8a 、R 8b Each is independently selected from hydrogen, hydroxy, halogen, amino, cyano, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl; R4 has 1, 2, 3, 4 or 5, and each is independently selected from hydrogen, hydroxy, halogen, amino, cyano, carboxyl, carbonyl, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl; R7 is selected from hydrogen, halogen, sulfone, sulfonyl, methylsulfonyl, methylsulfonylmethyl, C1-6 alkyl, -NHC1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl, C5-6 aryl, C5-6 heteroaryl, and the heterocycloalkyl or heteroaryl includes one or more heteroatoms, which may be the same or different and are independently selected from O, N, and S.

25. A compound according to any one of the preceding claims, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: R7 is selected from hydrogen, C1-6 alkoxy, Preferably, hydrogen, methoxy, 26. A compound according to any one of the preceding claims, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: R 8a 、R 8b Each is independently selected from hydrogen, halogen, C1-6 alkyl or C1-6 haloalkyl; preferably R 8a 、R 8b Each is independently selected from hydrogen, cyano, methyl or halomethyl; preferably R 8a is trifluoromethyl, R 8b It is a methyl group.

27. A compound according to any one of the preceding claims, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R4 is independently selected from hydrogen, hydroxyl, halogen, amino, carbonyl, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkoxy, C3-6 cycloalkyl, C3-6 heterocyclyl; preferably R4 is halogen.

28. A compound according to any one of the preceding claims, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound has the structure described below:

29. A compound according to any one of the preceding claims, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound has the structure described below:

30. A pharmaceutical composition comprising a therapeutically effective dose of a compound according to any one of claims 1 to 29, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

31. Use of the compound according to any one of claims 1 to 29, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 30 in the preparation of a medicament for treating a Polθ-mediated disease; preferably, the Polθ-mediated disease is liver cancer, breast cancer, ovarian cancer, lung cancer, kidney cancer, prostate cancer, skin cancer, bladder cancer, pancreatic cancer or head and neck cancer.

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