Substituted heteroaryl bicyclic compound as USP1 inhibitor and application thereof

Abstract

The present disclosure provides substituted heteroaryl bicyclic compounds represented by Formula I and uses thereof, where A1, A2, B1, B2, B3, rings Z, L, Cy1, and Cy2 are defined herein. The compounds of Formula I are useful for the prevention or treatment of USP1 modulation related diseases, disorders and conditions, such as cancer. The invention further provides application of the compound shown in the formula I in preparation of a medicine for treating or preventing USP1 regulation related diseases, and a composition containing the compound shown in the formula I. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry. The present invention particularly relates to substituted heteroaryl bicyclic compounds and their use as therapeutically effective USP1 inhibitors and anti-cancer drugs. Background Art

[0002] Ubiquitin is a polypeptide composed of 76 amino acids, which marks, degrades, and regulates the activity of proteins in cells by covalently binding to proteins. The process of ubiquitination leading to the degradation of target proteins involves a series of complex steps, including multiple ubiquitinating enzymes (E1 - E3). Studies have shown that protein ubiquitination in cells is a widespread protein function regulation mechanism, and thousands of proteins can be ubiquitinated. At the same time, protein ubiquitination is a reversible regulation mechanism, and the degree of protein ubiquitination in cells is balanced by ubiquitination and deubiquitination. Deubiquitination is achieved by a group of deubiquitinases (DUBs). DUBs catalyze the detachment of ubiquitin using ubiquitinated proteins as substrates. Therefore, protein ubiquitination in cells is a widespread and dynamic regulation mechanism. Protein ubiquitination is closely related to multiple important functions of cells, including gene expression, cell cycle progression, apoptosis, DNA repair, and cell migration (Garcia - Sanstisteban (2013) Mol Cancer 12:91 - 103).

[0003] Protein ubiquitination plays an important role in regulating important physiological functions such as the cell cycle and DNA damage repair. Studies have found that protein ubiquitination modification not only regulates protein degradation but also regulates the activity of proteins in DNA repair (Huang and D'Andrea (2006) Mol Cell Biol. 7:323 - 34). Since the DNA damage repair pathway is an important area in cancer treatment, ubiquitination and deubiquitinases that regulate DNA damage repair functions have become potential new targets for cancer treatment.

[0004] There are approximately 100 different human deubiquitinating proteases (Garcia-Sanstisteban (2013) Mol Cancer 12:91-103). Among them, ubiquitin-specific protease 1 (USP1) is one of the most studied deubiquitinating proteases. USP1 consists of 785 amino acids and has a molecular weight of 88.2 KDa. USP1 is a multifunctional protease and has regulatory functions at multiple levels in the DNA damage repair mechanism, including the Fanconi anemia (FA) pathway and the translesion DNA synthesis (TLS) pathway. USP1 regulates Fanconi anemia-BRCA (FA-BRCA)-mediated DNA repair by catalyzing the deubiquitination of monoubiquitinated FA proteins such as FANCD2 (Nijman et al. (2005) Mol Cell 17:331-39). Loss of USP1 function leads to increased levels of monoubiquitinated FANCD2, inhibits the FA-BRCA-mediated DNA damage repair pathway, and thus results in cells being highly sensitive to DNA crosslinking agents such as mitomycin C and cisplatin. Another deubiquitination substrate of USP1 is monoubiquitinated proliferating cell nuclear antigen (PCNA). Monoubiquitinated PCNA plays an important role in the DNA translesion replication mechanism (Huang et al. (2006) Nature Cell Biol. 8(4):339-47). Inhibition of USP1 activity by USP1 inhibitors can increase the sensitivity of cancer cells to DNA crosslinking agents and PARP inhibitors.

[0005] USP1 inhibitors can be used alone or in combination with DNA-damaging agents for cancer treatment; because they inhibit DNA damage repair mechanisms, which are more important for the survival of many cancer cells with high genomic instability than healthy normal cells. In fact, studies have shown that USP1 inhibitors are effective against cancer cells when used alone and can act as radiosensitizers and chemosensitizers. At the same time, USP1 inhibitors may also be used in combination with other DDR-related targeted drugs to treat cancer through synthetic lethality mechanisms, such as in combination with PARP inhibitors.

[0006] Thomas S. et al. discovered through screening that ML323 and related N-benzyl-2-phenylpyrimidin-4-amine derivatives have a high inhibitory effect on USP1 / UAF1 (Thomas S. et al. (2014) J. Med. Chem. 57: 8099-8110). The results showed that the inhibitory effect of these compounds on USP1 / UAF1 (e.g., ML323, IC 50 = 76 nM) was strongly correlated with the cytotoxicity to non-small cell lung cancer cells (ML323, H1299-EC 50 = 3.0 μM), that is, it increased the level of monoubiquitinated PCNA (Ub-PCNA) and decreased the cancer cell survival rate. This data shows the feasibility of the USP1 / UAF1 deubiquitinase complex as a drug target and the potential of developing USP1 inhibitors as anti-cancer targeted therapeutic drugs.

[0007] Multiple USP1 inhibitors have been disclosed, such as WO2014105952, WO2016034675, US20170145012, WO2020139988, WO2020132269, WO2021163530, WO2022174184, WO2022214053, WO2023083286, WO2023143424, and WO2023066299, etc. Summary of the Invention

[0008] The present invention provides substituted heteroaryl bicyclic compounds having the structure of formula I (including formula II, formula III, formula IV, and V), and such compounds can be used as USP1 inhibitors.

[0009] The present invention also provides a pharmaceutical composition containing an effective amount of a compound of formula I (including formula II, formula III, formula IV, and formula V) for treating cancer.

[0010] In a specific embodiment, the pharmaceutical composition may further contain one or more pharmaceutically acceptable carriers or excipients or diluents for treating cancer.

[0011] In a specific embodiment, the pharmaceutical composition may further contain at least one known anti-cancer drug or a pharmaceutically acceptable salt of the anti-cancer drug for treating cancer.

[0012] The present invention also relates to a method for preparing novel compounds of structural formula I (including formula II, formula III, formula IV, and V). Detailed Description of the Invention

[0013] It should be understood that the features of the embodiments described herein can be combined arbitrarily to form the technical solutions herein; the definitions of the various groups herein apply to any of the embodiments described herein. For example, the definition of the substituents of the alkyl group herein applies to any of the embodiments described herein, unless the substituents of the alkyl group have been clearly defined in that embodiment.

[0014] Specifically, the present invention provides a compound represented by the following formula I or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotope-labeled compound or pharmaceutically acceptable salt thereof, or a mixture thereof: Wherein, A 1 and A 2 are each independently selected from N, NR 1 , O and S; B 1 , B 2 and B 3 are each independently selected from N and CR 2 ; Ring Z is selected from optionally substituted cycloalkyl, optionally substituted heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl; L is selected from optionally substituted alkylene by R 4 and / or R 5 , NR 6 , O, S, SO, SO 2 and C═O; Cy 1 is selected from optionally substituted cycloalkyl, optionally substituted heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl; Cy 2 is selected from optionally substituted cycloalkyl, optionally substituted heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl; or ring Z and Cy 2 together form an optionally substituted 11- to 14-membered heterocyclic group; R 1 is selected from hydrogen and optionally substituted alkyl; R 2 is selected from hydrogen, halogen, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted amino; R 4 and R 5 are each independently selected from halogen, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted alkenyl and optionally substituted alkynyl; or R 4 and R 5 form a ring with the connected C atom; R 6Selected from hydrogen and optionally substituted alkyl groups.

[0015] Preferably, the optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, and optionally substituted alkynyl groups involved in each group of Formula I may be optionally substituted with 1-5 substituents selected from halogen, hydroxy, NR a R b , C 1-4 alkoxy, halo-C 1-4 alkoxy, carboxyl, and cyano, where the R a and R b are each independently H and C 1-4 alkyl. More preferably, the group may be optionally substituted with 1-5 substituents selected from halogen, hydroxy, and NR a R b , where the R a and R b are each independently H and C 1-4 alkyl.

[0016] Preferably, the optionally substituted amino group involved in each group of Formula I is represented as -NR a R b , where the R a and R b are each independently H, C 1-4 alkyl, or halo-C 1-4 alkyl.

[0017] Preferably, the optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl groups involved in each group of Formula I may be optionally substituted with 1-5 substituents selected from halogen, hydroxy, NR a R b , C 1-4 alkyl, halo-C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, halo-C 1-4 alkoxy, carboxyl, and cyano, where the R a and R b are each independently H and C 1-4 alkyl. More preferably, the group may be optionally substituted with 1-5 substituents selected from halogen, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, halo-C 1-4 alkyl, halo-C 1-4 alkoxy, hydroxy, and NR a R b , where the R a and Rb Each is independently H and C 1-4 alkyl group

[0018] In one or more embodiments of the compound of formula I, A 2 is N, A 1 is O, S or NR 1 , where R 1 is hydrogen or C 1-4 alkyl group, preferably methyl. In some embodiments, A 2 is N, A 1 is O or S. In some embodiments, A 2 is N, A 1 is O. In some embodiments, A 1 is N, A 2 is O or S, preferably O. It should be understood that the position of the double bond in the 5-membered ring containing A 1 and A 2 varies according to the selection of A 1 and A 2 , but should satisfy the valence bond theory.

[0019] In the aforementioned one or more embodiments of the compound of formula I, B 1 , B 2 and B 3 are each independently selected from N and CR 2 , where R 2 is H, halogen, C 1-4 alkyl group or C 1-4 alkoxy group. Preferably, B 1 , B 2 and B 3 are each independently N and CH, and at most one of B 1 , B 2 and B 3 is N. In some embodiments, B 1 and B 2 are CH, B 3 is N. In some embodiments, B 1 , B 2 and B 3 are all CH.

[0020] In the aforementioned one or more embodiments of the compound of formula I, the fused heteroaromatic bicyclic ring containing A 1 , A 2 , B 1 , B 2 and B 3 is selected from the following groups: Preferably selected from the following groups: More preferably, it is selected from the following groups: wherein, *1 and *2 respectively represent the connection positions of the said group with the compound Cy 1 and L.

[0021] In the foregoing one or more embodiments of the compound of formula I, L is alkylene, NH, N-C 1-3 alkyl or O; preferably, L is C 1-3 alkylene, more preferably methylene.

[0022] In the foregoing one or more embodiments of the compound of formula I, ring Z is an optionally substituted C 3-8 cycloalkyl, an optionally substituted 4- to 10-membered heterocyclic group, an optionally substituted 6- to 14-membered aryl group or an optionally substituted 5- to 10-membered heteroaryl group. In some embodiments, the C 3-8 cycloalkyl is C 5-8 cycloalkyl, preferably, the C 5-8 cycloalkyl is a bridged cycloalkyl, cubane or spirocycloalkyl. In some embodiments, the 6- to 14-membered aryl group is phenyl. In some embodiments, the 4- to 10-membered heterocyclic group is a heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, such as azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, tetrahydrofuranyl and tetrahydropyranyl, etc. In some embodiments, the 5- to 10-membered heteroaryl group is a heteroaryl group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, such as imidazolyl, pyrazolyl, triazolyl, pyridyl and pyrazinyl, etc. Preferably, when ring Z is substituted, the number of substituents can be 1 or 2, and can be selected from halogen, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted amino, the optionally substituted alkyl and optionally substituted alkoxy are preferably optionally substituted C 1-4 alkyl and optionally substituted C 1-3 alkoxy, the optionally substituted cycloalkyl is preferably optionally substituted C 3-8 cycloalkyl, the optionally substituted alkenyl and optionally substituted alkynyl are preferably optionally substituted C 2-4 alkenyl and optionally substituted C 2-4 alkynyl, the optionally substituted amino is -NR a R b , wherein, R a and R b are each independently H and C 1-4 alkyl; preferably, the alkyl, alkoxy, alkenyl, alkynyl and cycloalkyl are each optionally substituted by 1 to 5 selected from halogen, hydroxyl and -NR a R bis substituted by a group, said R a and R b are each independently H and C 1-4 alkyl. In some embodiments, the substituent on the Z ring is 1 or 2 substituents selected from halogen and C 1-3 alkoxy.

[0023] In one or more of the foregoing embodiments of the compound of formula I, ring Z and Cy 2 together form an optionally substituted 11- to 14-membered heterocyclic group, which is a tricyclic heterocyclic group containing 2, 3 or 4 heteroatoms selected from nitrogen and oxygen, such as benzimidazooxazine group, dihydrobenzimidazolooxazepine, dihydrobenzimidazolodiazepine group and benzimidazolooxazepine group, etc. When the 11- to 14-membered heterocyclic group is substituted, the number of substituents can be 1 or 2, and is optionally selected from halogen, optionally substituted alkyl and optionally substituted alkoxy, and the optionally substituted alkyl and optionally substituted alkoxy are preferably optionally substituted C 1-4 alkyl and optionally substituted C 1-3 alkoxy; preferably, the alkyl and alkoxy are optionally substituted by 1-5 groups selected from halogen, hydroxy and -NR a R b group, said R a and R b are each independently H and C 1-4 alkyl. In some embodiments, the substituent is halo C 1-4 alkyl.

[0024] In one or more of the foregoing embodiments of the compound of formula I, Cy 1 is an optionally substituted C 3-8 cycloalkyl, an optionally substituted 4- to 10-membered heterocyclic group, an optionally substituted 6- to 14-membered aryl group or an optionally substituted 5- to 10-membered heteroaryl group. In a further preferred embodiment, the 4- to 10-membered heterocyclic group is a heterocyclic group containing nitrogen and / or oxygen. In a further preferred embodiment, the 5- to 10-membered heteroaryl group is a nitrogen-containing monocyclic heteroaryl group. In a further preferred embodiment, the aryl group is a phenyl group. Preferably, Cy 1 is an optionally substituted phenyl group, an optionally substituted pyridyl group, an optionally substituted pyrimidinyl group, an optionally substituted pyrazinyl group, an optionally substituted pyridazinyl group, an optionally substituted piperidyl group, an optionally substituted piperazinyl group, an optionally substituted tetrahydrofuranyl group, an optionally substituted pyrrolidinyl group or an optionally substituted pyrazolyl group. More preferably, Cy 1 is an optionally substituted pyrimidinyl group or an optionally substituted pyrazolyl group.

[0025] Herein, when Cy 1 is substituted, the number of its substituents can be 1, 2 or 3, and is optionally selected from halogen, cyano, optionally substituted C 1-4Alkyl, optionally substituted C 1-4 Alkoxy, optionally substituted C 3-6 Cycloalkyl and optionally substituted amino; preferably, the C 1-4 Alkyl and C 1-4 Alkoxy is optionally substituted by 1-5 groups selected from deuterium, halogen, hydroxyl, and -NR a R b ; the C 3-6 Cycloalkyl is optionally substituted by 1-5 groups selected from halogen, hydroxyl, NR a R b , C 1-4 Alkyl, halo C 1-4 Alkyl, hydroxyl-substituted C 1-4 Alkyl, C 1-4 Alkoxy, and halo C 1-4 Alkoxy; the amino is optionally substituted by 1 or 2 groups selected from C 1-4 Alkyl and halo C 1-4 Alkyl, where the R a and R b are each independently H and C 1-4 Alkyl. Preferably, the substituent of Cy 1 is selected from halogen, C 1-4 Alkyl, C 1-4 Alkoxy, deuterated C 1-4 Alkoxy, and C 3-6 Cycloalkyl; more preferably, the substituent of Cy 1 is selected from C 1-4 Alkoxy, deuterated C 1-4 Alkoxy, and C 3-6 Cycloalkyl. Even more preferably, the substituent on Cy 1 is located at the ortho position of the position where the ring containing A 1 and A 2 is connected to Cy 1 .

[0026] In the foregoing one or more embodiments of the compound of formula I, Cy 2 is selected from optionally substituted 6-14-membered aryl, optionally substituted 5-10-membered heteroaryl, optionally substituted C 3-8A cycloalkyl group and an optionally substituted 4- to 10-membered heterocyclic group. In some embodiments, the 6- to 14-membered aryl group is a phenyl group. In some embodiments, the 4- to 10-membered heterocyclic group is a heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen and oxygen, including partially saturated 8- to 10-membered nitrogen- and / or oxygen-containing heterocyclic groups such as azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydroimidazopyrazinyl, and dihydroimidazoxazinyl, etc. In some embodiments, the 5- to 10-membered heteroaryl group is a heteroaryl group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, such as imidazolyl, pyrazolyl, triazolyl, pyridyl, and pyrazinyl, etc. Preferably, Cy 2 is an optionally substituted nitrogen-containing 5- to 10-membered heteroaryl group or an optionally substituted nitrogen- and / or oxygen-containing 8- to 10-membered heterocyclic group, more preferably a nitrogen-containing five-membered heteroaryl group. In some preferred embodiments, Cy 2 is an optionally substituted imidazolyl group or an optionally substituted pyrazolyl group. In some other embodiments, Cy 2 is an optionally substituted tetrahydroimidazopyrazinyl group or a dihydroimidazoxazinyl group.

[0027] As used herein, when Cy 2 is substituted, the number of substituents can be 1, 2, 3, 4, or 5, and the substituents can be selected from halogen, cyano, optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 4- to 10-membered heterocyclic group, and optionally substituted C 1-4 alkoxy. The C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 1-4 alkoxy are optionally substituted with 1 to 5 groups selected from deuterium, halogen, hydroxyl, and -NR a R b ; the C 3-6 cycloalkyl and 4- to 10-membered heterocyclic group are optionally substituted with 1 to 5 groups selected from halogen, hydroxyl, NR a R b , C 1-4 alkyl, halo C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, C 1-4 alkoxy, and halo C 1-4 alkoxy; wherein, the R a and R b are each independently H and C 1-4Alkyl. The 4- to 10-membered heterocyclic group is preferably a heterocyclic group containing oxygen and / or nitrogen, such as oxetanyl, azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, tetrahydrofuranyl, and tetrahydropyranyl, etc. Preferably, Cy 2 The substituents on are one or two selected from C 1-4 alkyl, C 2-4 alkynyl, halo C 1-4 alkyl, deuterated C 1-4 alkyl, 4- to 10-membered heterocyclic group, C 3-6 cycloalkyl, and C 1-4 alkoxy; preferably, Cy 2 is imidazolyl or pyrazolyl, optionally substituted by one or two substituents selected from C 1-4 alkyl, C 2-4 alkynyl, halo C 1-4 alkyl, deuterated C 1-4 alkyl, 4- to 10-membered heterocyclic group, C 3-6 cycloalkyl, and C 1-4 alkoxy. In some embodiments, Cy 2 is substituted by one to three substituents selected from C 1-4 alkyl, C 3 -C 6 cycloalkyl, and halo C 1-4 alkyl. In some embodiments, Cy 2 has two substituents selected from C 1-4 alkyl, C 3 -C 6 cycloalkyl, and halo C 1-4 alkyl. In some embodiments, one of the substituents of Cy 2 is located on its ring nitrogen atom.

[0028] In one or more of the foregoing embodiments of the compound of formula I, R 4 and R 5 are each independently selected from C 1-4 alkyl and hydroxy. In some embodiments, R 4 and R 5 form a 3- to 5-membered cycloalkyl or 3- to 5-membered heterocyclic group with the connected C atom. In some preferred embodiments, L is alkylene, and R 4 and R 5 form a 3- to 5-membered cycloalkyl with the C in the connected alkylene.

[0029] In one or more of the foregoing embodiments of the compound of formula I, R 6 is selected from hydrogen and C 1-3 alkyl.

[0030] One group of the preferred compounds of the present invention is represented by the compounds of formula II or their stereoisomers, tautomers, N-oxides, hydrates, solvates, isotopically labeled compounds or pharmaceutically acceptable salts, or mixtures thereof: wherein A 1 and A 2 and B 1 and B 2 and B 3 and L, Cy 1 and Cy 2 are as defined in any embodiment of formula I; D 1 and D 2 and D 3 and D 4 are each independently selected from N and CR 3 ; R 3 is selected from hydrogen, halogen, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted amino.

[0031] In one or more embodiments of the compounds of formula II, A 2 is N, A 1 is O, S or NR 1 wherein R 1 is hydrogen or C 1-4 alkyl, preferably methyl. In some embodiments, A 2 is N, A 1 is O or S. In some embodiments, A 2 is N, A 1 is O. In some embodiments, A 1 is N, A 2 is O or S, preferably O.

[0032] In the aforementioned one or more embodiments of the compounds of formula II, B 1 and B 2 and B 3 are each independently selected from N and CR 2 wherein R 2 is H, halogen, C 1-4 alkyl or C 1-4 alkoxy. Preferably, B 1 and B 2 and B 3 are each independently N and CH, and at most one of B 1 and B 2 and B 3 is N. In some embodiments, B 1and B 2 is CH, and B 3 is N. In some embodiments, B 1 , B 2 and B 3 are all CH.

[0033] In the foregoing one or more embodiments of the compound of Formula II, the fused heteroaromatic bicyclic ring containing A 1 , A 2 , B 1 , B 2 and B 3 is selected from the following groups: Preferably selected from the following groups: More preferably, selected from the following groups: wherein, *1 and *2 respectively represent the connection positions of the group with the compound Cy 1 and L.

[0034] In the foregoing one or more embodiments of the compound of Formula II, L is alkylene, NH, N-C 1-3 alkyl or O; preferably, L is C 1-3 alkylene, more preferably methylene.

[0035] In the foregoing one or more embodiments of the compound of Formula II, D 1 , D 2 , D 3 and D 4 are all CR 3 ; in some embodiments, D 1 , D 3 and D 4 are all CR 3 , and D 2 is N. Preferably, R 3 are each independently selected from hydrogen, halogen, cyano, optionally substituted C 1-4 alkyl, optionally substituted C 1-3 alkoxy, optionally substituted C 3-8 cycloalkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl and -NR a R b , wherein, R a and R b are each independently H and C 1-4 alkyl; further preferably, R 3 are each independently selected from halogen, optionally substituted C1-4 Alkyl and optionally substituted C 1-3 alkoxy; preferably, each of the alkyl, alkoxy, alkenyl, alkynyl, and cycloalkyl is optionally substituted with 1-5 groups selected from halogen, hydroxy, and -NR a R b groups, and the R a and R b are each independently H and C 1-4 alkyl. In some embodiments, R 3 is selected from H, halogen, and C 1-3 alkoxy. In some embodiments, D 1 and D 4 are both CH, D 2 and D 3 are each independently CR 3 , where R 3 are each independently hydrogen, halogen, C 1-3 alkyl, or C 1-3 alkoxy. In some embodiments, D 1 , D 2 , D 3 , and D 4 are all CH.

[0036] In one or more embodiments of the compound of formula II, the aryl or heteroaryl containing D 1 , D 2 , D 3 , D 4 , and C y2 together form an optionally substituted 11-14-membered heterocyclic group containing 2, 3, or 4 heteroatoms selected from nitrogen and oxygen, such as benzimidazole oxazine, dihydrobenzimidazole oxazepine, dihydrobenzimidazole azepine, and benzimidazole azooxazine. When the 11-14-membered heterocyclic group is substituted, the substituent can be 1 or 2 groups selected from halogen, optionally substituted alkyl, and optionally substituted alkoxy. The optionally substituted alkyl and optionally substituted alkoxy are preferably optionally substituted C 1-4 alkyl or optionally substituted C 1-3 alkoxy; preferably, the alkyl and alkoxy are each optionally substituted with 1-5 groups selected from halogen, hydroxy, and -NR a R b groups, where the R a and R b are each independently H or C 1-4 alkyl. In some embodiments, the substituent is halogen or halo C 1-4 alkyl.

[0037] In the foregoing one or more embodiments of the compound of formula II, Cy 1 is optionally substituted C3-8 A cycloalkyl group, an optionally substituted 4- to 10-membered heterocyclic group, an optionally substituted 6- to 14-membered aryl group, or an optionally substituted 5- to 10-membered heteroaryl group. In a further preferred embodiment, the 4- to 10-membered heterocyclic group is a heterocyclic group containing nitrogen and / or oxygen. In a further preferred embodiment, the 5- to 10-membered heteroaryl group is a nitrogen-containing monocyclic heteroaryl group. In a further preferred embodiment, the aryl group is a phenyl group. Preferably, Cy 1 is an optionally substituted phenyl group, an optionally substituted pyridyl group, an optionally substituted pyrimidinyl group, an optionally substituted pyrazinyl group, an optionally substituted pyridazinyl group, an optionally substituted piperidyl group, an optionally substituted piperazinyl group, an optionally substituted tetrahydrofuranyl group, an optionally substituted pyrrolidinyl group, or an optionally substituted pyrazolyl group. More preferably, Cy 1 is an optionally substituted pyrimidinyl group or an optionally substituted pyrazolyl group.

[0038] In the foregoing one or more embodiments of the compound of Formula II, when Cy 1 is substituted, the number of its substituents can be 1, 2, or 3, and can be selected from halogen, cyano, optionally substituted C 1-4 alkyl, optionally substituted C 1-4 alkoxy, optionally substituted C 3-6 cycloalkyl, and optionally substituted amino; preferably, the C 1-4 alkyl and C 1-4 alkoxy are optionally substituted by 1 to 5 groups selected from deuterium, halogen, hydroxy, and -NR a R b ; the C 3-6 cycloalkyl is optionally substituted by 1 to 5 substituents selected from halogen, hydroxy, NR a R b , C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, C 1-4 alkoxy, and halogenated C 1-4 alkoxy; the amino is optionally substituted by 1 or 2 substituents selected from C 1-4 alkyl and halogenated C 1-4 alkyl, wherein the R a and R b are each independently H and C 1-4 alkyl. Preferably, the substituent of Cy 1 is selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, deuterated C 1-4 alkoxy, and C 3-6 cycloalkyl; more preferably, the substituent of Cy 1 is selected from C 1-4 alkoxy, deuterated C 1-4Alkoxy and C 3-6 cycloalkyl. Further preferably, the substituent on Cy 1 is located at the ortho-position of the position where the ring containing A 1 and A 2 is connected to Cy 1 .

[0039] In the foregoing one or more embodiments of the compound of formula II, Cy 2 is selected from an optionally substituted 6- to 14-membered aryl group, an optionally substituted 5- to 10-membered heteroaryl group, an optionally substituted C 3-8 cycloalkyl group, and an optionally substituted 4- to 10-membered heterocyclic group. In some embodiments, the 6- to 14-membered aryl group is a phenyl group. In some embodiments, the 4- to 10-membered heterocyclic group is a heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen and oxygen, including partially saturated 8- to 10-membered nitrogen- and / or oxygen-containing heterocyclic groups such as azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydroimidazopyrazinyl, and dihydroimidazoxazinyl. In some embodiments, the 5- to 10-membered heteroaryl group is a heteroaryl group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, such as imidazolyl, pyrazolyl, triazolyl, pyridyl, and pyrazinyl. Preferably, Cy 2 is an optionally substituted nitrogen-containing 5- to 10-membered heteroaryl group or an optionally substituted nitrogen- and / or oxygen-containing 8- to 10-membered heterocyclic group, more preferably a nitrogen-containing five-membered heteroaryl group. In some preferred embodiments, Cy 2 is an optionally substituted imidazolyl group or an optionally substituted pyrazolyl group. In some other embodiments, Cy 2 is an optionally substituted tetrahydroimidazopyrazinyl group or a dihydroimidazoxazinyl group.

[0040] In the foregoing one or more embodiments of the compound of formula II, when Cy 2 is substituted, the number of substituents can be 1, 2, 3, 4, or 5, and the substituents are selected from halogen, cyano, optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 4- to 10-membered heterocyclic group, and optionally substituted C 1-4 alkoxy. The C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 1-4 alkoxy are optionally substituted with 1 to 5 groups selected from deuterium, halogen, hydroxyl, and -NR a R b ; the C 3-6 cycloalkyl and 4- to 10-membered heterocyclic group are optionally substituted with 1 to 5 groups selected from halogen, hydroxyl, NRa R b 、 C 1-4 alkyl, halo C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, C 1-4 alkoxy and halo C 1-4 alkoxy substituents; wherein said R a and R b are each independently H and C 1-4 alkyl. The 4- to 10-membered heterocyclic group is preferably a heterocyclic group containing oxygen and / or nitrogen, such as oxetanyl, azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, tetrahydrofuranyl, and tetrahydropyranyl. Preferably, the substituent on Cy 2 is one or two selected from C 1-4 alkyl, C 2-4 alkynyl, halo C 1-4 alkyl, deuterated C 1-4 alkyl, 4- to 10-membered heterocyclic group, C 3-6 cycloalkyl and C 1-4 alkoxy; preferably, Cy 2 is imidazolyl or pyrazolyl, optionally substituted by one or two selected from C 1-4 alkyl, C 2-4 alkynyl, halo C 1-4 alkyl, deuterated C 1-4 alkyl, 4- to 10-membered heterocyclic group, C 3-6 cycloalkyl and C 1-4 alkoxy substituents. In some embodiments, Cy 2 is substituted by one to three selected from C 1-4 alkyl, C 3 -C 6 cycloalkyl and halo C 1-4 alkyl substituents. In some embodiments, Cy 2 has two substituents selected from C 1-4 alkyl, C 3 -C 6 cycloalkyl and halo C 1-4 alkyl. In some embodiments, one of the substituents of Cy 2 is on its ring nitrogen atom.

[0041] In one or more of the foregoing embodiments of the compound of formula II, R 4 and R 5 are each independently selected from C 1-4 alkyl and hydroxy. In some embodiments, R 4 and R 5 form a 3- to 5-membered cycloalkyl or 3- to 5-membered heterocyclic group with the attached C atom. In some preferred embodiments, L is alkylene, R4 and R 5 forms a 3- to 5-membered cycloalkyl with the C in the linked alkylene group.

[0042] In the foregoing one or more embodiments of the compound of Formula II, R 6 is selected from hydrogen and C 1-3 alkyl.

[0043] One group of the preferred compounds of the present invention is represented by compounds of Formula III (including Formula IIIa and IIIb) or their stereoisomers, tautomers, N-oxides, hydrates, solvates, isotopically labeled compounds or pharmaceutically acceptable salts, or mixtures thereof: wherein A 1 、A 2 、B 2 、B 3 、L、D 2 、D 3 、Cy 1 and Cy 2 are as defined in any one of the embodiments of Formula I or II.

[0044] In one or more embodiments of the compound of Formula IIIa, A 1 is O, S or NR 1 , wherein R 1 is H or C 1-4 alkyl, preferably methyl. Preferably, A 1 is O or S; more preferably, A 1 is O.

[0045] In one or more embodiments of the compound of Formula IIIb, A 2 is O or S. In some embodiments, A 2 is O.

[0046] In one or more embodiments of the compounds of Formula IIIa and IIIb, B 2 and B 3 are each independently selected from N and CR 2 , wherein R 2 is H, halogen, C 1-4 alkyl or C 1-4 alkoxy. Preferably, B 2 and B 3 are each independently N and CH, and at most only one of B 2 and B 3 is N. In some embodiments, B 2 is CH, B 3 is N. In some embodiments, B 2 and B3 All are CH.

[0047] In the foregoing one or more embodiments of the compounds of Formulae IIIa and IIIb, those containing A 1 , B 2 and B 3 The fused heteroaromatic bicyclic ring and the fused heteroaromatic bicyclic ring containing A 2 , B 2 and B 3 are selected from the following groups: Preferably selected from the following groups: More preferably, selected from the following groups: wherein *1 and *2 respectively represent the connection positions of the group with the compounds Cy 1 and L.

[0048] In the foregoing one or more embodiments of the compounds of Formulae IIIa and IIIb, L is alkylene, NH, N-C 1-3 alkyl or O; preferably, L is C 1-3 alkylene, more preferably methylene.

[0049] In the foregoing one or more embodiments of the compounds of Formulae IIIa and IIIb, D 2 and D 3 are both CR 3 . Preferably, R 3 are each independently selected from hydrogen, halogen, optionally substituted alkyl and optionally substituted alkoxy, and the optionally substituted alkyl and optionally substituted alkoxy are preferably optionally substituted C 1-4 alkyl and optionally substituted C 1-3 alkoxy; preferably, the alkyl and alkoxy are optionally substituted by 1-5 groups selected from halogen, hydroxy and -NR a R b , and the R a and R b are each independently H and C 1-4 alkyl. In some embodiments, one of D 2 and D 3 is CH and the other is CR 3 , where R 3 is halogen, C 1-3 alkyl or C 1-3 alkoxy, preferably halogen. In some embodiments, D 2 and D 3 are both CH. In some embodiments, D2 and D 3 one of which is N and the other is CR 3 , wherein R 3 is hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy, preferably hydrogen.

[0050] In one or more embodiments of the compounds of Formulae IIIa and IIIb, the aryl or heteroaryl containing D 2 , D 3 and Cy 2 together form an optionally substituted 11- to 14-membered heterocyclic group containing 2, 3 or 4 heteroatoms selected from nitrogen and oxygen, such as benzimidazole oxazine, dihydrobenzimidazole oxazine, dihydrobenzimidazole diazine and benzimidazole benzoxazine. When the 11- to 14-membered heterocyclic group is substituted, the substituent may be one or two groups selected from halogen, optionally substituted alkyl and optionally substituted alkoxy. The optionally substituted alkyl and optionally substituted alkoxy are preferably optionally substituted C 1-4 alkyl and optionally substituted C 1-3 alkoxy; preferably, the alkyl and alkoxy are optionally substituted by 1-5 groups selected from halogen, hydroxy and -NR a R b , wherein said R a and R b are each independently H or C 1-4 alkyl. In some embodiments, the substituent is halogen or halo C 1-4 alkyl.

[0051] In the foregoing one or more embodiments of the compounds of Formulae IIIa and IIIb, Cy 1 is an optionally substituted C 3-8 cycloalkyl, an optionally substituted 4- to 10-membered heterocyclic group, an optionally substituted 6- to 14-membered aryl or an optionally substituted 5- to 10-membered heteroaryl. In a further preferred embodiment, the 4- to 10-membered heterocyclic group is a heterocyclic group containing nitrogen and / or oxygen. In a further preferred embodiment, the 5- to 10-membered heteroaryl is a nitrogen-containing monocyclic heteroaryl such as imidazolyl, pyrazolyl, triazolyl, pyrimidinyl and pyridyl. In a further preferred embodiment, the aryl is phenyl. Preferably, Cy 1 is an optionally substituted phenyl, an optionally substituted pyrazolyl, an optionally substituted pyridyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted pyridazinyl, an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted tetrahydrofuranyl, an optionally substituted pyrrolidinyl or an optionally substituted pyrazolyl. More preferably, Cy 1 is an optionally substituted pyrimidinyl or an optionally substituted pyrazolyl.

[0052] In the foregoing one or more embodiments of the compounds of Formulae IIIa and IIIb, when Cy 1 is substituted, the number of its substituents can be 1, 2 or 3, and is optionally selected from halogen, cyano, optionally substituted C 1-4 alkyl, optionally substituted C 1-4 alkoxy, optionally substituted C 3-6 cycloalkyl and optionally substituted amino; preferably, the C 1-4 alkyl and C 1-4 alkoxy are optionally substituted by 1-5 groups selected from deuterium, halogen, hydroxy and -NR a R b ; the C 3-6 cycloalkyl is optionally substituted by 1-5 groups selected from halogen, hydroxy, NR a R b , C 1-4 alkyl, halo C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, C 1-4 alkoxy and halo C 1-4 alkoxy; the amino is optionally substituted by 1 or 2 groups selected from C 1-4 alkyl and halo C 1-4 alkyl, wherein the said R a and R b are each independently H and C 1-4 alkyl. Preferably, the substituents of Cy 1 are selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, deuterated C 1-4 alkoxy and C 3-6 cycloalkyl; more preferably, the substituents of Cy 1 are selected from C 1-4 alkoxy, deuterated C 1-4 alkoxy and C 3-6 cycloalkyl. Even more preferably, the substituents on Cy 1 are located at the ortho positions of the position where the ring containing A 1 and A 2 is connected to Cy 1 .

[0053] In the foregoing one or more embodiments of the compounds of Formulae IIIa and IIIb, Cy 2 is selected from optionally substituted 6-14-membered aryl, optionally substituted 5-10-membered heteroaryl, optionally substituted C 3-8Cycloalkyl and optionally substituted 4- to 10-membered heterocyclic group. In some embodiments, the 6- to 14-membered aryl is phenyl. In some embodiments, the 4- to 10-membered heterocyclic group is a heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen and oxygen, including partially saturated 8- to 10-membered nitrogen- and / or oxygen-containing heterocyclic groups such as azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroimidazopyrazinyl, and dihydroimidazoxazinyl, etc. In some embodiments, the 5- to 10-membered heteroaryl is a heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, such as imidazolyl, pyrazolyl, triazolyl, pyridinyl, and pyrazinyl, etc. Preferably, Cy 2 is an optionally substituted nitrogen-containing 5- to 10-membered heteroaryl or an optionally substituted nitrogen- and / or oxygen-containing 8- to 10-membered heterocyclic group, more preferably a nitrogen-containing five-membered heteroaryl. In some preferred embodiments, Cy 2 is an optionally substituted imidazolyl or an optionally substituted pyrazolyl. In some other embodiments, Cy 2 is an optionally substituted tetrahydroimidazopyrazinyl or dihydroimidazoxazinyl.

[0054] In the foregoing one or more embodiments of the compounds of Formulae IIIa and IIIb, when Cy 2 is substituted, the number of substituents can be 1, 2, 3, 4, or 5, and the substituents are selected from halogen, cyano, optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 4- to 10-membered heterocyclic group, and optionally substituted C 1-4 alkoxy. The C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 1-4 alkoxy are optionally substituted with 1 to 5 groups selected from deuterium, halogen, hydroxy, and -NR a R b ; the C 3-6 cycloalkyl and 4- to 10-membered heterocyclic group are optionally substituted with 1 to 5 substituents selected from halogen, hydroxy, NR a R b , C 1-4 alkyl, halo C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, C 1-4 alkoxy, and halo C 1-4 alkoxy; wherein, the R a and R b are each independently H and C 1-4Alkyl. The 4- to 10-membered heterocyclic group is preferably a heterocyclic group containing oxygen and / or nitrogen, such as oxetanyl, azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, tetrahydrofuranyl, and tetrahydropyranyl, etc. Preferably, the substituent on Cy 2 is one or two selected from C 1-4 alkyl, C 2-4 alkynyl, halo C 1-4 alkyl, deuterated C 1-4 alkyl, 4- to 10-membered heterocyclic group, C 3-6 cycloalkyl, and C 1-4 alkoxy; preferably, Cy 2 is imidazolyl or pyrazolyl, optionally substituted by one or two substituents selected from C 1-4 alkyl, C 2-4 alkynyl, halo C 1-4 alkyl, deuterated C 1-4 alkyl, 4- to 10-membered heterocyclic group, C 3-6 cycloalkyl, and C 1-4 alkoxy. In some embodiments, Cy 2 is substituted by one to three substituents selected from C 1-4 alkyl, C 3 -C 6 cycloalkyl, and halo C 1-4 alkyl. In some embodiments, Cy 2 has two substituents selected from C 1-4 alkyl, C 3 -C 6 cycloalkyl, and halo C 1-4 alkyl. In some embodiments, one of the substituents of Cy 2 is located on its ring nitrogen atom.

[0055] In the foregoing one or more embodiments of the compounds of Formulae IIIa and IIIb: Cy 1 is an optionally substituted pyrimidinyl, wherein when Cy 1 is substituted, the number of substituents is one to three, preferably two, and the substituents are selected from halogen, cyano, optionally substituted C 1-4 alkyl, optionally substituted C 3-6 cycloalkyl, and optionally substituted C 1-4 alkoxy, and the preferred substituents are C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy; the fused heteroaromatic bicyclic ring containing A 1 / A 2 , B 2 and B 3 is selected from the following groups: Preferably selected from the following groups: More preferably, selected from the following groups: wherein, *1 and *2 respectively represent the connection positions of the said group with the compound Cy 1 and methylene; the ring containing D 2 and D 3 is a pyridyl or phenyl group optionally substituted by 1 or 2 substituents selected from halogen, C 1-4 alkyl and C 1-3 alkoxy; Cy 2 is an imidazolyl, pyrazolyl, tetrahydroimidazopyrazinyl or dihydroimidazoxazinyl group optionally substituted by 1-3 substituents selected from C 1-4 alkyl, C 3-6 cycloalkyl and halo C 1-4 alkyl.

[0056] One group of the preferred compounds of the present invention is represented by formula IV (including formula IVa and formula IVb) compounds or their stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-labeled compounds or pharmaceutically acceptable salts, or mixtures thereof: wherein, A 1 、A 2 、B 2 、B 3 and Cy 2 are as described in any embodiment of formula I, formula II or formula III; R 7 and R 9 each independently selected from hydrogen, halogen, cyano, optionally substituted C 1-4 alkyl, optionally substituted C 1-4 alkoxy, optionally substituted C 3-6 cycloalkyl and optionally substituted amino; R 8 is selected from hydrogen, halogen and optionally substituted C 1-4 alkyl; R 10 and R 11 each independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted amino.

[0057] In the foregoing one or more embodiments of the compound of formula IVa, A 1 is O, S or NR 1 , wherein R 1 is H or C1-4 An alkyl group, preferably a methyl group. Preferably, A 1 is O or S; more preferably, A 1 is O.

[0058] In one or more of the foregoing embodiments of the compound of formula IVb, A 2 is O or S. In some embodiments, A 2 is O.

[0059] In one or more of the foregoing embodiments of the compounds of formula IVa and IVb, B 2 and B 3 are each independently selected from N and CR 2 , where R 2 is H, halogen, C 1-4 alkyl or C 1-4 alkoxy. Preferably, B 2 and B 3 are each independently N and CH, and at most only one of B 2 and B 3 is N. In some embodiments, B 2 is CH, B 3 is N. In some examples, B 2 and B 3 are both CH.

[0060] In one or more of the foregoing embodiments of the compounds of formula IVa and IVb, the fused heteroaromatic bicyclic ring containing A 1 , B 2 and B 3 and the fused heteroaromatic bicyclic ring containing A 2 , B 2 and B 3 are selected from the following groups: Preferably selected from the following groups: More preferably, selected from the following groups: Wherein, *1 and *2 respectively represent the connection positions of the group with the substituted pyrimidinyl group and the methylene group of the compound.

[0061] In one or more of the foregoing embodiments of the compounds of formula IVa and IVb, R 7 and R 9 are each independently hydrogen, halogen, cyano, optionally substituted C 1-4 alkyl, optionally substituted C 1-4 alkoxy, optionally substituted C 3-6A cycloalkyl group or an optionally substituted amino group; preferably, the C 1-4 alkyl group and the C 1-4 alkoxy group are optionally substituted by 1-5 groups selected from halogen, hydroxyl, and -NR a R b ; the C 3-6 cycloalkyl group is optionally substituted by 1-5 groups selected from halogen, hydroxyl, NR a R b , C 1-4 alkyl, halo C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, C 1-4 alkoxy, and halo C 1-4 alkoxy; the amino group is optionally substituted by 1 or 2 groups selected from C 1-4 alkyl and halo C 1-4 alkyl, where the R a and R b are each independently H and C 1-4 alkyl. In one or more embodiments, R 7 and R 9 are each independently hydrogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, deuterated C 1-4 alkoxy, or C 3-6 cycloalkyl, and R 7 and R 9 are not both hydrogen; preferably, R 7 and R 9 are each independently C 1-4 alkoxy, deuterated C 1-4 alkoxy, or C 3-6 cycloalkyl.

[0062] In the foregoing one or more embodiments of the compounds of Formulas IVa and IVb, R 8 is hydrogen, halogen, or C a alkyl optionally substituted by 1-5 groups selected from halogen, hydroxyl, and -NR b R 1-4 , where R a and R b are each independently H and C 1-4 alkyl. Preferably, R 8 is hydrogen.

[0063] In the foregoing one or more embodiments of the compounds of Formulas IVa and IVb, R 10 and R 11 are each independently hydrogen, halogen, optionally substituted C 1-4 alkyl, or optionally substituted C 1-4 alkoxy; preferably, the C1-4 Alkyl and C 1-4 The alkoxy group is optionally substituted with 1 - 5 groups selected from halogen, hydroxy, and -NR a R b , wherein said R a and R b are each independently H and C 1-4 alkyl. In some embodiments, one of R 10 and R 11 is H, and the other is halogen, optionally substituted C 1-4 alkyl, or optionally substituted C 1-4 alkoxy.

[0064] In one or more of the foregoing embodiments of the compounds of Formula IVa and IVb, Cy 2 is selected from optionally substituted 6 - 14 - membered aryl, optionally substituted 5 - 10 - membered heteroaryl, optionally substituted C 3-8 cycloalkyl, and optionally substituted 4 - 10 - membered heterocyclic group. In some embodiments, the 6 - 14 - membered aryl is phenyl. In some embodiments, the 4 - 10 - membered heterocyclic group is a heterocyclic group containing 1 - 3 heteroatoms selected from nitrogen and oxygen, including partially saturated 8 - 10 - membered nitrogen - and / or oxygen - containing heterocyclic groups such as azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydroimidazopyrazinyl, and dihydroimidazoxazinyl, etc. In some embodiments, the 5 - 10 - membered heteroaryl is a heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, such as imidazolyl, pyrazolyl, triazolyl, pyridyl, and pyrazinyl, etc. Preferably, Cy 2 is an optionally substituted nitrogen - containing 5 - 10 - membered heteroaryl or an optionally substituted nitrogen - and / or oxygen - containing 8 - 10 - membered heterocyclic group, more preferably a nitrogen - containing five - membered heteroaryl. In some preferred embodiments, Cy 2 is an optionally substituted imidazolyl or an optionally substituted pyrazolyl. In some other embodiments, Cy 2 is an optionally substituted tetrahydroimidazopyrazinyl or dihydroimidazoxazinyl.

[0065] In one or more of the foregoing embodiments of the compounds of Formula IVa and IVb, when Cy 2 is substituted, the number of its substituents can be 1, 2, 3, 4, or 5, and the substituents are selected from halogen, cyano, optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 4 - 10 - membered heterocyclic group, and optionally substituted C 1-4 alkoxy. The C 1-4 alkyl, C 2-4 alkenyl, C2-4 The alkynyl group and C 1-4 alkoxy group are optionally substituted by 1 to 5 groups selected from deuterium, halogen, hydroxyl, and -NR a R b ; the C 3-6 cycloalkyl group and 4- to 10-membered heterocyclic group are optionally substituted by 1 to 5 substituents selected from halogen, hydroxyl, NR a R b , C 1-4 alkyl, halo C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, C 1-4 alkoxy, and halo C 1-4 alkoxy; wherein, the said R a and R b are each independently H and C 1-4 alkyl. The 4- to 10-membered heterocyclic group is preferably a heterocyclic group containing oxygen and / or nitrogen, such as oxetanyl, azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, tetrahydrofuranyl, and tetrahydropyranyl, etc. Preferably, the substituent on Cy 2 is 1 or 2 selected from C 1-4 alkyl, C 2-4 alkynyl, halo C 1-4 alkyl, deuterated C 1-4 alkyl, 4- to 10-membered heterocyclic group, C 3-6 cycloalkyl, and C 1-4 alkoxy; preferably, Cy 2 is imidazolyl or pyrazolyl, which may be optionally substituted by 1 or 2 substituents selected from C 1-4 alkyl, C 2-4 alkynyl, halo C 1-4 alkyl, deuterated C 1-4 alkyl, 4- to 10-membered heterocyclic group, C 3-6 cycloalkyl, and C 1-4 alkoxy. In some embodiments, Cy 2 is substituted by 1 to 3 substituents selected from C 1-4 alkyl, C 3 -C 6 cycloalkyl, and halo C 1-4 alkyl. In some embodiments, Cy 2 has two substituents, selected from C 1-4 alkyl, C 3 -C 6 cycloalkyl, and halo C 1-4 alkyl. In some embodiments, one of the substituents of Cy 2 is located on its ring nitrogen atom.

[0066] One group of the preferred compounds of the present invention is represented by formula V compounds or their stereoisomers, tautomers, N-oxides, hydrates, solvates, isotopically labeled compounds or pharmaceutically acceptable salts, or mixtures thereof: wherein A 1 、A 2 、B 2 and B 3 are as described in any embodiment of formula I, formula II and formula III; R 7 、R 9 、R 10 and R 11 are as described in any embodiment of formula IVa or IVb; R 12 is selected from hydrogen, optionally substituted C 1-4 alkyl, optionally substituted C 3-6 cycloalkyl and optionally substituted C 4-6 heterocyclyl; or, R 11 is linked to R 12 to form an optionally substituted 6-7 membered heterocyclyl; R 13 is selected from hydrogen, halogen, optionally substituted C 1-4 alkyl and optionally substituted C 1-4 alkoxy; or, R 12 is linked to R 13 to form an optionally substituted 5-7 membered heterocyclyl; R 14 is selected from halogen and optionally substituted C 1-4 alkyl.

[0067] In one or more of the foregoing embodiments of the formula V compound, A 1 is O, S or NR 1 , wherein R 1 is H or C 1-4 alkyl, preferably methyl. Preferably, A 1 is O or S; more preferably, A 1 is O.

[0068] In one or more of the foregoing embodiments of the formula V compound, B 2 and B 3 are each independently selected from N and CR 2 , wherein R 2 is H, halogen, C 1-4 alkyl or C 1-4 alkoxy. Preferably, B 2 and B 3 are each independently N and CH, and B 2 and B 3At most one of them is N. In some embodiments, B 2 is CH, and B 3 is N. In some embodiments, B 2 and B 3 are both CH.

[0069] In one or more of the foregoing embodiments of the compound of Formula V, the fused heteroaromatic bicyclic ring containing A 1 , B 2 and B 3 is selected from the following groups: Preferably, it is selected from the following groups: wherein *1 and *2 respectively represent the connection positions of the group to the pyrimidinyl group and the methylene group substituted by the compound.

[0070] In one or more of the foregoing embodiments of the compound of Formula V, R 7 and R 9 are each independently hydrogen, halogen, cyano, optionally substituted C 1-4 alkyl, optionally substituted C 1-4 alkoxy, optionally substituted C 3-6 cycloalkyl or optionally substituted amino; preferably, the C 1-4 alkyl and C 1-4 alkoxy are optionally substituted by 1-5 groups selected from halogen, hydroxy and -NR a R b , the C 3-6 cycloalkyl is optionally substituted by 1-5 groups selected from halogen, hydroxy, NR a R b , C 1-4 alkyl, halo C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, C 1-4 alkoxy and halo C 1-4 alkoxy, and the amino is optionally substituted by 1 or 2 groups selected from C 1-4 alkyl and halo C 1-4 alkyl, wherein the R a and R b are each independently H and C 1-4 alkyl. In one or more embodiments, R 7 and R 9 are each independently hydrogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, deuterated C 1-4 alkoxy or C 3-6 cycloalkyl, and R 7and R 9 are not hydrogen at the same time; preferably, R 7 and R 9 are each independently C 1-4 alkoxy, deuterated C 1-4 alkoxy or C 3-6 cycloalkyl.

[0071] In the foregoing one or more embodiments of the compound of formula V, R 10 and R 11 are each independently hydrogen, halogen, optionally substituted C 1-4 alkyl or optionally substituted C 1-4 alkoxy; preferably, the C 1-4 alkyl and C 1-4 alkoxy are optionally substituted with 1-5 groups selected from halogen, hydroxy and -NR a R b wherein the R a and R b are each independently H and C 1-4 alkyl. In some embodiments, R 10 and R 11 one of them is H and the other is halogen, optionally substituted C 1-4 alkyl or optionally substituted C 1-4 alkoxy.

[0072] In the foregoing one or more embodiments of the compound of formula V, R 12 is selected from hydrogen, optionally substituted C 1-4 alkyl, optionally substituted C 1-4 alkoxy, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, optionally substituted C 3-6 cycloalkyl and optionally substituted C 4-6 heterocyclic group; preferably, the optionally substituted C 4-6 heterocyclic group is a heterocyclic group containing N or O, such as oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl and piperazinyl, etc. The substituents of R 12 can be 1-3 substituents selected from halogen, hydroxy and -NR a R b wherein the R a and R b are each independently H and C 1-4 alkyl. Preferably, R 12 is C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl or C 3-6 cycloalkyl.

[0073] In one or more of the foregoing embodiments of the compound of formula V, R 13 is selected from hydrogen, halogen, optionally substituted C 1-4 alkyl, and optionally substituted C 1-4 alkoxy; preferably, R 13 is hydrogen.

[0074] In one or more of the foregoing embodiments of the compound of formula V, R 14 is selected from halogen, optionally substituted C 1-4 alkyl. The alkyl is optionally substituted with 1-5 substituents selected from hydroxy and halogen. Preferably, R 14 is halo C 1-4 alkyl, such as trifluoromethyl.

[0075] In one or more of the foregoing embodiments of the compound of formula V, R 11 is linked to R 12 to form an optionally substituted 6-7 membered heterocyclic group, which together with the phenyl and imidazolyl groups shown forms an 11-14 membered heterotricyclic group containing 2, 3 or 4 heteroatoms selected from nitrogen and oxygen as described herein, such as benzimidazooxazinyl, dihydrobenzimidazolooxazepinyl, dihydrobenzimidazolodiazepinyl and benzimidazolooxazepinyl.

[0076] In one or more of the foregoing embodiments of the compound of formula V, R 12 is linked to R 13 to form an optionally substituted 5-7 membered heterocyclic group containing nitrogen and / or oxygen, which together with the imidazolyl group forms a 7-10 membered bicyclic heterocyclic group containing nitrogen and / or oxygen, such as tetrahydroimidazopyrazinyl and dihydroimidazoxazinyl.

[0077] In one or more embodiments of the compound of formula V: A 1 is O; B 2 and B 3 are each independently N or CH, and at most one of B 2 and B 3 is N; R 7 and R 9 are each independently C 1-4 alkyl, C 1-4 alkoxy, deuterated C 1-4 alkoxy or C 3-6 cycloalkyl, preferably, R 7 is C 1-4 alkyl or C 3-6 cycloalkyl, R 9 is C 1-4 alkoxy or deuterated C 1-4 alkyl; R 10 and R 11Each independently is hydrogen, a halogen or a C 1-4 alkoxy group; R 12 is hydrogen, C 1-4 alkyl, deuterated C 1-4 alkyl or C 3-6 cycloalkyl; R 13 is hydrogen; R 14 is a halogen, C 1-4 alkyl or halo C 1-4 alkyl.

[0078] In one or more of the foregoing embodiments, exemplary preferred compounds of Formula I (including Formulas II, III, IV and V) include, but are not limited to: or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound or pharmaceutically acceptable salt thereof, or a mixture thereof.

[0079] As used herein, "hydrogen" includes its isotopes D and T.

[0080] As used herein, "alkyl" means an alkyl group per se or a group having up to ten carbon atoms in a straight or branched chain. Useful alkyl groups include straight or branched chain C 1-10 alkyl, preferably C 1-6 alkyl. In certain embodiments, the alkyl group is C 1-4 alkyl; in some embodiments, the alkyl group is C 1-3 alkyl. Typical C 1-10 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl and octyl.

[0081] As used herein, "alkenyl" means a straight or branched chain containing 2-10 carbon atoms, unless the carbon chain length is otherwise limited, wherein there is at least one double bond between two carbon atoms in the chain; preferably C 2-6 alkenyl. Typical alkenyl groups include vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl.

[0082] As used herein, "alkynyl" means a straight or branched chain containing 2-10 carbon atoms, unless the carbon chain length is otherwise limited, wherein there is at least one triple bond between two carbon atoms in the chain; preferably C 2-6Alkynyl. Typical alkynyl groups include ethynyl, 1-propynyl, 1-methyl-2-propynyl, 2-propynyl, 1-butynyl, and 2-butynyl.

[0083] Useful alkoxy groups include those substituted by the above-mentioned C 1-10 alkyl groups, preferably C 1-6 alkyl or C 1-4 alkyl-substituted oxy groups, such as methoxy, ethoxy, etc. The alkyl groups in the alkoxy groups can be optionally substituted. The substituents of the alkoxy groups include, but are not limited to, halogen, morpholino, amino, said amino including alkylamino and dialkylamino, and carboxyl (including its ester group).

[0084] In this text, amino is represented as -NH 2 . The amino group can be optionally substituted, and the substituted amino group can be represented as –NHR' and –NR'R”, where R' and R” are each independently hydrogen, optionally substituted C 1-10 alkyl (preferably C 1-4 alkyl), optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, in the substituted amino groups described herein, R' and R” together with the N to which they are attached form an optionally substituted 4- to 7-membered cyclic amino group, and the cyclic amino group optionally contains one or more (such as 2, 3) additional heteroatoms selected from O, N, and S.

[0085] As used herein, “aryl” refers to an aryl group itself or as part of another group, and is a monocyclic, bicyclic, or tricyclic aromatic group containing 6 to 14 carbon atoms. The aryl group can be substituted by one or more of the substituents described herein.

[0086] Useful aryl groups include C 6-14 aryl, preferably C 6-10 aryl. Typical C 6-14 aryl groups include phenyl, naphthyl, phenanthryl, anthryl, indenyl, azulenyl, biphenyl, biphenylene, and fluorenyl.

[0087] As used herein, “carbocyclic” includes cycloalkyl and partially saturated carbocyclic groups. Useful cycloalkyl groups are C 3-8 cycloalkyl. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The carbocyclic groups can be substituted by one or more of the substituents described herein.

[0088] Useful partially saturated carbocyclic groups include cycloalkenyl, such as C 3-8 cycloalkenyl, such as cyclopentenyl, cycloheptenyl, and cyclooctenyl.

[0089] Useful halogen or halogen groups include fluorine, chlorine, bromine, and iodine.

[0090] As used herein, the heterocycle (heterocyclic group) refers to a saturated or partially saturated monocyclic group having 3 to 7 ring atoms, or a bicyclic group, spirocyclic group or bridged cyclic group having 7 to 10 ring atoms, or a tricyclic group, spirocyclic group or bridged cyclic group having 11 to 14 ring atoms, which is composed of carbon atoms and 1 to 4 heteroatoms selected from O, N and S, wherein the heteroatoms nitrogen and sulfur can be optionally oxidized, and nitrogen can be optionally quaternized, and includes the fusion of any of the above-defined heterocycles with a benzene ring in a bicyclic system. If the resulting compound is stable, then the carbon atom or nitrogen atom of the heterocycle can be substituted. Preferably, the heterocyclic group has 4 to 10 ring atoms. The heterocyclic group can be substituted by one or more substituents described herein. The above-mentioned heterocyclic group herein also includes a 5- to 8-membered heterocycloalkyl group, i.e., a heterocyclic group obtained by replacing one or more ring C atoms in the cycloalkyl group with a heteroatom selected from N, O and S.

[0091] Useful saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, tetrahydropyranyl, pyranyl, piperidyl, piperazinyl, oxetanyl, azetidinyl, 1,4-diazepanyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, dihydroindolyl, iso-dihydroindolyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl, tetrahydroisoquinolinyl, tetronoyl and tetramoyl, and these groups can be substituted by one or more substituents described herein.

[0092] As used herein, the "heteroaromatic ring" refers to a ring having 5 to 14, preferably 5 to 10 ring atoms, and having 6, 10 or 14 π electrons shared in the ring system. Moreover, the ring atoms contained are carbon atoms and 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur. The heteroaryl group can be substituted by one or more substituents described herein.

[0093] Useful heteroaryl groups include thienyl (phenylthio), benzo[d]isothiazol-3-yl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl (including but not limited to 2-pyridyl, 3-pyridyl, and 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, naphthimidazolyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, 7-aminoisocoumarin, benzisoxazolyl such as 1,2-benzisoxazol-3-yl, benzimidazolyl, 2-hydroxyindolyl, thiazolyl, 2-oxobenzimidazolyl, imidazopyridazinyl, imidazopyridyl, imidazotriazinyl, triazolopyrimidinyl, triazolopyridyl, triazolopyrazinyl, triazolopyridazinyl, triazolotriazinyl, pyrazolopyrimidinyl, pyrazolotriazinyl, pyrrolopyrimidinyl, pyrrolopyridyl, pyrrolopyrazinyl, pyrrolotriazinyl, or triazolopyrazinyl. When the heteroaryl group contains a nitrogen atom in the ring, such a nitrogen atom can be in the form of an N-oxide, such as pyridyl N-oxide, pyrazinyl N-oxide, and pyrimidinyl N-oxide.

[0094] As used herein, unless otherwise specified, when substituted, the alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, heterocyclic, aryl, or heteroaryl group described in any embodiment herein can be substituted by one or more (e.g., 1, 2, 3, or 4) substituents selected from the following groups: halogen, amino, cyano, C 1-6 alkoxy, C 1-6 alkyl, C 6-10 aryl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, heterocyclic, and heteroaryl, etc. The substituents themselves can also be optionally substituted. More preferred substituents include but are not limited to cyano, halo C 1-6 alkyl, halogen, amino, C 1-6 alkoxy, C 1-6 alkyl, and C 3-8 cycloalkyl.

[0095] In some embodiments, one or more hydrogens in the alkyl, alkoxy, alkenyl, and alkynyl groups described herein are replaced by their isotopes deuterium (D) and / or tritium (T), and exemplary such groups include trideuteriomethyl, trideuteriomethoxy, etc.

[0096] It should be understood that in the embodiments of the present invention, when the substituent is a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, the number of the cyano group, heterocyclic group, aryl group or heteroaryl group substituents is usually 1.

[0097] Some compounds of the present invention may exist as stereoisomers, including optical isomers. The present invention includes all stereoisomers and racemic mixtures of such stereoisomers, as well as individual enantiomers that can be separated by methods well known to those skilled in the art.

[0098] Examples of pharmaceutically acceptable salts include inorganic and organic acid salts, such as hydrochloride, hydrobromide, phosphate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalate; and inorganic and organic base salts formed with bases such as sodium hydroxide, tris(hydroxymethyl)aminomethane (TRIS, tromethamine) and N-methylglucamine.

[0099] Examples of prodrugs of the compounds of the present invention include simple esters of compounds containing carboxylic acids (e.g., esters obtained by condensation with C 1-4 alcohols according to methods known in the art); esters of compounds containing hydroxyl groups (e.g., esters obtained by condensation with C 1-4 carboxylic acids, C 3-6 dicarboxylic acids or their acid anhydrides such as succinic anhydride and maleic anhydride); imines of compounds containing amino groups (e.g., imines obtained by condensation with C 1-4 aldehydes or ketones according to methods known in the art); carbamates of compounds containing amino groups, such as those described by Leu et al. (J. Med. Chem. 42:3623-3628 (1999)) and Greenwald et al. (J. Med. Chem. 42:3657-3667 (1999)); acetals or ketals of compounds containing alcohols (e.g., those acetals obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether according to methods known in the art).

[0100] The compounds of the present invention can be prepared by methods known to those skilled in the art or by new methods of the present invention. Specifically, the compounds of the present invention having formula I (including formula II, formula III, formula IV and V) can be prepared by the following reaction scheme 1. Under the catalysis of [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (Pd(dppf)Cl 2 ) and potassium acetate (KOAc), 3-bromo-2-methoxyaniline undergoes a Miyaura borylation reaction with bis(pinacolato)diboron to obtain 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. In Pd(dppf)Cl 2 and cesium carbonate (Cs 2 CO3 ) Under the catalysis of, 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline reacts with 2-(4-(bromomethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole to obtain 2-methoxy-3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)aniline. 2-Methoxy-3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)aniline reacts with boron tribromide (BBr 3 ) to obtain 2-amino-6-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)phenol. Under the catalysis of iodobenzene diacetate (PhI(OAc) 2 ), 2-amino-6-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)phenol reacts with 4-cyclopropyl-6-methoxypyrimidine-5-carbaldehyde to obtain the target compound 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)benzo[d]oxazole. Reaction Scheme 1

[0101] Other related compounds can be prepared by similar methods. For example, replacing 3-bromo-2-methoxyaniline with 2-bromo-6-methoxyaniline can prepare the target compound 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)benzo[d]oxazole. Replacing 2-(4-(bromomethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole with 2-(4-(bromomethyl)phenyl)-1-cyclopropyl-4-(trifluoromethyl)-1H-imidazole can prepare the target compound 7-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)benzo[d]oxazole. Replacing 2-(4-(bromomethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole with 2-(4-(bromomethyl)-2-fluorophenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole can prepare the target compound 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)benzo[d]oxazole. Replacing 3-bromo-2-methoxyaniline with 3-bromo-2-(methylthio)aniline can prepare the target compound 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)benzo[d]thiazole. Replacing 3-bromo-2-methoxyaniline with 2-chloro-3-methoxypyridin-4-amine can prepare the target compound 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine.

[0102] The compounds of the present invention can be prepared by methods known to those skilled in the art or the new methods of the present invention. Specifically, the compounds of the present invention having formula I (including formula II, formula III, formula IV and V) can be prepared by the following reaction scheme 2. Under the catalysis of 4-dimethylaminopyridine (DMAP), 3-bromobenzene-1,2-diamine reacts with di-tert-butyl dicarbonate to obtain di-tert-butyl (3-bromo-1,2-phenylene)dicarbonate. Under the catalysis of Pd(dppf)Cl 2 and KOAc, di-tert-butyl (3-bromo-1,2-phenylene)dicarbonate undergoes a Miyaura borylation reaction with bis(pinacolato)diboron to obtain di-tert-butyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-phenylene)dicarbonate. Under the catalysis of Pd(dppf)Cl 2 and Cs 2 CO 3Under the catalysis of, di-tert-butyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-phenylene) dicarbamate reacts with 2-(4-(bromomethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole through Suzuki coupling reaction to obtain di-tert-butyl (3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,2-phenylene) dicarbamate. Under the catalysis of HCl / dioxane, di-tert-butyl (3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,2-phenylene) dicarbamate removes the protecting group to obtain the target compound 3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)benzene-1,2-diamine. Under the catalysis of copper acetate (Cu(OAc) 2 ), 3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)benzene-1,2-diamine reacts with 4-cyclopropyl-6-methoxypyrimidine-5-carbaldehyde to obtain 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-benzo[d]imidazole. Under the catalysis of potassium carbonate (K 2 CO 3 ), 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-benzo[d]imidazole reacts with methyl iodide (MeI) to obtain the target compound 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-7-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-benzo[d]imidazole. Reaction Scheme 2

[0103] The compounds of the present invention can be prepared by methods known to those skilled in the art or the new methods of the present invention. Specifically, the compounds of the present invention having formula I (including formula II, formula III, formula IV and V) can be prepared by the following Reaction Scheme 3. Under the catalysis of triethylamine (TEA) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 4-amino-2-bromopyridin-3-ol reacts with 4-cyclopropyl-6-methoxypyrimidine-5-carboxylic acid to obtain the product N-(2-bromo-3-hydroxypyridin-4-yl)-4-cyclopropyl-6-methoxypyrimidine-5-carboxamide. Under hexachloroethane (C 2 Cl 6 ) and triphenylphosphine (PPh 3) Under the catalysis of, N-(2-bromo-3-hydroxypyridin-4-yl)-4-cyclopropyl-6-methoxypyrimidine-5-carboxamide cyclizes to obtain the product 4-bromo-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)oxazolo[5,4-c]pyridine. In Zn, I 2 , TMSCl and Pd(PPh 3 ), 4 under the conditions of, 4-bromo-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)oxazolo[5,4-c]pyridine undergoes a Negishi cross-coupling reaction with 2-(4-(bromomethyl)-2-fluorophenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole to obtain the final product 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine. Reaction Scheme 3

[0104] Other related compounds can be prepared by similar methods. For example, replacing 2-(4-(bromomethyl)-2-fluorophenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole with 2-(4-(bromomethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole can prepare the target compound 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine. Replacing 2-(4-(bromomethyl)-2-fluorophenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole with 2-(4-(bromomethyl)-2-methoxyphenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole can prepare the target compound 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(3-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine. Replacing 2-(4-(bromomethyl)-2-fluorophenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole with 2-(4-(bromomethyl)-3-fluorophenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole can prepare the target compound 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(2-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine.

[0105] The compounds of the present invention can be prepared by methods known to those skilled in the art or the new methods of the present invention. Specifically, the compounds of the present invention having formula I (including formula II, formula III, formula IV and V) can be prepared by the following Reaction Scheme 4. In Zn, I2 , TMSCl and Pd(PPh 3 ), 4 Under the conditions of, 2-bromo-3-methoxypyridin-4-amine undergoes a Negishi cross-coupling reaction with 2-(4-(bromomethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole to obtain the product 3-methoxy-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyridin-4-amine. Boron tribromide (BBr 3 ) reacts with 3-methoxy-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyridin-4-amine to obtain the product 4-amino-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyridin-3-ol. Under the catalysis of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIEA), 4-chloro-1-isopropyl-1H-pyrazole-5-carboxylic acid reacts with 4-amino-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyridin-3-ol to obtain the product 4-chloro-N-(3-hydroxy-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyridin-4-yl)-1-isopropyl-1H-pyrazole-5-carboxamide. Under the catalysis of C 2 Cl 6 and triphenylphosphine PPh 3 , 4-chloro-N-(3-hydroxy-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyridin-4-yl)-1-isopropyl-1H-pyrazole-5-carboxamide undergoes ring closure to obtain the final product 2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine. Reaction Scheme 4

[0106] Other related compounds can be prepared by a similar method. For example, replacing 4-chloro-1-isopropyl-1H-pyrazole-5-carboxylic acid with 4-methoxy-6-methylpyrimidine-5-carboxylic acid can prepare the target compound 2-(4-methoxy-6-methylpyrimidin-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine. Replacing 4-chloro-1-isopropyl-1H-pyrazole-5-carboxylic acid with 4-isopropylpyrimidine-5-carboxylic acid can prepare the target compound 2-(4-isopropylpyrimidin-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine. Replacing 4-chloro-1-isopropyl-1H-pyrazole-5-carboxylic acid with 4,6-dimethoxypyrimidine-5-carboxylic acid can prepare the target compound 2-(4,6-dimethoxypyrimidin-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine.

[0107] An important aspect of the present invention is the discovery that the compounds of formula I (including the compounds of formula II, III, IV and V described herein) are USP1 inhibitors. Therefore, the compounds of formula I (including the compounds of formula II, III, IV and V described herein) can be used for treating or preventing diseases related to USP1 regulation (also referred to herein as "USP1-mediated diseases"), or for preparing drugs for treating or preventing diseases related to USP1 regulation.

[0108] In this article, diseases related to USP1 regulation or USP1-mediated diseases refer to diseases in which USP1 is involved in the occurrence and development of the disease and benefits from the inhibition of USP1 activity. Preferably, the diseases related to USP1 regulation include cancers, especially cancers related to USP1 regulation. Preferably, the cancers related to USP1 regulation have DDR functional defects. Diseases related to USP1 regulation that can be treated or prevented by the methods or pharmaceutical compositions of the present invention include, but are not limited to, liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myelogenous leukemia, primary brain cancer, malignant melanoma, non-small cell lung cancer, small cell lung cancer, gastric cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute granulocytic leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, urogenital system neoplasms, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell cancer, endometrial cancer, polycythemia vera, essential thrombocythemia, adrenocortical carcinoma, skin cancer, and prostate cancer.

[0109] Accordingly, in some embodiments, the present application provides the use of a compound of formula I (including compounds of formula II, III, IV, and V described herein) or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound, or pharmaceutically acceptable salt thereof, or a mixture thereof, or a pharmaceutical composition thereof, described in any embodiment of the present application in the preparation of a medicament for treating a disease related to USP1 regulation or a USP1-mediated disease, and the use of a compound of formula I (including compounds of formula II, III, IV, and V described herein) or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound, or pharmaceutically acceptable salt thereof, or a mixture thereof, or a pharmaceutical composition thereof, described in any embodiment of the present application in a method for treating a disease related to USP1 regulation or a USP1-mediated disease.

[0110] In some embodiments, the present application also provides methods for treating or preventing diseases associated with USP1 regulation and methods for treating or preventing diseases caused by DDR functional defects, said methods comprising administering to a subject in need thereof (especially a mammal, more specifically a human) an effective amount of a compound of formula I (including the compounds of formula II, formula III, formula IV and V described herein) or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound or pharmaceutically acceptable salt thereof, or a mixture thereof, or a pharmaceutical composition containing an effective amount of a compound of formula I (including the compounds of formula II, formula III, formula IV and V described herein) or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound or pharmaceutically acceptable salt thereof, or a mixture thereof.

[0111] In some embodiments, the present application also provides methods for treating or preventing other diseases caused by excessive or abnormal cell proliferation, including proliferative or hyperproliferative diseases, such as myeloproliferative diseases, especially proliferative or hyperproliferative diseases caused by excessive or abnormal cell proliferation associated with USP1 regulation, said methods comprising administering to a subject in need thereof (especially a mammal, more specifically a human) an effective amount of a compound of formula I (including the compounds of formula II, formula III, formula IV and V described herein) or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound or pharmaceutically acceptable salt thereof, or a mixture thereof, or a pharmaceutical composition containing an effective amount of a compound of formula I (including the compounds of formula II, formula III, formula IV and V described herein) or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound or pharmaceutically acceptable salt thereof, or a mixture thereof.

[0112] When practicing the treatment or prevention methods of the present invention, a pharmaceutical preparation in an effective amount is administered to a patient having one or more of these symptoms. The pharmaceutical preparation contains a compound of formula I (including the compounds of formula II, formula III, formula IV and V described herein) at an effective therapeutic or prophylactic concentration and is formulated for oral, intravenous, topical or external administration for treating or preventing cancer and other USP1-mediated diseases. The dosage administered is an amount effective to ameliorate or eliminate one or more of the conditions. For the treatment of a particular disease, an effective amount is an amount sufficient to ameliorate or in some manner alleviate the symptoms associated with the disease. Such an amount may be administered as a single dose or may be administered according to an effective treatment regimen. The dosage may cure the disease, but administration is usually for the purpose of ameliorating the symptoms of the disease. Repeated administration is generally required to achieve the desired amelioration of symptoms.

[0113] In another embodiment, the present application provides a pharmaceutical composition comprising a compound of formula I (including the compounds of formula II, formula III, formula IV and V described herein) as a USP1 inhibitor, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0114] Another embodiment of the present invention relates to a pharmaceutical composition capable of effectively treating cancer, which comprises a compound of formula I (including the compounds of formula II, formula III, formula IV and V described herein) that is a USP1 inhibitor, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound or pharmaceutically acceptable salt thereof, in combination with at least one known anti-cancer drug or a pharmaceutically acceptable salt of an anti-cancer drug. In particular, it is used in combination with other anti-cancer drugs related to DNA damage and repair mechanisms, including PARP inhibitors olaparib, niraparib, rucaparib, talazoparib, pamiparib, fluzoparib and senaparib; HDAC inhibitors vorinostat, romidepsin, panobinostat and belinostat; and so on. And it is used in combination with other anti-cancer drugs related to cell division checkpoints, including Chk1 / 2 inhibitors, CDK4 / 6 inhibitors such as palbociclib, ATM inhibitors, Wee1 inhibitors, ATR inhibitors, MYT1 inhibitors, DNA-PK inhibitors; and so on. And it is used in combination with other targeted anti-cancer drugs, including PRMT5 inhibitors, Polθ inhibitors, RAD51 inhibitors, and so on.Other known anticancer drugs that can be used in combination cancer therapy include, but are not limited to, alkylating agents such as busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, and carboplatin; topoisomerase I inhibitors such as camptothecin, irinotecan, and topotecan; topoisomerase II inhibitors such as doxorubicin, epirubicin, aclarubicin, mitoxantrone, methydroxyellipticine, and etoposide; RNA / DNA antimetabolites such as 5-azacytidine, gemcitabine, 5-fluorouracil, and methotrexate; DNA antimetabolites such as 5-fluoro-2'-deoxyuridine, fludarabine, nelarabine, cytarabine, pralatrexate, pemetrexed, hydroxyurea, and thioguanine; antimicrotubule agents such as colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, and docetaxel; antibodies such as monoclonal antibodies, panitumumab, necitumumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab, tositumomab, brentuximab vedotin, daratumumab, elotuzumab, ofatumumab, dinutuximab, blinatumomab, ipilimumab, avastin, herceptin, and rituxan; antibody-drug conjugates (ADCs) such as trastuzumab emtansine (T-DM1), trastuzumab deruxtecan, trastuzumab emtansine, datopotamab deruxtecan, gemtuzumab ozogamicin, brentuximab vedotin, inotuzumab ozogamicin, sacituzumab govitecan, enfortumab vedotin, and belantamab mafodotin; kinase inhibitors such as imatinib, gefitinib, erlotinib, osimertinib, afatinib, ceritinib, alectinib, crizitinib, erlotinib, lapatinib, sorafenib, regorafenib, vemurafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, pralsetinib, ibrutinib, cabozantinib, lenvatinib, vandetanib, trametinib, cobimetinib, axitinib, temsirolimus, idelalisib, pazopanib, tucatinib, and everolimus.Other known anticancer drugs that can be used in combination cancer therapy include tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenic trioxide, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide, Venetoclax, Aldesleukin (recombinant human interleukin-2), and Sipuleucel-T (a prostate cancer treatment vaccine).

[0115] When practicing the methods of the present invention, the compounds of the present invention and at least one known anticancer drug can be administered together as a single pharmaceutical composition. Additionally, the compounds of the present invention can also be administered separately from at least one known anticancer drug. In one embodiment, the compounds of the present invention and at least one known anticancer drug are administered substantially simultaneously, i.e., all the drugs are administered simultaneously or sequentially, as long as the compounds reach therapeutic concentrations in the blood simultaneously. In another embodiment, the compounds of the present invention and at least one known anticancer drug are administered according to their respective dosage regimens, as long as the compounds reach therapeutic concentrations in the blood.

[0116] Another embodiment of the present invention is a tumor-inhibiting bioconjugate composed of the compound and acting as a USP1 inhibitor. This tumor-inhibiting bioconjugate is composed of the compound and at least one known therapeutic antibody, such as Herceptin or Rituxan, or growth factor, such as EGF or FGF, or cytokine, such as interleukin 2 or 4, or any molecule capable of binding to the cell surface. The antibody and other molecules can deliver the compound to its target, making it an effective anticancer drug. This bioconjugate can also enhance the anticancer effect of therapeutic antibodies, such as Herceptin or Rituxan.

[0117] Another embodiment of the present invention relates to a pharmaceutical composition capable of effectively inhibiting tumors, comprising a USP1 inhibitor of formula I (including formula II, III, IV, and V described herein), or a pharmaceutically acceptable salt thereof, in combination with radiotherapy. In this embodiment, the compounds of the present invention and radiotherapy can be administered at the same time or at different times.

[0118] Another embodiment of the present invention relates to a pharmaceutical composition capable of effectively treating cancer after surgery, comprising a USP1 inhibitor of formula I (including formula II, III, IV, and V described herein), or a pharmaceutically acceptable salt thereof. The present invention also relates to a treatment method for treating cancer in a mammal by surgically removing the tumor and then treating with the pharmaceutical composition of the present invention.

[0119] The pharmaceutical compositions of the present invention include pharmaceutical preparations in which the content of all the compounds of the present invention can effectively achieve their intended objectives. Although the needs of each individual vary, those skilled in the art can determine the optimal dosage of each part in the pharmaceutical preparation. Generally, the compound, or its pharmaceutically acceptable salt, is orally administered to mammals daily in an amount of about 0.0025 to 50 mg / kg body weight. Preferably, however, the oral administration is about 0.01 to 10 mg / kg per kg. If a known anti-cancer drug is also administered, its dosage should be effective to achieve its intended purpose. The optimal dosages of these known anti-cancer drugs are well known to those skilled in the art.

[0120] The unit oral dose may include about 0.01 to 50 mg, preferably about 0.1 to 10 mg of the compound of the present invention. The unit dose may be administered once or multiple times a day as one or more tablets, each tablet containing about 0.1 to 50 mg, suitably about 0.25 to 10 mg of the compound of the present invention or its solvate.

[0121] In topical preparations, the concentration of the compound of the present invention may be about 0.01 to 100 mg per gram of carrier.

[0122] The compounds of the present invention can be administered as raw drugs. The compounds of the present invention can also be administered as part of a suitable pharmaceutical preparation containing pharmaceutically acceptable carriers (including excipients and adjuvants). These pharmaceutically acceptable carriers facilitate the processing of the compound into a pharmaceutically acceptable pharmaceutical preparation. Preferred pharmaceutical preparations, especially those for oral administration and preferred dosage form types, such as tablets, lozenges and capsules, as well as solutions suitable for injection or oral administration, contain about 0.01% to 99%, preferably from about 0.25% to 75% of the active compound and excipients.

[0123] The scope of the present invention also includes non-toxic pharmaceutically acceptable salts of the compounds of the present invention. Acid addition salts are formed by mixing a solution of a non-toxic pharmaceutically acceptable acid and a solution of the compound of the present invention. Examples of such acids are hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, etc. Base addition salts are formed by mixing a solution of a non-toxic pharmaceutically acceptable base and a solution of the compound of the present invention. Examples of such bases are sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, tris(hydroxymethyl)aminomethane, N-methyl-glucamine, etc.

[0124] The pharmaceutical preparations of the present invention can be administered to any mammal as long as they can obtain the therapeutic effect of the compounds of the present invention. Among these mammals, humans and veterinary animals are the most important, although the present invention is not intended to be so limited.

[0125] The pharmaceutical preparation of the present invention can be administered by any route to achieve its intended purpose. For example, it can be administered by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, intrathecal, intracranial, nasal or topical routes. As an alternative or in parallel, it can be administered orally. The dosage of the drug will be determined according to the patient's age, health and weight, the type of concurrent treatment, the frequency of treatment, and the desired therapeutic benefit.

[0126] The pharmaceutical preparation of the present invention can be manufactured by known methods. For example, it can be manufactured by traditional mixing, granulation, tabletting, dissolution, or lyophilization processes. When manufacturing an oral preparation, solid excipients can be combined with the active compound, and the mixture can be selectively ground. After adding appropriate auxiliaries if necessary, the granular mixture is processed to obtain a tablet or tablet core.

[0127] Suitable excipients are especially fillers, such as saccharides like lactose or sucrose, mannitol or sorbitol; cellulose preparations and / or calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate; and binders, such as starch pastes, including corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone. If necessary, disintegrants can be added, such as the starches mentioned above, as well as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate. Auxiliaries are especially flow regulators and lubricants, for example, silica, talc, stearic acid or its salts, such as magnesium stearate or calcium stearate, and / or polyethylene glycol. If necessary, the tablet core can be provided with a suitable coating that resists gastric juice. For this purpose, concentrated saccharide solutions can be applied. This solution can contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. To prepare a gastric juice-resistant coating, suitable cellulose solutions can be used, such as cellulose acetate phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments can be added to the coating of the tablet or tablet core. For example, for identification or to characterize the combination of the active ingredient dosage.

[0128] Other orally administrable pharmaceutical preparations include snap-fit capsules made of gelatin, and sealed soft capsules made of gelatin and plasticizers such as glycerol or sorbitol. The snap-fit capsules can contain the active compound in particulate form, mixed with fillers such as lactose; binders such as starch; and / or lubricants such as talc or magnesium stearate, as well as stabilizers. In the soft capsules, the active compound is preferably dissolved or suspended in a suitable liquid such as an oil or liquid paraffin, in which stabilizers can be added.

[0129] Formulations suitable for parenteral administration include aqueous solutions of the active compound, such as solutions of water-soluble salts and alkaline solutions. In addition, oily injection suspensions of the appropriate active compound can be administered. Suitable lipophilic solvents or carriers include fats such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides or polyethylene glycol 400, or hydrogenated castor oil, or cyclodextrin. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, and / or dextran. Suspension stabilizers may also be included.

[0130] According to one aspect of the present invention, the compounds of the present invention are formulated for topical and parenteral use and are used for the treatment of skin cancer.

[0131] The topical formulations of the present invention can be made into oils, creams, emulsions, ointments, etc. by preferably suitable carriers. Suitable carriers include vegetable or mineral oils, white mineral oil (white soft paraffin), branched-chain fats or oils, animal fats and higher alcohols (greater than C 12 ). Preferred carriers are those in which the active ingredient can be dissolved. Emulsifiers, stabilizers, humectants and antioxidants may also be included, and, if desired, agents that impart color or fragrance. In addition, these topical formulations may contain transdermal penetration enhancers. Examples of such enhancers can be found in U.S. Patent Nos. 3,989,816 and 4,444,762.

[0132] Creams are preferably formulated from a mixture of mineral oil, self-emulsifying beeswax and water, mixed with the active ingredient dissolved in a small amount of oil such as almond oil. A typical example of a cream includes about 40 parts water, 20 parts beeswax, 40 parts mineral oil and 1 part almond oil.

[0133] Ointments can be formulated by mixing a vegetable oil such as almond oil containing the active ingredient with warm soft paraffin and then allowing the mixture to cool. A typical example of an ointment includes about 30% by weight of almond oil and 70% by weight of white soft paraffin.

[0134] The present invention also relates to the use of the compounds of the present invention in the preparation of a medicament for treating clinical conditions effective in inhibiting the activity of USP1. These medicaments may include the above-mentioned pharmaceutical compositions.

[0135] The following examples are illustrative and not limiting of the methods and formulations of the present invention. Other modifications and improvements that are obvious to those skilled in the art and that are commonly encountered in clinical treatment for various conditions and parameters are within the spirit and scope of the present invention. Examples General description All reagents used were of commercial quality, and the solvents were dried and purified according to standard methods. The mass spectrometry samples were analyzed using an electrospray single quadrupole mass spectrometer (Platform II, Agilent 6110). The 1 1H NMR spectra (300 MHz or 400 MHz) were recorded using a Brücker Ascend NMR spectrometer. The chemical shifts were recorded in ppm starting from the low field with TMS as the internal standard (0.00 ppm), and the coupling constant J values were in Hz. Example 1 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-7-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)benz[d]oxazole a) Preparation of 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline: 3-Bromo-2-methoxyaniline (1.5 g, 7.3 mmol), bis(pinacolato)diboron (2.8 g, 11.1 mmol), KOAc (2.2 g, 22.2 mmol) and Pd(dppf)Cl 2 (150 mg, 0.18 mmol) were dissolved in dioxane (10 mL), and the mixture was stirred at 100 °C overnight under nitrogen protection. After the reaction solution was cooled to room temperature, it was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine and dried over anhydrous Na 2 2SO 4 4. The crude product was purified by silica gel column chromatography (PE:EA = 5:1) to obtain the target compound (1.3 g, white solid, yield 70%). MS(ESI): 250.10[M+H] + . b) Preparation of 2-methoxy-3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)aniline: 2-Methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.3 g, 5.2 mmol), 2-(4-(bromomethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (2.5 g, 7.8 mmol), Cs 2 2CO 3 (5.07 g, 15.6 mmol) and Pd(dppf)Cl 2 (570 mg, 0.78 mmol) were dissolved in dioxane / water (10 mL, v / v = 1 / 1), and the mixture was stirred at 90 °C overnight under nitrogen protection. After the reaction solution was cooled to room temperature, it was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine and dried over anhydrous Na 2 2SO 4After drying, it was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain the target compound (800 mg, white solid, yield 44%). MS (ESI): 362.25 [M+H] + . c) Preparation of 2-amino-6-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)phenol: Dissolve 2-methoxy-3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)aniline (400 mg, 1.1 mmol) in dichloromethane (10 mL), and add BBr 3 (5.5 ml, 5.5 mmol) dropwise at 0 °C, and then stir at room temperature for 3 hours. After the reaction was complete, methanol (3 mL) was added to quench the reaction, and the solvent was removed under reduced pressure. The crude product was purified by preparative liquid phase to obtain the target compound (310 mg, white solid, yield 80%). MS (ESI): 348.05 [M+H] + . d) Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)benzothiazole: Dissolve 2-amino-6-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)phenol (310 mg, 0.89 mmol) and 4-cyclopropyl-6-methoxypyrimidine-5-carbaldehyde (158 mg, 0.89 mmol) in ethanol (5 mL), stir at room temperature for 30 minutes, and then add PhI(Oac) 2 (311 mg, 1.35 mmol) and stir for another 30 minutes. After the reaction was complete, water (20 mL) was added for dilution, and it was extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with saturated brine and dried over anhydrous Na 2 SO 4 After drying, it was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 3:1) to obtain the target compound (41.68 g, white solid, yield 28.6%). Examples 2-8 were prepared by a synthetic method similar to that of Example 1. Example 9 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)benzothiazole a) Preparation of 2-(4-(2-fluoro-3-nitrobenzyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole: Dissolve 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.0 g, 11.23 mmol) in dioxane / water (30 mL, v / v = 5 / 1). At room temperature, add 2-(4-(bromomethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (3.6 g, 11.23 mmol), Cs 2 CO 3 (7.3 g, 22.47 mmol) and Pd(dppf)Cl 2 (822 mg, 1.1 mmol). Stir overnight at 90 °C under nitrogen protection in a sealed tube. After the reaction is complete, cool the reaction solution to room temperature, dilute with water (50 mL), and extract with ethyl acetate (50 mL × 3). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (PE / EA = 10 / 1–5 / 1) to obtain the product (1.8 g, yellow solid, yield: 42.3%). MS(ESI): 380.09 [M+H] + . b) Preparation of 2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-nitrobenzenethiol: Dissolve 2-(4-(2-fluoro-3-nitrobenzyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (800 mg, 2.11 mmol) in DMSO (8 mL). Slowly add sodium hydrosulfide (NaHS, 608 mg, 7.60 mmol) at 0 °C. Let the reaction solution return to room temperature and stir for 2 hours. After the reaction is complete, adjust the pH of the reaction solution to about 2 with 1.0 M hydrochloric acid. Extract the resulting solution with ethyl acetate (50 mL × 3). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by preparative thin layer plate to obtain the product (240 mg, white solid, yield: 28.9%). MS(ESI): 394.08 [M+H] + . c) Preparation of 2-amino-6-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)benzenethiol: Dissolve 2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-nitrobenzenethiol (140 mg, 0.36 mmol) in acetic acid (4 mL), add Zn (116 mg, 1.78 mmol) at room temperature, and stir the reaction solution at 70 °C for 2 hours. After the reaction is complete, dilute with water (5 mL) and extract with ethyl acetate (50 mL × 3). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by preparative thin-layer plate to obtain the product (100 mg, white solid, yield: 77.2%). d) Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)benzothiazole: Dissolve 2-amino-6-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)benzenethiol (20 mg, 0.06 mmol) in ethanol (5 mL), add 4-cyclopropyl-6-methoxypyrimidine-5-carbaldehyde (15 mg, 0.08 mmol) and 1 drop of acetic acid at room temperature, stir for 30 minutes, then add iodobenzene diacetate (PhI(OAc) 2 , 26 mg, 0.08 mmol), and stir the reaction solution at room temperature for 2 hours. After the reaction is complete, dilute with water (20 mL) and extract with ethyl acetate (20 mL × 3). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by preparative high performance liquid chromatography to obtain the target product (3.2 mg, white solid, yield: 11.2%). MS(ESI): 522.15 [M+H] + . 1 HNMR(400 MHz) CDCl 3 : δ 8.63 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.58 - 7.56 (m, 2H), 7.50 - 7.48 (m, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.29 (s, 1H), 7.25 (s, 1H), 4.30 (s, 2H), 3.96 (s, 3H), 3.75 (s, 3H), 2.20–2.16 (m, 1H), 1.26–1.23 (m, 2H), 1.02–0.98 (m, 2H). Example 10 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c] pyridine Example 10 was prepared by a synthetic method similar to that of Example 11. MS(ESI): 507.25[M+H] + 。 1 1H NMR(400 MHz, CDCl3): δ 8.69(s, 1H), 8.53(d, J = 4.0 Hz, 1H), 7.65(d, J = 4.0 Hz, 1H), 7.55 - 7.49(m, 4H), 7.26(s, 1H), 4.51(s, 2H), 4.01(s, 3H), 3.71(s, 3H), 2.27–2.23(m, 1H), 1.31–1.28(m, 2H), 1.06–1.02(m, 2H). Example 11 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo [5,4-c]pyridine a) Preparation of N-(2-bromo-3-hydroxypyridin-4-yl)-4-cyclopropyl-6-methoxypyrimidine-5-carboxamide: Dissolve 4-amino-2-bromopyridin-3-ol (500 mg, 1.4 mmol) in DMF (10 mL), add 4-cyclopropyl-6-methoxypyrimidine-5-carboxylic acid (335 mg, 1.7 mmol), TBTU (692 mg, 2.2 mmol) and TEA (436 mg, 4.31 mmol) at room temperature, and stir the reaction mixture overnight at room temperature. After the reaction is complete, dilute with water (20 mL) and extract with ethyl acetate (20 mL × 3). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain the product (370 mg, yellow solid, yield: 49%). MS(ESI): 525.25[M+H] + 。 b) Preparation of 4-bromo-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)oxazolo[5,4-c]pyridine: Dissolve N-(2-bromo-3-hydroxypyridin-4-yl)-4-cyclopropyl-6-methoxypyrimidine-5-carboxamide (8.3 g, 22.8 mmol) in DCM (80 mL), add C 2 Cl 6 (14.5 g, 57.0 mmol), PPh 3(19.3 g, 68.4 mmol) and TEA (18.4 g, 182.4 mmol), and the reaction solution was stirred at room temperature for 48 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the crude product was purified by column chromatography (PE / EA = 10 / 1) to obtain the product (5.5 g, white solid, yield: 70%). MS (ESI): 349.00 [M+H] + 。 c) Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine: Zn (79 mg, 1.21 mmol) and I 2 (5 mg, 0.02 mmol) were dissolved in DMF (2 mL), and the reaction system was purged with nitrogen three times and stirred at 30 °C for 10 minutes. After adding TMSCl (3 mg, 0.02 mmol), it was stirred for another 45 minutes. 2-(4-(Bromomethyl)-2-fluorophenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (40 mg, 0.121 mmol) was dissolved in DMF (1 mL) and then added to the above reaction solution, and it was stirred at 45 °C for 1 hour. The prepared solution was added to a DMF (6 mL) solution of Pd(PPh 3 ) 4 (12 mg, 0.01 mmol) and 4-bromo-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)oxazolo[5,4-c]pyridine (35 mg, 0.101 mmol), and it was stirred at 60 °C for 2 hours under nitrogen protection. After the reaction was complete, water (30 mL) was added for dilution, and it was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography to obtain the target product (13 mg, white solid, yield: 24.6%). Examples 12 to 18 were prepared by a synthetic method similar to that of Example 11. Example 19 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-7-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H- benzo[d]imidazole a) Preparation of N-methyl-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-nitroaniline: Dissolve 2-(4-(2-fluoro-3-nitrobenzyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (500 mg, 1.32 mmol) in THF (5 mL), and add methylamine (5 mL, 2 mmol, 1.0 M THF solution) dropwise at room temperature. The reaction mixture is stirred at 60 °C for 2 hours. After the reaction is complete, concentrate it to dryness under reduced pressure to obtain the crude product (419 mg, yellow solid). MS(ESI): 391.10[M+H] + 。b) N 1 -methyl-6-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)benzene-1,2-diamine preparation: Dissolve N-methyl-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-nitroaniline (350 mg, 0.89 mmol) in MeOH (20 mL), and add Pd / C (70 mg, 0.72 mmol) at room temperature. The reaction system is stirred at room temperature for 3 hours under H 2 environment. After the reaction is complete, filter the reaction mixture and concentrate the filtrate under reduced pressure. The crude product is purified by silica gel column chromatography (PE / EA = 10 / 1 - 1 / 1) to obtain the product (50 mg, white solid, yield: 15%). MS(ESI): 361.10[M+H] + 。 c) Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-7-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-benzo[d]imidazole: Dissolve N 1 -methyl-6-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)benzene-1,2-diamine (35 mg, 0.10 mmol) in AcOH (5 mL), and add 4-cyclopropyl-6-methoxypyrimidine-5-carbaldehyde (18 mg, 0.10 mmol) and Cu(OAc) 2 (60 mg, 0.30 mmol) at room temperature. The reaction mixture is stirred at 70 °C for 3 hours. After the reaction is complete, cool the reaction mixture to room temperature and concentrate it under reduced pressure. Dilute it with water (20 mL) and extract it with ethyl acetate (20 mL×3). Combine the organic phases, wash them with saturated brine, dry them over anhydrous sodium sulfate, and concentrate them under reduced pressure to obtain the crude product. The crude product is purified by preparative high performance liquid chromatography to obtain the target product (15 mg, white solid, yield: 29%). MS(ESI): 519.20[M+H] + 。 1 HNMR(400MHz,CDCl 3): δ 8.67 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.56 - 7.54 (m, 2H), 7.29 (s, 1H), 7.27 - 7.22 (m, 3H), 7.07 (d, J = 8.0 Hz, 1H), 4.56 (s, 2H), 3.90 (s, 3H), 3.74 (s, 3H), 3.59 (s, 3H), 1.59 - 1.57 (m, 1H), 1.31–1.29 (m, 1H), 1.14–1.13 (m, 1H), 1.02–0.98 (m, 1H), 0.88 - 0.86 (m, 1H). Examples 20 - 29 were prepared by a synthetic method similar to that of Example 1 or 11. Example 30 4-(4-(1-(Azetidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5- yl)oxazolo[5,4-c]pyridine a) Preparation of tert-butyl 3-(2-(4-((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl))oxazolo[5,4-c]pyridin-4-yl)methyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)azetidine-1-carboxylate: 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine (100 mg, 0.2 mmol) was dissolved in toluene (2 mL), and tert-butyl 3-hydroxyazetidine-1-carboxylate (105 mg, 0.6 mmol) and cyanomethylenetributylphosphine (96 mg, 0.4 mmol) were added at room temperature. The reaction mixture was stirred at 120 °C for 16 h. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative thin-layer chromatography (PE / EA = 3 / 1) to give the product (20 mg, yellow solid, yield: 15%). MS (ESI): 648.10 [M + H] + . b) Preparation of 4-(4-(1-(azetidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)oxazolo[5,4-c]pyridine: Dissolve tert-butyl 3-(2-(4-((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl))oxazolo[5,4-c]pyridin-4-yl)methyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)azetidine-1-carboxylate (20 mg, 0.03 mmol) in DCM (2 mL), add TFA (2 mL), and stir the reaction solution at 50 °C for 2 hours. After the reaction is complete, dilute the reaction solution with saturated NaHCO 3 solution (10 mL), and extract with ethyl acetate (10 mL × 3). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by preparative high performance liquid chromatography to obtain the target product (3 mg, white solid, yield: 18%). MS (ESI): 548.05 [M+H] + . 1 1H NMR (400 MHz, CDCl3): δ 8.69 (s, 1H), 8.52 (s, 1H), 7.98 (s, 1H), 7.65 (s, 1H), 7.50 (s, 2H), 7.36 (s, 2H), 5.25 (s, 1H), 4.51 (s, 2H), 4.39 - 4.10 (m, 4H), 4.01 (s, 3H), 2.26 - 2.25 (m, 1H), 1.33–1.28 (m, 2H), 1.08 - 1.02 (m, 2H). Example 31 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-(oxetidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine Example 31 was prepared by a synthetic method similar to that of Example 30. MS (ESI): 549.20 [M+H] + . 1HNMR (400MHz, CD3Cl): δ8.71 (s, 1H), 8.56 (d, J = 5.4Hz, 1H), 7.86 (s, 1H), 7.6 8(d,J=5.4Hz,1H),7.53(d,J=7.9Hz,2H),7.35(d,J=7.9Hz,2H),5.42(p,J=6. 6Hz,1H),5.02(t,J=7.4Hz,2H),4.81(t,J=6.6Hz,2H),4.03(s,3H),2.27(tt ,J=8.4,4.7Hz,1H),1.32(dt,J=6.8,3.3Hz,2H),1.07(dq,J=7.2,3.9Hz,2H). Embodiment 32 2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine a) Preparation of 3-methoxy-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyridin-4-amine: Zn (3.8 g, 59.4 mmol) and I 2 (380 mg, 1.0 mmol) was dissolved in DMF (6 mL), the reaction system was replaced with nitrogen three times, and stirred at 30 ° C for 10 minutes. TMSCl (53 mg, 0.5 mmol) was added and stirred for 45 minutes. 2-(4-(bromomethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (2.7 g, 7.4 mmol) was dissolved in DMF (5 mL), added to the above reaction system, and stirred at 45 ° C for 1 hour. Pd(PPh 3 ) 4 (856.0mg, 0.74mmol) and 2-bromo-3-methoxypyridin-4-amine (1.0g, 4.95mmol) in DMF (6mL) solution, stirred at 60°C for 2 hours under nitrogen protection. After the reaction is complete, the reaction solution is cooled to room temperature, diluted with water (40mL), and extracted with ethyl acetate (40mL×3). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography (PE / EA=1 / 1) to obtain the product (330mg, yellow solid, yield: 18%). MS(ESI):363.15[M+H] + . b) Preparation of 4-amino-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyridin-3-ol: Dissolve 3-methoxy-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyridin-4-amine (120.0 mg, 0.4 mmol) in DCM (5 mL), and dropwise add BBr 3 (2.0 ml, 2.0 mmol, 1M DCM solution) at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. After the reaction was complete, MeOH (3 mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / MeOH = 100 / 1 - 15 / 1) to obtain the product (88 mg, yellow solid, yield: 63%). MS (ESI): 348.10 [M+H] + . c) Preparation of 4-chloro-N-(3-hydroxy-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyridin-4-yl)-1-isopropyl-1H-pyrazole-5-carboxamide: Dissolve 4-amino-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyridin-3-ol (90.0 mg, 0.26 mmol) in DMF (2 mL), and add 4-chloro-1-isopropyl-1H-pyrazole-5-carboxylic acid (53.0 mg, 0.28 mmol), HATU (118.0 mg, 0.31 mmol) and DIEA (100.0 mg, 0.78 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. After the reaction was complete, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative thin layer chromatography (DCM / MeOH = 10 / 1) to obtain the product (60 mg, yellow solid, yield: 44%). MS (ESI): 519.15 [M+H] + . d) Preparation of 2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine: Dissolve 4-chloro-N-(3-hydroxy-2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyridin-4-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (60.0 mg, 0.12 mmol) in DCM (5 mL), and add C 2 Cl 6 (68.0 mg, 0.29 mmol), PPh 3(90.0 mg, 0.35 mmol) and TEA (92.0 mg, 0.92 mmol). The reaction mixture was stirred at room temperature for 48 h. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and the crude product was purified by preparative HPLC to obtain the target product (4.5 mg, white solid, yield: 1.3%). MS (ESI): 501.10 [M+H] + 。 1 1H NMR (400 MHz) CD3OD: δ 8.51 (d, J = 5.6 Hz, 1H), 7.77 (d, J = 5.4 Hz, 1H), 7.72 (s, 1H), 7.65 (s, 1H), 7.58 (d, J = 1.3 Hz, 4H), 5.85–5.70 (m, 1H), 4.57 (s, 2H), 3.73 (s, 3H), 1.52 (d, J = 6.6 Hz, 6H). Examples 33 and 34 2-(1-Isopropyl-4-methyl-1H-pyrazol-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine (Example 33) and 2-(1-isopropyl-1H-pyrazol-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine (Example 34) 2-(4-Chloro-1-isopropyl-1H-pyrazol-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine (60.0 mg, 0.12 mmol) was dissolved in dioxane / water (1 mL, v / v = 5 / 1), and trimethylcyclotriboroxane (0.34 ml, 1.2 mmol), K 3 PO 4 (72.0 mg, 0.36 mmol) and Pd(dppf)Cl 2 (9.6 mg, 0.01 mmol) were added at room temperature. The reaction mixture was stirred at 105 °C overnight under nitrogen protection. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC to obtain the target product Example 33 (3.1 mg, white solid, yield: 5%) and Example 34 (1 mg, white solid, yield: 2%). Example 33: MS (ESI): 481.20 [M+H] + 。 1 1H NMR (400 MHz, CD3 OD): δ8.49(d,J=5.4Hz,1H),7.74(d,J=5.5Hz,1H),7.65(s,1H),7.60(d,J=8.0Hz,2H),7.55– 7.50(m,3H),5.82–5.71(m,1H),4.57(s,2H),3.73(s,3H),2.41(s,3H),1.50(d,J=6.4Hz,6H). Example 34: MS (ESI): 467.25 [M+H] + . 1 H NMR (400MHz, CD 3 OD): δ8.48(d,J=5.5Hz,1H),7.73(d,J=5.6Hz,1H),7.68(d,J=2.1Hz,1H),7.65(s,1H),7.58(q,J=8. 1Hz, 4H), 7.17 (d, J = 2.1Hz, 1H), 5.94–5.83 (m, 1H), 4.57 (s, 2H), 3.73 (s, 3H), 1.55 (d, J = 6.6Hz, 6H). Examples 35 to 46 are prepared using a synthetic method similar to that of Example 1, 11 or 32. Embodiment 55 The inhibitory effect of the compounds of the present invention on USP1 / UAF1 enzyme activity was determined by using the ubiquitin-rhodamine 110 assay The inhibitory effect of compounds on USP1 / UAF1 enzyme activity was detected using the ubiquitin-rhodamine 110 method. The enzymatic reaction was carried out in a detection buffer (HEPES (pH7.8) 50mM, NaCl 100mM, EDTA 0.5mM, DTT 1mM, BSA 0.01%, Tween-20 0.01%) containing 0.3nM USP1 / UAF1 enzyme. Each compound was tested in 10 concentrations ranging from 0.0005-10μM. After incubation for 30min, 1μL of ubiquitin-rhodamine 110 (150nM) was added to initiate the enzymatic reaction. Finally, the luminescent signal was recorded using an Envision plate reader under Ex480 / Em540 conditions. The inhibition rate of the test compound on USP1 / UAF1 enzyme activity was calculated according to the following formula. IC50 The values were obtained by fitting with the sigmoidal dose-response curve equation using XL Fit software. The curve equation is: Y = 100 / (1 + 10 ^ (LogC - LogIC 50 )), where C is the compound concentration. Table 1 summarizes the inhibitory effects (IC 50 ) of the compounds of the present invention on USP1 / UAF1 enzyme activity. Table 1 Embodiment <![CDATA[IC 50 (nM)]]> Embodiment <![CDATA[IC 50 (nM)]]> 1 5.55 20 44.07 2 68.26 21 4.96 3 33.94 23 23.56 4 173.0 24 82.51 5 21.44 28 40.09 7 40.25 29 92.10 8 49.99 32 23.57 10 8.94 39 75.65 11 6.25 40 112.37 15 37.55 Therefore, as detected by the ubiquitin-rhodamine 110-glycine assay, the compounds disclosed herein have good inhibitory effects on USP1 / UAF1 enzyme activity. Example 56 Proliferation inhibitory effect of the compounds of the present invention on human breast cancer cell MDA-MB-436 After cell resuscitation, the cells were cultured and passaged with complete medium (DMEM medium + 10% FBS + insulin + glutathione). When the cell confluence reached about 80%, the cells were gently blown off from the bottom of the culture dish with a 1 mL pipette, and the cell suspension was collected and centrifuged at 500 rpm for 3 min; the supernatant was discarded, the cells were resuspended with complete medium, inoculated into the culture dish at an appropriate ratio, and then placed in an incubator at 37°C and 5% CO 2 and cultured statically. When the cells were cultured and passaged to a good growth state and a confluence of about 80%, they were started to be used for experiments. The cells in the logarithmic growth phase were gently blown down with a 1 mL pipette, centrifuged at 500 rpm for 3 min, the supernatant was discarded, resuspended with fresh medium, dispersed into single cells, and counted. The cells were inoculated into a 96-well cell culture plate (the first column was left empty) at a density of 3000 cells per well, and placed in an incubator at 37°C and 5% CO 2 overnight. The next day, the compound stock solution was serially diluted 8 concentrations in a 1:3 ratio with DMSO respectively. 5 μL of each concentration was added to 120 μL of medium (25-fold dilution), and a DMSO control well was also made and mixed well by oscillation. From the CO 2 incubator, the cells were taken out, the old medium in the wells was aspirated, 195 μL of fresh medium was added to each well, and then 5 μL of the compound containing the corresponding concentration diluted in the medium was added to the corresponding wells. Subsequently, the culture plate was placed in an incubator at 37°C and 5% CO 2 and cultured for a total of 7 days, and the drug was changed once on the 4th day. After 7 days, 20 μL of CCK-8 was added to each well and shaken, and then continued to be cultured. After 4 h, it was shaken for 5 min, and the absorbance values at wavelengths of 450 nm and 650 nm (OD value = absorbance value 450nm - absorbance value 650nm ) were read on a multi-functional reader respectively. Data were analyzed using GraphPad Prism 6.0 software. The inhibitory activity of the compounds on cell proliferation was plotted with cell viability and compound concentration as coordinates. Cell viability % = (OD 化合物 - OD 背景 ) / (OD DMSO - OD 背景 ) × 100. IC 50 values were fitted to the sigmoidal dose-response curve equation: Y = 100 / (1 + 10^(LogC - LogIC 50 ))), where C is the compound concentration. Table 2 summarizes the inhibitory data (IC 50 ) of the compounds on human breast cancer cell MDA-MB-436. Table 2 Therefore, as determined by the CCK-8 assay, the compounds of the present invention have good inhibitory effects on the growth of human breast cancer cell MDA-MB-436.

[0136] Although the present invention has been fully described, those skilled in the art should understand that the same implementation can be carried out within a wide and equivalent range of conditions, formulations, and other parameters without affecting the scope of the present invention or any of its embodiments. All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety.

Claims

1. A compound represented by the following formula I, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound, or pharmaceutically acceptable salt thereof, or a mixture thereof: Wherein, A 1 and A 2 each independently selected from N, NR 1 , O, and S; B 1 , B 2 and B 3 are each independently selected from N and CR 2 ; Ring Z is selected from an optionally substituted cycloalkyl, an optionally substituted heterocyclic group, an optionally substituted aryl, and an optionally substituted heteroaryl; L is selected from optionally R 4 and / or R 5 substituted alkylene, NR 6 , O, S, SO, SO 2 and C═O; Cy 1 selected from optionally substituted cycloalkyl, optionally substituted heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl; Cy 2 is selected from optionally substituted cycloalkyl, optionally substituted heterocyclic group, optionally substituted aryl and optionally substituted heteroaryl; or ring Z and Cy 2 together form an optionally substituted 11- to 14-membered heterocyclic group; R 1 selected from hydrogen and an optionally substituted alkyl group; R 2 selected from hydrogen, halogen, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted amino; R 4 and R 5 each independently selected from halogen, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted alkenyl and optionally substituted alkynyl; or R 4 and R 5 form a ring with the atoms of the attached L; R 6 selected from hydrogen and an optionally substituted alkyl group.

2. The compound according to claim 1, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound, or pharmaceutically acceptable salt thereof, or a mixture thereof, Characterized in that: A 2 is N, A 1 is O, S or NR 1 , where R 1 is hydrogen or C 1-4 alkyl, preferably methyl; or A 2 is N, A 1 is O or S; or A 2 is N, A 1 is O; or A 1 is N, A 2 is O or S, preferably O; and / or B 1 、 B 2 and B 3 are each independently selected from N and CR 2 , where R 2 is H, halogen, C 1-4 alkyl or C 1-4 alkoxy; preferably, B 1 、 B 2 and B 3 are each independently N and CH, and B 1 、 B 2 and B 3 at most only one of them is N; preferably B 1 and B 2 are CH, B 3 is N, or B 1 、 B 2 and B 3 are all CH; Preferably, containing A 1 , A 2 , B 1 , B 2 and B 3 The fused heteroaromatic bicyclic ring containing B is selected from the following groups: Preferably selected from the following groups: More preferably, selected from the following groups: wherein, *1 and *2 respectively represent the connection positions of the said group with the compound Cy 1 and L.

3. The compound according to claim 1 or 2, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound, or pharmaceutically acceptable salt thereof, or a mixture thereof, Characterized in that: Ring Z is an optionally substituted C 3-8 cycloalkyl group, an optionally substituted 4- to 10-membered heterocyclic group, an optionally substituted 6- to 14-membered aryl group or an optionally substituted 5- to 10-membered heteroaryl group; preferably, when Ring Z is substituted, the number of substituents is 1 or 2 and is selected from halogen, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted amino; preferably, the optionally substituted alkyl and optionally substituted alkoxy are optionally substituted C 1-4 alkyl and optionally substituted C 1-3 alkoxy, the optionally substituted cycloalkyl is an optionally substituted C3-8 cycloalkyl, the optionally substituted alkenyl and optionally substituted alkynyl are an optionally substituted C 2-4 alkenyl and an optionally substituted C 2-4 alkynyl, the optionally substituted amino is -NR a R b , wherein, R a and R b are each independently H and C 1-4 alkyl; preferably, the alkyl, alkoxy, alkenyl, alkynyl and cycloalkyl are each optionally substituted by 1 to 5 groups selected from halogen, hydroxy and -NR a R b , the R a and R b are each independently H and C 1-4 alkyl; preferably, the substituents on Ring Z are 1 or 2 substituents selected from halogen and C 1-3 alkoxy; or Ring Z and Cy 2 together form an optionally substituted 11- to 14-membered heterocyclic group, which is a tricyclic hetero group containing 2, 3 or 4 heteroatoms selected from nitrogen and oxygen, such as benzimidazooxazinyl, dihydrobenzimidazoxazepinyl, dihydrobenzimidazodiazepinyl and benzimidazoxazepinyl; preferably, when the 11- to 14-membered heterocyclic group is substituted, the number of substituents can be 1 or 2, and is selected from halogen, optionally substituted alkyl and optionally substituted alkoxy; preferably, the optionally substituted alkyl and optionally substituted alkoxy are preferably optionally substituted C 1-4 alkyl and optionally substituted C 1-3 alkoxy; preferably, the alkyl and alkoxy are optionally substituted by 1 to 5 groups selected from halogen, hydroxy and -NR a R b , and the R a and R b are each independently H and C 1-4 alkyl.

4. The compound according to any one of claims 1 to 3, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound, or pharmaceutically acceptable salt thereof, or a mixture thereof, Characterized in that: Cy 1 is an optionally substituted C 3-8 cycloalkyl group, an optionally substituted 4- to 10-membered heterocyclic group, an optionally substituted 6- to 14-membered aryl group or an optionally substituted 5- to 10-membered heteroaryl group; preferably, the 4- to 10-membered heterocyclic group is a heterocyclic group containing nitrogen and / or oxygen, the 5- to 10-membered heteroaryl group is a monocyclic heteroaryl group containing nitrogen, and the aryl group is a phenyl group; preferably, Cy 1 is an optionally substituted phenyl group, an optionally substituted pyridyl group, an optionally substituted pyrimidinyl group, an optionally substituted pyrazinyl group, an optionally substituted pyridazinyl group, an optionally substituted piperidyl group, an optionally substituted piperazinyl group, an optionally substituted tetrahydrofuranyl group, an optionally substituted pyrrolidinyl group or an optionally substituted pyrazolyl group; more preferably, Cy 1 is an optionally substituted pyrimidinyl group; Wherein, when Cy 1 is substituted, the number of substituents is 1, 2 or 3, and is selected from halogen, cyano, optionally substituted C 1-4 alkyl, optionally substituted C 1-4 alkoxy, optionally substituted C 3-6 cycloalkyl and optionally substituted amino; preferably, the C 1-4 alkyl and C 1-4 alkoxy are optionally substituted by 1-5 groups selected from deuterium, halogen, hydroxy and -NR a R b ; the C 3-6 cycloalkyl is optionally substituted by 1-5 groups selected from halogen, hydroxy, NR a R b , C 1-4 alkyl, halo C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, C 1-4 alkoxy and halo C 1-4 alkoxy; the amino is optionally substituted by 1 or 2 groups selected from C 1-4 alkyl and halo C 1-4 alkyl, wherein the R a and R b are each independently H and C 1-4 alkyl; Preferably, Cy 1 substituents are selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, deuterated C 1-4 alkoxy and C 3-6 cycloalkyl; More preferably, Cy 1 substituents are selected from C 1-4 alkoxy, deuterated C 1-4 alkoxy and C 3-6 cycloalkyl; More preferably, the substituent on Cy 1 is located at the ortho-position of the position where the ring containing A 1 and A 2 is connected to Cy 1 and the position of the connection.

5. The compound according to any one of claims 1 to 4, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound, or pharmaceutically acceptable salt thereof, or a mixture thereof, Characterized in that: Cy 2 is selected from an optionally substituted 6- to 14-membered aryl group, an optionally substituted 5- to 10-membered heteroaryl group, an optionally substituted C 3-8 cycloalkyl group, and an optionally substituted 4- to 10-membered heterocyclic group; preferably, the 6- to 14-membered aryl group is a phenyl group, the 4- to 10-membered heterocyclic group is a heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen and oxygen, including a partially saturated 8- to 10-membered nitrogen- and / or oxygen-containing heterocyclic group, such as azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydroimidazopyrazinyl, and dihydroimidazoxazinyl, the 5- to 10-membered heteroaryl group is a heteroaryl group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, such as imidazolyl, pyrazolyl, triazolyl, pyridyl, and pyrazinyl, etc.; preferably, Cy 2 is an optionally substituted nitrogen-containing 5- to 10-membered heteroaryl group or an optionally substituted nitrogen- and / or oxygen-containing 8- to 10-membered heterocyclic group, more preferably a nitrogen-containing five-membered heteroaryl group; more preferably, Cy 2 is an optionally substituted imidazolyl group or an optionally substituted pyrazolyl group; Preferably, when Cy 2 is substituted, the number of substituents is 1, 2, 3, 4 or 5, and the substituents are selected from halogen, cyano, optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 4- to 10-membered heterocyclic group, and optionally substituted C 1-4 alkoxy; wherein, when the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 1-4 alkoxy are substituted, the substituents are selected from 1 to 5 groups selected from deuterium, halogen, hydroxy and -NR a R b ; wherein, the C 3-6 cycloalkyl and 4- to 10-membered heterocyclic group are optionally substituted by 1 to 5 substituents selected from halogen, hydroxy, NR a R b , C 1-4 alkyl, halo C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, C 1-4 alkoxy and halo C 1-4 alkoxy; wherein, the R a and R b are each independently H and C 1-4 alkyl; Preferably, Cy 2 is substituted with 1 or 2 substituents selected from C 1-4 alkyl, C 2-4 alkynyl, halo C 1-4 alkyl, deuterated C 1-4 alkyl, 4- to 10-membered heterocyclic group, C 3-6 cycloalkyl and C 1-4 alkoxy; Preferably, Cy 2 is an imidazolyl or pyrazolyl group, optionally substituted by 1 or 2 substituents selected from C 1-4 alkyl, C 2-4 alkynyl, halo C 1-4 alkyl, deuterated C 1-4 alkyl, 4- to 10-membered heterocyclic group, C 3-6 cycloalkyl and C 1-4 alkoxy; Preferably, Cy 2 is substituted by 1-2 substituents selected from C 1-4 alkyl, C 3 -C 6 cycloalkyl and halo C 1-4 alkyl.

6. The compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound, or pharmaceutically acceptable salt thereof, or a mixture thereof, Characterized in that: L is an alkylene group, NH, N-C 1-3 alkyl or O; preferably, L is C 1-3 alkylene, more preferably methylene; and / or R 4 and R 5 are each independently selected from C 1-4 alkyl and hydroxy; or R 4 and R 5 together with the atoms of the attached L form a 3- to 5-membered cycloalkyl or 3- to 5-membered heterocyclic group; and / or R 6 is hydrogen or C 1-3 alkyl group.

7. The compound according to claim 1, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound, or pharmaceutically acceptable salt thereof, or a mixture thereof, Characterized in that, The structure of the compound of formula I is as shown in formula II, IIIa, IIIb, IVa, IVb or V: In the formula: A 1 、A 2 、B 1 、B 2 、B 3 、L, Cy 1 and Cy 2 as defined in any one of claims 1 to 6; D 1 、 D 2 、 D 3 and D 4 are each independently selected from N and CR 3 ; R 3 selected from hydrogen, halogen, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted amino; R 7 and R 9 each independently selected from hydrogen, halogen, cyano, optionally substituted C 1-4 alkyl, optionally substituted C 1-4 alkoxy, optionally substituted C 3-6 cycloalkyl and optionally substituted amino; R 8 selected from hydrogen, a halogen, and optionally substituted C 1-4 alkyl; R 10 and R 11 each independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted amino; R 12 selected from hydrogen, optionally substituted C 1-4 alkyl, optionally substituted C 3-6 cycloalkyl and optionally substituted C 4-6 heterocyclic group; or, R 11 is linked to R 12 to form an optionally substituted 6- to 7-membered heterocyclic group; R 13 selected from hydrogen, a halogen, an optionally substituted C 1-4 alkyl, and an optionally substituted C 1-4 alkoxy; or, R 12 is linked to R 13 to form an optionally substituted 5- to 7-membered heterocyclic group; R 14 selected from halogen and optionally substituted C 1-4 alkyl groups.

8. The compound according to claim 7, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound, or pharmaceutically acceptable salt thereof, or a mixture thereof, Characterized in that: R 3 Each independently selected from hydrogen, halogen, cyano, optionally substituted C 1-4 alkyl, optionally substituted C 1-3 alkoxy, optionally substituted C 3-8 cycloalkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl and -NR a R b wherein, R a and R b are each independently H and C 1-4 alkyl; preferably, R 3 are each independently selected from halogen, optionally substituted C 1-4 alkyl and optionally substituted C 1-3 alkoxy; preferably, the alkyl, alkoxy, alkenyl, alkynyl and cycloalkyl are each optionally substituted by 1 - 5 groups selected from halogen, hydroxy and -NR a R b wherein the R a and R b are each independently H and C 1-4 alkyl; more preferably, R 3 is selected from H, halogen and C 1-3 alkoxy; and / or R 7 and R 9 In, said C 1-4 alkyl and C 1-4 alkoxy are optionally substituted by 1 - 5 groups selected from halogen, hydroxyl, and -NR a R b ; said C 3-6 cycloalkyl is optionally substituted by 1 - 5 substituents selected from halogen, hydroxyl, NR a R b , C 1-4 alkyl, halo - C 1-4 alkyl, hydroxyl - substituted C 1-4 alkyl, C 1-4 alkoxy, and halo - C 1-4 alkoxy; said amino is optionally substituted by 1 or 2 substituents selected from C 1-4 alkyl and halo - C 1-4 alkyl, wherein, said R a and R b are each independently H and C 1-4 alkyl; preferably, R 7 and R 9 are each independently hydrogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, deuterated C 1-4 alkoxy, or C 3-6 cycloalkyl, and R 7 and R 9 are not both hydrogen; more preferably, R 7 and R 9 are each independently C 1-4 alkoxy, deuterated C 1-4 alkoxy, or C 3-6 cycloalkyl; and / or R 8 is hydrogen, halogen or C a R b alkyl optionally substituted by 1-5 groups selected from halogen, hydroxy and -NR 1-4 , where R a and R b are each independently H and C 1-4 alkyl; preferably, R 8 is hydrogen; and / or R 10 and R 11 each independently is hydrogen, a halogen, an optionally substituted C 1-4 alkyl or an optionally substituted C 1-4 alkoxy; preferably, the C 1-4 alkyl and C 1-4 alkoxy are optionally substituted by 1-5 groups selected from halogen, hydroxy and -NR a R b wherein the R a and R b each independently is H and C 1-4 alkyl; preferably, R 10 and R 11 one of which is H and the other is halogen, an optionally substituted C 1-4 alkyl or an optionally substituted C 1-4 alkoxy; and / or R 12 selected from hydrogen, optionally substituted C 1-4 alkyl, optionally substituted C 1-4 alkoxy, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, optionally substituted C 3-6 cycloalkyl and optionally substituted C 4-6 heterocyclyl; preferably, the optionally substituted C 4-6 heterocyclyl is a heterocyclyl containing N or O, such as oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, etc.; preferably, the substituent of R 12 is 1-3 substituents selected from halogen, hydroxyl and -NR a R b wherein the R a and R b are each independently H and C 1-4 alkyl; more preferably, R 12 is C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl or C 3-6 cycloalkyl; and / or R 13 selected from hydrogen, halogen, optionally substituted C 1-4 alkyl and optionally substituted C 1-4 alkoxy; preferably, R 13 is hydrogen; and / or R 14 selected from halogen, optionally substituted C 1-4 alkyl; preferably, the alkyl is optionally substituted with 1-5 substituents selected from hydroxy and halogen; more preferably, R 14 is halo C 1-4 alkyl, such as trifluoromethyl; or R 11 and R 12 are linked to form an optionally substituted 6- to 7-membered heterocyclic group, which together with the phenyl group and imidazolyl group shown forms an 11- to 14-membered tricyclic heteroaryl group containing 2, 3 or 4 heteroatoms selected from nitrogen and oxygen as described herein, such as benzimidazooxazine group, dihydrobenzimidazolooxazepine, dihydrobenzimidazolodiazepine group and benzimidazolooxazepine group; and / or R 12 and R 13 are linked to form an optionally substituted 5- to 7-membered heterocyclic group containing nitrogen and / or oxygen, which together with the imidazolyl group forms a 7- to 10-membered bicyclic heterocyclic group containing nitrogen and / or oxygen, such as 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl and 5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-3-yl.

9. The compound of claim 1, wherein the compound is selected from: 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-7-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)benz[d]oxazole; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)benz[d]oxazole; 7-(4-(1-Cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)benz[d]oxazole; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-7-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)benz[d]oxazole; 2-(4-Cyclobutyl-6-methoxypyrimidin-5-yl)-7-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)benz[d]oxazole; 2-(4,6-Dimethoxypyrimidin-5-yl)-7-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)benzo[d]oxazole; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-7-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)benzo[d]oxazole; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-7-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3,5-difluorobenzyl)benzo[d]oxazole; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-7-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)benzo[d]thiazole; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine; 4-(4-(1-Cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)oxazolo[5,4-c]pyridine; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3,5-difluorobenzyl)oxazolo[5,4-c]pyridine; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-fluoro-5-methoxybenzyl)oxazolo[5,4-c]pyridine; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-7-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[4,5-c]pyridine; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-7-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[4,5-b]pyridine; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)thiazolo[5,4-c]pyridine; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[4,5-c]pyridine; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1-methyl-7-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-benzo[d]imidazole; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-7-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)benzo[d]oxazole; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-(methyl-d3)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-(2-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-(3-methoxy-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)oxazolo[5,4-c]pyridine; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1,4-dimethyl-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine; 4-(4-(4-Chloro-1-methyl-1H-imidazol-2-yl)benzyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)oxazolo[5,4-c]pyridine; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)benzyl)oxazolo[5,4-c]pyridine; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-(trifluoromethyl)-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-3-yl)benzyl)oxazolo[5,4-c]pyridine; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine; 4-(4-(1-(Azetidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)oxazolo[5,4-c]pyridine; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-(Oxetidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine; 2-(4-Chloro-1-isopropyl-1H-pyrazol-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine; 2-(1-Isopropyl-4-methyl-1H-pyrazol-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine; 2-(1-Isopropyl-1H-pyrazol-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine; 2-(4-Cyclopropyl-6-(methoxy-d3)pyrimidin-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine; 2-(4,6-Dimethoxypyrimidin-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine; 2-(4-Isopropylpyrimidin-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine; 2-(4-Methoxy-6-methylpyrimidin-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine; 9-((2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)oxazolo[5,4-c]pyridin-4-yl)methyl)-2-(trifluoromethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine; 8-((2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)oxazolo[5,4-c]pyridin-4-yl)methyl)-2-(trifluoromethyl)-5H-benzo[e]imidazo[1,2-c][1,3]oxazine; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazin-9-yl)methyl)oxazolo[5,4-c]pyridine; 9-((2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)oxazolo[5,4-c]pyridin-4-yl)methyl)-2-(trifluoromethyl)-5H,7H-benzo[e]imidazo[1,2-c][1,3]oxazepine; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[e]imidazo[1,2-c][1,3]diazepin-9-yl)methyl)oxazolo[5,4-c]pyridine; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-((6-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3-yl)methyl)oxazolo[5,4-c]pyridine; 1-(4-((2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl))oxazolo[5,4-c]pyridin-4-yl)methyl)phenyl)-5-methyl-1H-pyrazole-3-carbonitrile; 6-Cyclopropyl-5-(4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridin-2-yl)pyrimidine-4-carbonitrile; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-(prop-2-yn-1-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)oxazolo[5,4-c]pyridine; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(7-methyl-1-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)benzyl)oxazolo[5,4-c]pyridine; 4-(4-(1-Chloro-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)benzyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)oxazolo[5,4-c]pyridine; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-fluoro-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)benzyl)oxazolo[5,4-c]pyridine; 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)benzyl)oxazolyl[5,4-c]pyridine 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(4-fluoro-1-methyl-1H-imidazol-2-yl)benzyl)oxazolo[5,4-c]pyridine; 2-(4-((2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl))oxazolo[5,4-c]pyridin-4-yl)methyl)phenyl)-1-methyl-1H-imidazole-4-carbonitrile; or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound or pharmaceutically acceptable salt thereof, or a mixture thereof.

10. Use of a compound according to any one of claims 1 to 9, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound, pharmaceutically acceptable salt or mixture thereof, in the manufacture of a medicament for the treatment or prevention of a disease associated with USP1 modulation; preferably, the disease is cancer; Preferably, the cancer is liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myelogenous leukemia, primary brain cancer, malignant melanoma, non-small cell lung cancer, small cell lung cancer, gastric cancer, colon cancer, malignant pancreatic islet cell tumor, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute myelocytic leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, urogenital system neoplasms, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, essential thrombocythemia, adrenocortical carcinoma, skin cancer and prostate cancer; Preferably, the drug further comprises at least one known anti-cancer drug or a pharmaceutically acceptable salt of the anti-cancer drug;Preferably, the anti-cancer drug is selected from one or more of the following groups: vorinostat, romidepsin, panobinostat, belinostat, palbociclib, busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, methyl hydroxy ellipticine, mintonite, 5-azacytidine, gemcitabine, 5-fluorouracil, methotrexate, 5-fluoro-2'-deoxyuridine, fludarabine, nelarabine, cytarabine, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, monoclonal antibodies, panitumumab, necitumumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab, tositumomab, brentuximab vedotin, daratumumab, elotuzumab, Ofatumumab, Dinutuximab, Blinatumomab, ipilimumab, avastin, herceptin, rituxan, trastuzumab emtansine (T-DM1), trastuzumab deruxtecan, datopotamab deruxtecan, gemtuzumab ozogamicin, CD30-directed antibody-drug conjugate brentuximab vedotin, inotuzumab ozogamicin, sacituzumab govitecan, enfortumab vedotin, belantamab mafodotin, imatinib, gefitinib, erlotinib, osimertinib, afatinib, ceritinib, alectinib, crizitinib, erlotinib, lapatinib, sorafenib, regorafenib, vemurafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, pralsetinib, ibrutinib, cabozantinib, lenvatinib, vandetanib, trametinib, cobimetinib, axitinib, temsirolimus, idelalisib, pazopanib, tucotuzumab celmoleukin, everolimus, tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenic trioxide, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide, Venetoclax, Aldesleukin (recombinant human interleukin-2), and Sipuleucel-T (prostate cancer therapeutic vaccine); Preferably, the drug is used in combination with radiotherapy.

11. A pharmaceutical composition comprising the compound or its stereoisomer, tautomer, N-oxide, hydrate, solvate, isotope-labeled compound, pharmaceutically acceptable salt or a mixture thereof according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier; preferably, the composition further contains at least one known anti-cancer drug, or a pharmaceutically acceptable salt of the anti-cancer drug; preferably, the at least one known anti-cancer drug is selected from the group consisting of: vorinostat, romidepsin, panobinostat, belinostat, palbociclib, busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, methyl hydroxyellipticine, mintonite, 5-azacytidine, gemcitabine, 5-fluorouracil, methotrexate, 5-fluoro-2'-deoxyuridine, fludarabine, nelarabine, cytarabine, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, monoclonal antibodies, panitumumab, necitumumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab, tositumomab, brentuximab vedotin, daratumumab, elotuzumab, T-DM1, Ofatumumab, Dinutuximab, Blinatumomab, ipilimumab, avastin, herceptin, rituxan, imatinib, gefitinib, erlotinib, osimertinib, afatinib, ceritinib, alectinib, crizotinib, erlotinib, lapatinib, sorafenib, regorafenib, vemurafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, pralsetinib, ibrutinib, cabozantinib, lenvatinib, vandetanib, trametinib, cobimetinib, axitinib, temsirolimus, Idelalisib, sunitinib, nilotinib, dasatinib, pazopanib, tecadenoson, everolimus, tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenic trioxide, zoledronic acid, bortezomib, carfilzomib, Ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide, Venetoclax, Aldesleukin (recombinant human interleukin-2), Sipueucel-T (prostate cancer treatment vaccine), olaparib, niraparib, rucaparib, talazoparib and senaparib.

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