Substituted triazoloheteroaryl compounds as USP1 inhibitors and their applications

Abstract

The present invention provides substituted triazoloheteroaryl compounds represented by formula I as USP1 inhibitors and their uses, wherein A1, A2, B1, B2, B3, B4, B5, D1, D2, D3, D4, L, Cy1 and Cy2 are defined herein. Therefore, the compounds of formula I of the present invention can be used to prevent or treat diseases, disorders and conditions related to USP1 regulation, such as cancer.

Description

Technical Field

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

[0002] Ubiquitin is a polypeptide composed of 76 amino acids. It marks, degrades and regulates the activity of proteins in cells by covalently binding to proteins. The process of ubiquitination leading to degradation of target proteins includes a series of complex steps, including multiple ubiquitinases (E1-E3). Studies have shown that ubiquitination of intracellular proteins is a widespread protein function regulation mechanism, and thousands of proteins can be ubiquitinated. At the same time, protein ubiquitination is a reversible regulatory mechanism, and the degree of ubiquitination of intracellular proteins 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, intracellular protein ubiquitination is a widespread dynamic regulatory mechanism. Protein ubiquitination is closely related to many important functions of cells, including gene expression, cell cycle progression, apoptosis, DNA repair and cell movement (Garcia-Sanstisteban (2013) Mold Cancer 12:91-103).

[0003] Ubiquitination of proteins plays an important role in regulating important physiological functions such as cell cycle and DNA damage repair. Studies have found that in addition to regulating protein degradation, protein ubiquitination also regulates the activity of proteins in DNA repair (Huang and D'Andrea (2006) Mol Cell Biol. 7: 323-34). Targeting the DNA damage repair pathway is an important area in tumor treatment, so ubiquitination and deubiquitinating enzymes that regulate DNA damage repair function have become possible new targets for tumor treatment.

[0004] There are about 100 different human deubiquitinating proteases (Garcia-Sanstisteban (2013) Mold 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 that has certain regulatory functions at multiple levels in the DNA damage repair mechanism, including the Fanconi Anemia (FA) pathway and the Translesion Synthesis (TLS) pathway. USP1 regulates Fanconi Anemia-BRCA (FA-BRCA)-dominated DNA repair by catalyzing the deubiquitination of FA proteins such as monoubiquitinated FANCD2 (Nijman et al. (2005) Mol Cell 17:331-39). Loss of USP1 function leads to increased levels of monoubiquitinated FANCD2, inhibiting the FA-BRCA-mediated DNA damage repair pathway, resulting in high sensitivity of cells to DNA cross-linking agents such as mitomycin C and cisplatin. Another deubiquitinated 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 cross-linking 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 serve as sensitizers for radiotherapy and chemotherapy. At the same time, USP1 inhibitors may also be used in combination with other targeted drugs related to DDR to treat cancer through synthetic lethality mechanisms, such as in combination with PARP inhibitors.

[0006] Thomas S. et al. found through screening that ML323 and related N-benzyl-2-phenylpyrimidine-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 was IC50 There was a strong correlation between the values ​​and the activity against non-small cell lung cancer cells, namely increasing the level of monoubiquitinated PCNA (Ub-PCNA) and reducing the survival rate of cancer cells. These data show the feasibility of the USP1 / UAF1 deubiquitinase complex as a drug target and its potential for developing USP1 inhibitors as anticancer targeted therapeutics.

[0007] A variety of USP1 inhibitors have been disclosed, such as WO2014105952; WO2016034675; US20170145012; WO2020139988; WO2020132269; WO2021163530 and WO2022174184A1. Summary of the invention

[0008] The present invention provides substituted triazoloheteroaryl compounds having a structure as shown in Formula I (including Formula IIa / b and Formula IIIa / b), and such compounds can be used as USP1 inhibitors.

[0009] The present invention also provides a pharmaceutical composition comprising an effective amount of a compound of formula I (including formula IIa / b and formula IIIa / b) for treating cancer.

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

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

[0012] The present invention also relates to a method for preparing novel compounds of structural formula I (including formula IIa / b and formula IIIa / b). DETAILED DESCRIPTION

[0013] It should be understood that the features of the various embodiments described herein can be arbitrarily combined to form the technical solutions of this invention; the definition of each group herein is applicable to any embodiment described herein, for example, the definition of substituents of alkyl groups herein is applicable to any embodiment described herein, unless the embodiment has clearly defined substituents of alkyl groups.

[0014] Specifically, the present invention provides a compound represented by the following formula I or its stereoisomer, tautomer, N-oxide, hydrate, solvate, isotope-labeled compound or pharmaceutically acceptable salt, or a mixture thereof, or a prodrug thereof:

[0015]

[0016] wherein A1 and A2 are each independently selected from N or CR1;

[0017] B1 and B2 are each independently selected from N and C, and at most one of B1 and B2 is N;

[0018] B3, B4 and B5 are each independently selected from N and CR2;

[0019] D1, D2, D3 and D4 are each independently selected from N and CR3;

[0020] L is selected from alkylene optionally substituted by R4 and / or R5, NR6, O, S, SO, SO2 and C=O;

[0021] Cy1 is selected from optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl;

[0022] Cy2 is selected from optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl;

[0023] R1, R2 and R3 are each independently selected from hydrogen, halogen, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted carbocyclyl, optionally substituted alkenyl, optionally substituted alkynyl and optionally substituted amino;

[0024] R4 and R5 are each independently selected from halogen, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted carbocyclyl, optionally substituted alkenyl and optionally substituted alkynyl; or R4 and R5 form a ring with the atom of C to which they are attached;

[0025] R6 is selected from hydrogen and optionally substituted alkyl.

[0026] Preferably, the optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl and optionally substituted alkynyl involved in each group of formula I may be optionally substituted by 1-5 selected from halogen, hydroxyl, NR a R b , C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, carboxyl and cyano are substituted, wherein the R a and R b Each is independently H or C 1-4 More preferably, the group may be optionally substituted by 1 to 5 groups selected from halogen, hydroxyl and NR a R b Substituents are substituted, wherein the R a and R b Each is independently H or C 1-4 alkyl.

[0027] Preferably, the optionally substituted carbocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group and optionally substituted heterocyclic group involved in each group of formula I can be optionally substituted by 1-5 groups selected from halogen, hydroxyl, NR a R b , C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, carboxyl and cyano are substituted, wherein the R a and R b Each is independently H or C 1-4 More preferably, the optionally substituted carbocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group and optionally substituted heterocyclic group may be optionally substituted by 1-5 groups selected from halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, hydroxyl and NR a R b Substituents are substituted, wherein the R a and R b Each is independently H or C 1-4 Preferably, the carbocyclic group is C 3-8 Preferably, the aryl group is C 6-14 Preferably, the heteroaryl group is C 5-10 Heteroaryl, more preferably a heteroaryl containing 1 to 3 nitrogen atoms in the ring. Preferably, the heterocyclic group is C 4-10 The heterocyclic group preferably contains 1 to 3 heteroatoms selected from O, N and S.

[0028] In one or more embodiments of the compound of formula I, A1 and A2 are both N.

[0029] In one or more of the foregoing embodiments of the compound of formula I, at most one of B1 and B2 is N; preferably, B1 is N and B2 is C; or B1 is C and B2 is N.

[0030] In one or more of the foregoing embodiments of the compounds of Formula I, B3, B4 and B5 are each independently selected from N and CR2, wherein R2 is H, halogen, C 1-4 Alkyl or C 1-4 Preferably, B3, B4 and B5 are each independently N or CH. In some embodiments, B3, B4 and B5 are all CR2, wherein R2 is H, halogen or C 1-4In some embodiments, B3 is N, B4 and B5 are CR2, wherein R2 is H, halogen or C 1-4 In some embodiments, B4 is N, B3 and B5 are CR2, wherein each R2 is independently H, halogen or C 1-4 In some embodiments, B5 is N, B3 and B4 are both CR2, wherein each R2 is independently H, halogen or C 1-4 Alkyl, preferably, each R2 is H.

[0031] In one or more of the foregoing embodiments of the compounds of Formula I, the fused heteroaromatic bicyclic ring containing A1, A2, B1, B2, B3, B4 and B5 is selected from the following groups:

[0032]

[0033] Preferably:

[0034]

[0035] Wherein, *1 and *2 represent the connection positions of the group with the compound Cy1 and L, respectively.

[0036] In one or more of the foregoing embodiments of the compounds of Formula I, L is alkylene, NH, NC 1-3 alkyl or O; preferably, L is C 1-3 Alkylene, more preferably methylene or -CH(CH3)- group.

[0037] In one or more of the foregoing embodiments of the compound of formula I, D1, D2, D3 and D4 are all CR3. Preferably, R3 is 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 1-4 Alkoxy; preferably, the alkyl or alkoxy is optionally substituted by 1-5 groups selected from halogen, hydroxyl and NR a R b wherein R a and R b Independently H or C 1-4 In some preferred embodiments, D1 and D4 are CH, D2 and D3 are CR3, wherein each R3 is hydrogen, halogen or C 1-4 Alkoxy; preferably, in some embodiments, at least one R3 is a non-hydrogen substituent, such as halogen or C 1-4Alkoxy. In some preferred embodiments, D1, D2, D3 and D4 are all CH. In some embodiments, D1, D2, D3 and D4 are each independently N or CH. In some preferred embodiments, at most 2 of D1, D2, D3 and D4 are N. In some preferred embodiments, D1, D2, D3 and D4 have and only 2 are N. Preferably, the aryl or heteroaryl containing D1, D2, D3 and D4 is an optionally substituted phenyl, an optionally substituted pyridyl, an optionally substituted pyrimidyl or an optionally substituted pyrazinyl; preferably, when the aryl or heteroaryl is substituted, the substituent may be selected from the group described in R3, including but not limited to halogen or optionally substituted by 1-5 selected from halogen, hydroxyl and -NR a R b The group substituted C 1-4 Alkyl or C 1-4 Alkoxy, wherein R a and R b Independently H or C 1-4 alkyl.

[0038] In one or more of the foregoing embodiments of the compound of Formula I, Cy1 is an optionally substituted C 3-8 Cycloalkyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 6-14 membered aryl or optionally substituted 5-10 membered heteroaryl. In a further preferred embodiment, the 5-10 membered heteroaryl is a nitrogen-containing monocyclic heteroaryl. Preferably, Cy1 is optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted tetrahydrofuranyl, optionally substituted pyrrolidinyl or optionally substituted pyrazolyl. Preferably, when Cy1 is substituted, its substituent is selected from halogen, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Alkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted amino and cyano; preferably, the C 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 The cycloalkyl group is optionally substituted by 1-5 groups selected from halogen, hydroxy, C 1-4 Alkyl, and -NR a R b wherein R a and R b Independently H or C 1-4 Alkyl, the amino group is optionally replaced by 1 or 2 C 1-4 Alkyl Substitution

[0039] In one or more of the foregoing embodiments of the compound of Formula I, Cy2 is an optionally substituted 6-14 membered aryl, an optionally substituted 5-10 membered heteroaryl, an optionally substituted C 3-8 Cycloalkyl or an optionally substituted 4-10 membered heterocyclyl. Preferably, Cy2 is an optionally substituted heteroaryl, preferably an optionally substituted 5-10 membered nitrogen-containing heteroaryl, more preferably a 5-membered nitrogen-containing heteroaryl. In some preferred embodiments, Cy2 is an optionally substituted imidazolyl or an optionally substituted pyrazolyl. Preferably, when Cy2 is substituted, its substituents may be 1-5 selected from halogen, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Alkoxy and optionally substituted C 3-6 Preferably, Cy2 is a C 1-4 an alkyl-substituted imidazolyl group or an optionally substituted C 1-4 Preferably, the C 1-4 Alkyl and C 1-4 Each alkoxy group is optionally substituted by 1 to 5 groups selected from halogen, hydroxy and -NR a R b wherein R a and R b Independently H or C 1-4 In some further preferred embodiments, Cy2 is replaced by 1-3 groups selected from C 1-4 Alkyl, C 3-6 Cycloalkyl and halogenated C 1-4 In some further preferred embodiments, Cy2 is substituted by 1-3 substituents selected from C 1-4 Alkyl and halogenated C 1-4 In some embodiments, Cy2 is replaced by C 1-4 Alkyl and halogenated C 1-4 In some embodiments, Cy2 is substituted with two substituents selected from C 1-4 Alkyl, C 3-6 Cycloalkyl and halogenated C 1-4 An imidazolyl group substituted with an alkyl substituent wherein one of the nitrogen atoms is replaced by a C 1-4 Alkyl substitution.

[0040] In one or more of the foregoing embodiments of the compound of Formula I, R4 and R5 are each independently selected from halogen and halogenated C 1-4 In some embodiments, R4 and R5 form a 3-5 membered cycloalkyl with the attached C atom.

[0041] In one or more of the foregoing embodiments of the compounds of Formula I, R6 is hydrogen or C 1-3 alkyl.

[0042] The present invention provides compounds represented by Formula IIa and IIb or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-labeled compounds or pharmaceutically acceptable salts thereof, or mixtures thereof, or prodrugs thereof:

[0043]

[0044] wherein A1, A2, B3, B4, B5, D1, D2, D3, D4, Cy1 and Cy2 are as defined in any one of the embodiments of Formula I.

[0045] In one or more embodiments of the compounds of Formula IIa and IIb, A1 and A2 are both N.

[0046] In one or more embodiments of the compounds of Formula IIa and IIb, B3, B4 and B5 are each independently selected from N and CR2, wherein R2 is H, halogen, C 1-4 Alkyl or C 1-4 Preferably, B3, B4 and B5 are each independently N or CH. In some embodiments, B3, B4 and B5 are all CR2, wherein R2 is H, halogen or C 1-4 In some embodiments, B3 is N, B4 and B5 are CR2, wherein R2 is independently H, halogen or C 1-4 In some embodiments, B4 is N, B3 and B5 are both CR2, wherein each R2 is independently H, halogen or C 1-4 In some embodiments, B5 is N, B3 and B4 are both CR2, wherein R2 is each independently H, halogen or C 1-4 Alkyl, preferably, each R2 is H.

[0047] In one or more of the foregoing embodiments of the compounds of Formula IIa and IIb, the fused heteroaromatic bicyclic ring containing A1, A2, B3, B4 and B5 is selected from the following groups:

[0048]

[0049] Preferably:

[0050]

[0051] Wherein, *1 and *2 represent the connection positions of the group with the compound Cy1 and L, respectively.

[0052] In one or more of the foregoing embodiments of the compounds of formula IIa and IIb, D1, D2, D3 and D4 are all CR3. Preferably, R3 is selected from hydrogen, halogen, optionally substituted alkyl and optionally substituted alkoxy, wherein the optionally substituted alkyl and optionally substituted alkoxy are each preferably an optionally substituted C 1-4 Alkyl and optionally substituted C 1-4 Alkoxy; preferably, the alkyl or the alkoxy is optionally substituted by 1-5 groups selected from halogen, hydroxyl and -NR a R b wherein R a and R b Each is independently H or C 1-4 In some preferred embodiments, D1 and D4 are CH. D2 and D3 are CR3, wherein each R3 is hydrogen, halogen or C 1-4 Alkoxy; preferably, in some embodiments, at least one R3 is a non-hydrogen substituent, such as halogen or C 1-4 Alkoxy. In some preferred embodiments, D1, D2, D3 and D4 are all CH. In some embodiments, D1, D2, D3 and D4 are each independently N or CH. In some preferred embodiments, at most 2 of D1, D2, D3 and D4 are N. In some preferred embodiments, D1, D2, D3 and D4 have and only 2 are N. Preferably, the aryl or heteroaryl containing D1, D2, D3 and D4 is preferably an optionally substituted phenyl, pyridyl, pyrimidinyl or pyrazinyl; preferably, when the aryl or heteroaryl is substituted, the substituent can be selected from the group described in R3, including but not limited to halogen or optionally substituted by 1-5 selected from halogen, hydroxyl and -NR a R b The group substituted C 1-4 Alkyl or C 1-4 Alkoxy, wherein R a and R b Each is independently H or C 1-4 alkyl.

[0053] In one or more of the foregoing embodiments of the compounds of Formula IIa and IIb, Cy1 is an optionally substituted C 3-8Cycloalkyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 6-14 membered aryl or optionally substituted 5-10 membered heteroaryl. In a further preferred embodiment, the 5-10 membered heteroaryl is a nitrogen-containing monocyclic heteroaryl. Preferably, Cy1 is optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted tetrahydrofuranyl, optionally substituted pyrrolidinyl or optionally substituted pyrazolyl. More preferably, Cy1 is optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl or optionally substituted pyrazolyl. Preferably, when Cy1 is substituted, its substituent is selected from halogen, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Alkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted amino and cyano; preferably, the C 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 The cycloalkyl group is optionally substituted by 1-5 groups selected from halogen, hydroxy, C 1-4 Alkyl and -NR a R b The group substituted, the R a and R b Each is independently H or C 1-4 Alkyl, the amino group is optionally replaced by 1 or 2 C 1-4 Alkyl substitution.

[0054] In one or more of the foregoing embodiments of the compounds of Formula IIa and IIb, Cy2 is an optionally substituted 6-14 membered aryl, an optionally substituted 5-10 membered heteroaryl, an optionally substituted C 3-8 Cycloalkyl or an optionally substituted 4-10 membered heterocyclyl. Preferably, Cy2 is an optionally substituted heteroaryl, preferably an optionally substituted nitrogen-containing 5-10 membered heteroaryl, more preferably a nitrogen-containing 5-membered heteroaryl. In some preferred embodiments, Cy2 is an optionally substituted imidazolyl or an optionally substituted pyrazolyl. Preferably, when Cy2 is substituted, the number of substituents may be 1-5, and the substituents may be selected from halogen, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Alkoxy and optionally substituted C 3-6 Preferably, Cy2 is a C 1-4 an alkyl-substituted imidazolyl group or an optionally substituted C 1-4 Preferably, each of the C 1-4 Alkyl and C 1-4 The alkoxy group is optionally substituted by 1 to 5 groups selected from halogen, hydroxy and -NR a Rb wherein R a and R b Each is independently H or C 1-4 In some further preferred embodiments, Cy2 is replaced by 1-3 groups selected from C 1-4 Alkyl, C 3-6 Cycloalkyl and halogenated C 1-4 In some further preferred embodiments, Cy2 is substituted by 1-3 substituents selected from C 1-4 Alkyl and halogenated C 1-4 In some embodiments, Cy2 is replaced by C 1-4 Alkyl and halogenated C 1-4 In some embodiments, Cy2 is an imidazolyl group substituted with two substituents selected from C 1-4 Alkyl, C 3-6 Cycloalkyl and halogenated C 1-4 Alkyl, one of the nitrogen atoms is replaced by a C 1-4 Alkyl substitution.

[0055] In one or more of the foregoing embodiments of the compounds of Formula IIa and IIb: Cy1 is optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl or optionally substituted pyrazolyl, preferably, Cy1 is optionally substituted phenyl or optionally substituted pyrimidinyl, preferably, when Cy1 is substituted, the number of substituents is 1-5, preferably 1-3, and the substituents are selected from halogen, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Alkoxy and optionally substituted C 3-6 Cycloalkyl, preferably C 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 Cycloalkyl; the fused heteroaromatic bicyclic ring containing A1, A2, B3, B4 and B5 is selected from the following groups:

[0056]

[0057] Wherein, *1 and *2 represent the connection position of the group with the compound Cy1 and the methylene group respectively; the aryl or heteroaryl containing D1, D2, D3 and D4 is optionally substituted by 1-2 halogen, C 1-4 Alkyl and C 1-4 Cy2 is optionally substituted with 1-3 groups selected from C 1-4 Alkyl, halogenated C 1-4 Alkyl and C 3-6The substituents of the cycloalkyl group are imidazolyl or pyrazolyl substituted, preferably, Cy2 is imidazolyl substituted by two substituents, the substituents are selected from C 1-4 Alkyl, C 3-6 Cycloalkyl and halogenated C 1-4 Alkyl, one of the nitrogen atoms is replaced by a C 1-4 Alkyl substitution.

[0058] One group of preferred compounds of the present invention is represented by compounds of formula IIIa and IIIb or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotopically labeled compounds or pharmaceutically acceptable salts thereof, or mixtures thereof, or prodrugs thereof:

[0059]

[0060] Wherein, B3, B4, B5, Cy1 and Cy2 are as defined by Formula I or Formula II.

[0061] In one or more of the foregoing embodiments of compounds of Formula IIIa and IIIb, B3, B4 and B5 are each independently selected from N and CR2, wherein R2 is H, halogen, C 1-4 Alkyl or C 1-4 Preferably, B3, B4 and B5 are each independently N or CH. In some embodiments, B3, B4 and B5 are all CR2, wherein R2 is H, halogen or C 1-4 In some embodiments, B3 is N, B4 and B5 are CR2, wherein R2 is H, halogen or C 1-4 In some embodiments, B4 is N, B3 and B5 are both CR2, wherein R2 is each independently H, halogen or C 1-4 In some embodiments, B5 is N, B3 and B4 are both CR2, wherein each R2 is independently H, halogen or C 1-4 Alkyl, preferably, each R2 is H.

[0062] In one or more of the foregoing embodiments of the compounds of formula IIIa and IIIb, the fused heteroaromatic bicyclic ring containing B3, B4 and B5 is selected from the following groups:

[0063]

[0064] Wherein, *1 and *2 represent the connection positions of the group to compound Cy1 and the rest of the compound, respectively.

[0065] In one or more of the foregoing embodiments of the compounds of Formula IIIa and IIIb, Cy1 is an optionally substituted C 3-8Cycloalkyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 6-14 membered aryl or optionally substituted 5-10 membered heteroaryl. In some further preferred embodiments, the 5-10 membered heteroaryl is a nitrogen-containing monocyclic heteroaryl. Preferably, Cy1 is optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted tetrahydrofuranyl, optionally substituted pyrrolidinyl or optionally substituted pyrazolyl. Preferably, when Cy1 is substituted, its substituent is selected from halogen, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Alkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted amino and cyano; preferably, each of the C 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 The cycloalkyl group is optionally substituted by 1 to 5 groups selected from halogen, hydroxy and -NR a R b Substituted C 1-4 Alkyl groups substituted, wherein R a and R b Each is independently H or C 1-4 Alkyl, the amino group is optionally replaced by 1 or 2 C 1-4 Alkyl substitution.

[0066] In one or more of the foregoing embodiments of the compounds of Formula IIIa and IIIb, Cy2 is an optionally substituted 6-14 membered aryl, an optionally substituted 5-10 membered heteroaryl, an optionally substituted C 3-8 Cycloalkyl or an optionally substituted 4-10 membered heterocyclyl. Preferably, Cy2 is an optionally substituted heteroaryl, preferably an optionally substituted nitrogen-containing 5-10 membered heteroaryl, more preferably a 5-membered nitrogen-containing heteroaryl. In some preferred embodiments, Cy2 is an optionally substituted imidazolyl or an optionally substituted pyrazolyl. Preferably, when Cy2 is substituted, the number of substituents may be 1-5, and the substituents may be selected from halogen, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Alkoxy and optionally substituted C 3-6 Preferably, Cy2 is a C 1-4 an alkyl-substituted imidazolyl group or an optionally substituted C 1-4 Preferably, the C 1-4 Alkyl and C 1-4 The alkoxy group is optionally substituted by 1 to 5 groups selected from halogen, hydroxy and -NR a R b The group substituted, the R a and R bEach is independently H or C 1-4 In some further preferred embodiments, Cy2 is replaced by 1-3 groups selected from C 1-4 Alkyl, C 3-6 Cycloalkyl and halogenated C 1-4 In some further preferred embodiments, Cy2 is substituted by 1-3 substituents selected from C 1-4 Alkyl and halogenated C 1-4 In some embodiments, Cy2 is replaced by a C 1-4 Alkyl and halogenated C 1-4 In some embodiments, Cy2 is an imidazolyl group substituted with two substituents selected from C 1-4 Alkyl, C 3-6 Cycloalkyl and halogenated C 1-4 Alkyl, one of the nitrogen atoms is replaced by a C 1-4 Alkyl substitution.

[0067] In one or more of the foregoing embodiments of the compounds of formula IIIa and IIIb: Cy1 is optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl or optionally substituted pyrazolyl, preferably optionally substituted phenyl or optionally substituted pyrimidinyl, wherein when Cy1 is substituted, the number of substituents is 1-5, preferably 1-3, and the substituents are selected from halogen, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Alkoxy and optionally substituted C 3-6 Cycloalkyl, preferably C 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 Cycloalkyl; the fused heteroaromatic bicyclic ring containing B3, B4 and B5 is selected from the following groups:

[0068]

[0069] Wherein, *1 and *2 represent the connection position of the group with the compound Cy1 and the methylene group respectively; the aryl or heteroaryl containing D1, D2, D3 and D4 is optionally substituted by 1-2 halogen, C 1-4 Alkyl and C 1-4 Cy2 is optionally substituted with 1-3 groups selected from C 1-4 Alkyl, halogenated C 1-4 Alkyl and C 3-6 The substituents of the cycloalkyl group are imidazolyl or pyrazolyl substituted, preferably Cy2 is imidazolyl substituted with two substituents, the substituents are selected from C 1-4 Alkyl, C 3-6 Cycloalkyl and halogenated C 1-4Alkyl, one of the nitrogen atoms is replaced by a C 1-4 Alkyl substitution.

[0070] In one or more of the foregoing embodiments, preferred examples of compounds of Formula I (including Formula IIa and IIb and Formula IIIa and IIIb) include but are not limited to:

[0071] 8-(4-(1,4-dimethyl-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-[1,2,4]triazolo[1,5-a]pyridine (Example 1);

[0072] 8-(4-(1,4-dimethyl-1H-imidazol-2-yl)benzyl)-2-(2-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine (Example 2);

[0073] 2-(2-isopropylphenyl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine (Example 3);

[0074] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine (Example 4);

[0075] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine (Example 5);

[0076] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine (Example 6);

[0077] 2-(2-isopropylphenyl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazine (Example 7);

[0078] 2-(2-isopropylphenyl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-c]pyrimidine (Example 8);

[0079] 2-(2-isopropylphenyl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-b]pyridazine (Example 9);

[0080] 2-(2-isopropylphenyl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine (Example 10);

[0081] 2-(2-isopropylphenyl)-7-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrimidine (Example 11);

[0082] 2-(2-isopropylphenyl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazine (Example 12);

[0083] 2-(2-isopropylphenyl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-c]pyrimidine (Example 13);

[0084] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine (Example 14);

[0085] 2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine (Example 15);

[0086] 2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine (Example 16);

[0087] 2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-b]pyridazine (Example 17);

[0088] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazine (Example 18);

[0089] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-c]pyrimidine (Example 19);

[0090] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-b]pyridazine (Example 20);

[0091] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-c]pyrimidine (Example 21);

[0092] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazine (Example 22);

[0093] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrimidine (Example 23);

[0094] 8-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-a]pyridine (Example 24);

[0095] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine (Example 25);

[0096] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-fluoro-5-methoxybenzyl)-[1,2,4]triazolo[1,5-a]pyridine (Example 26);

[0097] 2-(4,6-dimethoxypyrimidin-5-yl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine (Example 27);

[0098] 2-(4-cyclobutyl-6-methoxypyrimidin-5-yl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine (Example 28);

[0099] 8-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-a]pyrazine (Example 29);

[0100] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazine (Example 30);

[0101] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3,5-difluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazine (Example 31);

[0102] 8-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-c]pyrimidine (Example 32);

[0103] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-c]pyrimidine (Example 33);

[0104] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3,5-difluorobenzyl)-[1,2,4]triazolo[1,5-c]pyrimidine (Example 34);

[0105] 2-(4-cyclopropyl-6-cyanopyrimidin-5-yl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine (Example 35);

[0106] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-[1,2,4]triazolo[1,5-a]pyridine (Example 36);

[0107] 5-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-a]pyridine (Example 37);

[0108] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine (Example 38);

[0109] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-fluoro-5-methoxybenzyl)-[1,2,4]triazolo[1,5-a]pyridine (Example 39);

[0110] 5-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-c]pyrimidine (Example 40);

[0111] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-c]pyrimidine (Example 41);

[0112] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3,5-difluorobenzyl)-[1,2,4]triazolo[1,5-c]pyrimidine (Example 42);

[0113] 5-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-a]pyrazine (Example 43);

[0114] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazine (Example 44);

[0115] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3,5-difluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazine (Example 45);

[0116] 2-(4-cyclopropyl-6-cyanopyrimidin-5-yl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine (Example 46);

[0117] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-[1,2,4]triazolo[1,5-a]pyridine (Example 47);

[0118] or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotope-labeled compound or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof.

[0119] As used herein, "hydrogen (H)" includes its isotopes deuterium (D) and tritium (T).

[0120] As used herein, "alkyl" refers to an alkyl group itself or a straight or branched chain group of up to ten carbon atoms. Useful alkyl groups include straight or branched chain C 1-10 Alkyl, preferably C 1-6 In certain embodiments, the alkyl group is C 1-4 In some embodiments, the alkyl group is C 1-3 In some embodiments, the alkyl group is a deuterated C 1-3 Alkyl. Typical C 1-10 The alkyl group includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl and octyl groups which may be optionally substituted.

[0121] As used herein, "alkenyl" refers to a straight or branched chain containing 2 to 10 carbon atoms, unless the carbon chain length is otherwise limited, wherein at least two carbon atoms in the chain contain a double bond; preferably C 2-6 Typical alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl.

[0122] As used herein, "alkynyl" refers to a straight or branched chain containing 2 to 10 carbon atoms, unless the carbon chain length is otherwise limited, wherein at least two carbon atoms in the chain contain a triple bond; preferably C 2-6Typical alkynyl groups include ethynyl, 1-propynyl, 1-methyl-2-propynyl, 2-propynyl, 1-butynyl and 2-butynyl.

[0123] Useful alkoxy groups include those represented by the above C 1-10 Alkyl, preferably C 1-6 Alkyl or C 1-4 Alkyl substituted oxy, such as methoxy, ethoxy, etc. The alkyl in the alkoxy group may be optionally substituted. The substituent of the alkoxy group includes, but is not limited to, halogen, morpholinyl, amino, including alkylamino and dialkylamino, and carboxyl (including ester groups thereof).

[0124] Herein, amino is represented by -NH2. The amino group may be optionally substituted, and the substituted amino group may be represented by -NHR' and -NR'R", wherein R' and R" are each independently hydrogen, optionally substituted C 1-10 Alkyl (preferably C 1-4 In some embodiments, in the substituted amino groups described herein, the R' and R" together with the N to which they are attached form an optionally substituted 4- to 7-membered cyclic amino group, which optionally contains one or more (e.g., 2 or 3) additional heteroatoms selected from O, N, and S.

[0125] As used herein, "aryl" refers to an aromatic group, either by itself or as part of another group, containing 6 to 14 carbon atoms, a monocyclic, bicyclic or tricyclic aromatic group. The aryl group may be substituted with one or more substituents described herein.

[0126] Useful aromatic groups include C 6-14 Aryl, preferably C 6-10 Aryl. Typical C 6-14 Aryl groups include phenyl, naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylene and fluorenyl.

[0127] As used herein, "carbocycle" 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 group may be substituted with one or more substituents as described herein.

[0128] Useful partially saturated carbocyclic groups include cycloalkenyl groups such as C 3-8 Cycloalkenyl groups, such as cyclopentenyl, cycloheptenyl and cyclooctenyl.

[0129] Useful halogens or halogen groups include fluorine, chlorine, bromine and iodine.

[0130] As used herein, heterocycle (heterocyclic group) refers to a saturated or partially saturated 3-7-membered monocyclic ring, or a 7-10-membered bicyclic ring system, which is composed of carbon atoms and 1-4 heteroatoms selected from O, N, and S, wherein the heteroatoms nitrogen and sulfur can be oxidized at will, and the nitrogen can be quaternized at will, and includes the fusion of any heterocycle defined above with a benzene ring in the bicyclic ring system. If the resulting compound is stable, the carbon atoms or nitrogen atoms of the heterocycle can be substituted. The heterocyclic group can be substituted with one or more substituents described herein. The above-mentioned heterocyclic groups herein also include 5- to 8-membered heterocycloalkyl groups, i.e., heterocyclic groups obtained by replacing one or more ring C atoms in the cycloalkyl group with heteroatoms selected from N, O, and S.

[0131] Useful saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, tetrahydropyranyl, pyranyl, piperidinyl, piperazinyl, oxetanyl, azetidinyl, 1,4-diazepanyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl, tetrahydroisoquinolinyl, tetronoyl and tetramoyl, which groups may be substituted with one or more substituents as described herein.

[0132] As used herein, "heteroaromatic ring" refers to a ring containing 5-14, preferably 5-10 ring atoms, and having 6, 10 or 14 π electrons shared in the ring system. The ring atoms are carbon atoms and 1-3 heteroatoms selected from oxygen, nitrogen and sulfur. The heteroaryl group may be substituted with one or more substituents described herein.

[0133] Useful heteroaryl groups include thiophenyl (phenylthio), benzo[d]isothiazol-3-yl, benzo[b]thiophenyl, naphtho[2,3-b]thiophenyl, thianthrenyl, furanyl, pyranyl, isobenzofuranyl, chromenyl, xanthrenyl, 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, carbazole 1,2-benzisoxazol-3-yl, benzimidazolyl, 2-oxindolyl, thiadiazolyl, 2-oxobenzimidazolyl, imidazopyridinyl, imidazopyridinyl, imidazotriazine, triazolopyrimidinyl, triazolopyridinyl, triazolopyrazinyl, triazolopyridazinyl, triazolotriazinyl, pyrazolopyrimidinyl, pyrazolotriazinyl, pyrrolopyrimidinyl, pyrrolopyridinyl, pyrrolopyrazinyl, pyrrolotriazinyl or triazolopyrazinyl. When the heteroaryl group contains a nitrogen atom in a ring, such nitrogen atom may be in the form of an N-oxide, for example, pyridinyl N-oxide, pyrazinyl N-oxide and pyrimidinyl N-oxide.

[0134] Herein, unless otherwise indicated, when substituted, the alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, heterocyclyl, aryl or heteroaryl groups described in any embodiment herein may be substituted with one or more (e.g., 1, 2, 3 or 4) substituents selected from the group consisting of 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 substituent itself may also be optionally substituted. More preferred substituents include, but are not limited to, cyano, halo 1-6 Alkyl, halogen, amino, C 1-6 Alkoxy, C 1-6 Alkyl and C 3-8 Cycloalkyl.

[0135] It should be understood that in the embodiments herein, when the substituent is cyano, cycloalkyl, heterocyclyl, aryl or heteroaryl, the number of the cyano, heterocyclyl, aryl or heteroaryl substituent is generally one.

[0136] Some of the 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 which may be separated according to methods well known to those skilled in the art.

[0137] Examples of pharmaceutically acceptable salts include inorganic and organic acid salts, such as hydrochlorides, hydrobromides, phosphates, sulfates, citrates, lactates, tartrates, maleates, fumarates, mandelates and oxalates; and inorganic and organic base salts formed with bases such as sodium hydroxy, tris(hydroxymethyl)aminomethane (TRIS, tromethamine) and N-methylglucamine.

[0138] Examples of prodrugs of the compounds of the invention include simple esters of carboxylic acid-containing compounds (e.g., by reacting with C 1-4 esters obtained by condensation of hydroxyl groups (for example, by condensation of hydroxyl groups with C 1-4 Carboxylic acid, C 3-6 esters obtained by condensation of diacids or their anhydrides, such as succinic anhydride and fumaric anhydride); imines of compounds containing amino groups (for example, by reacting with C 1-4 (J. Med. Chem. 42:3657-3667 (1999)); acetals or ketal of compounds containing alcohols (e.g., those obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether according to methods known in the art).

[0139] The compounds of the present invention can be prepared using methods known to those skilled in the art or the novel methods of the present invention. Specifically, the compounds of the present invention having formula I (including formula IIa and IIb and formula IIIa and IIIb) can be prepared using the following reaction scheme 1. 2-aminonicotinic acid methyl ester reacts with 2,4,6-trimethylbenzenesulfonate at room temperature to obtain the product 1,2-diamino-3-(methoxycarbonyl)pyridin-1-ium﹒2,4,6-trimethylbenzenesulfonate. 1,2-diamino-3-(methoxycarbonyl)pyridin-1-ium﹒2,4,6-trimethylbenzenesulfonate reacts with 2-isopropylbenzaldehyde under the catalysis of KOH to obtain the product 2-(2-isopropylphenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid methyl ester. 2-(2-isopropylphenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid methyl ester was reduced by LiAlH4 to obtain the product (2-(2-isopropylphenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-yl)methanol. (2-(2-isopropylphenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-yl)methanol was brominated with PBr3 to obtain the product 8-(bromomethyl)-2-(2-isopropylphenyl)-[1,2,4]triazolo[1,5-a]pyridine. 8-(Bromomethyl)-2-(2-isopropylphenyl)-[1,2,4]triazolo[1,5-a]pyridine and 1,4-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazole underwent Suzuki coupling under the catalysis of Pd(PPh3)2Cl2 to give the product 8-(4-(1,4-dimethyl-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-[1,2,4]triazolo[1,5-a]pyridine.

[0140] Reaction Scheme 1

[0141]

[0142] Other related compounds can be prepared by similar methods. For example, by replacing 2-isopropylbenzaldehyde with 2-methoxybenzaldehyde, the target compound 8-(4-(1,4-dimethyl-1H-imidazol-2-yl)benzyl)-2-(2-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine can be prepared. By replacing 1,4-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazole with 1-methyl-4-(trifluoromethyl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazole, the target compound 2-(2-isopropylphenyl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine can be obtained.

[0143] The compounds of the present invention can be prepared by the following reaction scheme 2. 6-Methylpyridin-2-amine reacts with ethyl isothiocyanate to obtain [[(6-methyl-2-pyridinyl)amino]thiomethyl]-carbamic acid ethyl ester. [[(6-methyl-2-pyridinyl)amino]thiomethyl]-carbamic acid ethyl ester reacts with hydroxylamine hydrochloride to obtain 5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine. 5-Methyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine reacts with NaNO2 / HCl to obtain 2-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyridine. Under the catalysis of 2,2'-azobisisobutyronitrile (AIBN), 2-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyridine reacts with NBS to give 5-(bromomethyl)-2-chloro-[1,2,4]triazolo[1,5-a]pyridine. Under the catalysis of Pd(PPh3)2Cl2, 5-(bromomethyl)-2-chloro-[1,2,4]triazolo[1,5-a]pyridine reacts with (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)boronic acid to give 2-chloro-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine. 2-Chloro-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine was reacted with (2-isopropylphenyl)boronic acid in the presence of (1-butyldi(1-adamantyl)phosphine)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (cataCXium A Pd G3) to give 2-(2-isopropylphenyl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine.

[0144] Reaction Scheme 2

[0145]

[0146] Other related compounds can be prepared by similar methods. For example, the target compound 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine can be prepared by replacing (2-isopropylphenyl)boronic acid with (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid. The target compound 2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine can be prepared by replacing (2-isopropylphenyl)boronic acid with (1-isopropyl-4-methyl-1H-pyrazol-5-yl)boronic acid.

[0147] The compound of the present invention can be prepared by the following reaction scheme 3. Under the catalysis of Pd(PPh3)4, 3-bromopyrazin-2-amine and 2-(4-(bromomethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole undergo Negishi coupling reaction to obtain 3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrazin-2-amine. 3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrazin-2-amine reacts with 2-[(aminooxy)sulfonyl]-1,3,5-trimethylbenzene to obtain 1,2-diamino-3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrazin-1-ium·2,4,6-trimethylbenzenesulfonate. Under the catalysis of Cs2CO3, 1,2-diamino-3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrazin-1-ium·2,4,6-trimethylbenzenesulfonate reacted with 4-cyclopropyl-6-methoxypyrimidine-5-carbaldehyde to obtain 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazine.

[0148] Reaction Scheme 3

[0149]

[0150] Other related compounds can be prepared by similar methods. For example, replacing 3-bromopyrazin-2-amine with 5-bromopyrimidin-4-amine can obtain the target compound 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-c]pyrimidine. Replacing 3-bromopyrazin-2-amine with 2-bromopyrimidin-4-amine can obtain the target compound 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-c]pyrimidine. The target compound 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazine can be prepared by replacing 3-bromopyrazin-2-amine with 6-bromopyrazin-2-amine. The target compound 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrimidine can be prepared by replacing 3-bromopyrazin-2-amine with 4-bromopyrimidin-2-amine.

[0151] An important aspect of the present invention is the discovery that compounds of Formula I (including compounds of Formulas IIa and IIb and IIIa and IIIb described herein) are USP1 inhibitors. Therefore, compounds of Formula I (including compounds of Formulas IIa and IIb and IIIa and IIIb described herein) can be used to treat or prevent diseases associated with USP1 regulation (also referred to herein as "USP1-mediated diseases"), such as cancer; or for the preparation of medicaments for treating or preventing diseases associated with USP1 regulation, such as cancer. Herein, diseases associated with 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.

[0152] The present invention also includes a method for treating or preventing diseases associated with USP1 regulation and a method for treating or preventing diseases caused by DDR functional defects, which comprises administering to a subject in need thereof (especially a mammal, more particularly a human) an effective amount of a compound of Formula I (including compounds of Formulas IIa and IIb and IIIa and IIIb as described herein) or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug, or a pharmaceutical composition containing an effective amount of a compound of Formula I (including compounds of Formulas IIa and IIb and IIIa and IIIb as described herein) or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof.

[0153] In the present invention, the diseases associated with USP1 regulation include cancer, especially cancer associated with USP1 regulation. Preferably, the cancer associated with USP1 regulation has DDR function defects. The diseases associated with USP1 regulation that can be treated or prevented by the method or pharmaceutical composition of the present invention include but are not limited to liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, non-small cell lung cancer, small Lung cancer, gastric cancer, colon cancer, malignant pancreatic insulinoma, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi sarcoma, genitourinary neoplasia, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, essential thrombocythemia, adrenocortical carcinoma, skin cancer and prostate cancer.

[0154] The present invention also includes the use of compounds of formula I (including compounds of formula IIa and IIb and formula IIIa and IIIb as described herein) for the treatment or prevention of 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. Therefore, the present invention also includes the use of compounds of formula I (including compounds of formula IIa and IIb and formula IIIa and IIIb as described herein) for the preparation of other diseases caused by excessive or abnormal cell proliferation, especially proliferative or hyperproliferative diseases caused by excessive or abnormal cell proliferation associated with USP1 regulation.

[0155] When implementing the treatment or prevention method of the present invention, an effective amount of a pharmaceutical preparation is administered to a patient with one or more of these symptoms. The pharmaceutical preparation contains an effective therapeutic or preventive concentration of a compound of formula I (including the compounds of formula IIa and IIb and formula IIIa and IIIb described herein), which is formulated for oral, intravenous, local or external administration, for the treatment or prevention of cancer and other diseases mediated by USP1. The dosage is an amount that effectively improves or eliminates one or more symptoms. For the treatment of a specific disease, an effective amount is an amount sufficient to improve or alleviate in some way the symptoms associated with the disease. Such an amount can be administered as a single dose, or it can be administered according to an effective treatment regimen. The dosage may cure the disease, but the administration is usually to improve the symptoms of the disease. Repeated administration is generally required to achieve the desired symptom improvement.

[0156] In another embodiment, a pharmaceutical composition is provided, which contains a compound of formula I (including compounds of formula IIa and IIb and formula IIIa and IIIb described herein) as a USP1 inhibitor, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotope-labeled compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0157] Another embodiment of the present invention relates to a pharmaceutical composition that can effectively treat cancer, wherein the compound of formula I (including the compounds of formula IIa and IIb and formula IIIa and IIIb described herein) containing a USP1 inhibitor, or its stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-labeled compounds or pharmaceutically acceptable salts, is used in combination with at least one known anticancer drug or a pharmaceutically acceptable salt of an anticancer drug. In particular, it is used in combination with other anticancer 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 the like. And in combination with other anticancer 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 the like. And combined with other targeted anti-cancer drugs, including PRMT5 inhibitors, Polθ inhibitors, RAD51 inhibitors, etc.Other known anticancer drugs that can be used for anticancer combination 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, methylhydroxyellipticine, and menthopop; 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; antimitotic agents such as colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel and docetaxel; antibodies such as monoclonal antibodies, panitumumab, nelazolizumab, nivolumab, pembrolizumab, Ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab tiuxetan, tositumomab, brentuximab, daratumumab, elotuzumab, T-DM1, ofatumumab, dinutuximab, blinatumomab, ipilimumab, Avastin, Herceptin, and rituximab; kinase inhibitors such as imatinib, gemtuzumab, Felotinib, 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, pazopanib, temozolomide, and everolimus. Other known anticancer drugs that can be used in anticancer combination therapy include tamoxifen, letrozole, fulvestrant, mitoguanidine, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegi, denosumab, thalidomide, lenalidomide, venetoclax, Aldesleukin (recombinant human interleukin-2) and Sipueucel-T (prostate cancer treatment vaccine).

[0158] In practicing the method of the present invention, the compound of the present invention and at least one known anticancer drug can be administered together as a single pharmaceutical composition. In addition, the compound of the present invention can also be administered separately from at least one known anticancer drug. In one embodiment, the compound of the present invention and at least one known anticancer drug are administered at about the same time, that is, all drugs are administered at the same time or successively, as long as the compound reaches a therapeutic concentration in the blood at the same time. In another embodiment, the compound of the present invention and at least one known anticancer drug are administered according to their respective dosage regimens, as long as the compound reaches a therapeutic concentration in the blood.

[0159] Another embodiment of the present invention is a bioconjugate composed of the compound that is effective in inhibiting tumors and is used as a USP1 inhibitor. This bioconjugate that can inhibit tumors is composed of the compound and at least one known medical antibody, such as Herceptin or Rituxan, or growth factors, such as EGF or FGF, or cytokines, such as interleukin 2 or 4, or any molecule that can bind to the cell surface. The antibody and other molecules can deliver the compound to its target, making it an effective anti-cancer drug. This bioconjugate can also enhance the anti-cancer effect of medical antibodies, such as Herceptin or Rituxan.

[0160] Another embodiment of the present invention relates to a pharmaceutical composition that can effectively inhibit tumors, comprising a USP1 inhibitor represented by Formula I (including Formula IIa and IIb and Formula IIIa and IIIb described herein), or a pharmaceutically acceptable salt thereof, in combination with radiotherapy. In this embodiment, the compound of the present invention and radiotherapy can be administered at the same time or at different times.

[0161] Another embodiment of the present invention relates to a pharmaceutical composition that can be effectively used for postoperative treatment of cancer, comprising a USP1 inhibitor represented by Formula I (including Formula IIa and IIb and Formula IIIa and IIIb described herein), or a pharmaceutically acceptable salt thereof. The present invention also relates to a method of treating cancer in a mammal by surgically removing a tumor and then using the pharmaceutical composition of the present invention to treat the cancer.

[0162] The pharmaceutical composition of the present invention includes a pharmaceutical preparation containing all the compounds of the present invention in an amount that can effectively achieve its intended purpose. Although each person's needs are different, those skilled in the art can determine the optimal dose of each part in the pharmaceutical preparation. Generally, the compound, or its pharmaceutically acceptable salt, is orally administered to a mammal daily in an amount of about 0.0025 to 50 mg / kg body weight. However, it is preferably administered orally at about 0.01 to 10 mg / kg per kilogram. If a known anticancer drug is also administered, its dosage should be effective to achieve its intended purpose. The optimal doses of these known anticancer drugs are well known to those skilled in the art.

[0163] The unit oral dose may include about 0.01 to 50 mg, preferably about 0.1 to 10 mg of the compound of the invention. The unit dose may be administered once or more, one or more tablets per day, each tablet containing about 0.1 to 50 mg, conveniently about 0.25 to 10 mg of the compound of the invention or its solvate.

[0164] In external preparations, the concentration of the compound of the present invention may be about 0.01 to 100 mg per gram of carrier.

[0165] 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 a pharmaceutically acceptable carrier (including excipients and adjuvants). These pharmaceutically acceptable carriers facilitate the processing of the compounds into pharmaceutical preparations that can be used for pharmaceutical purposes. Preferred pharmaceutical preparations, especially those oral and preferred administration types, such as tablets, lozenges and capsules, and solutions suitable for injection or oral administration, contain about 0.01% to 99%, preferably from about 0.25% to 75% of active compounds and excipients.

[0166] 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 non-toxic pharmaceutically acceptable acid solution with a solution of the compound of the present invention. The acid is, for example, 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 non-toxic pharmaceutically acceptable base solution with a solution of the compound of the present invention. The base is, for example, sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, trishydroxymethylaminomethane, N-methyl-glucamine, etc.

[0167] 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. The most important of these mammals are humans and veterinary animals, although the present invention is not intended to be so limited.

[0168] The pharmaceutical preparation of the present invention can be administered by any route to achieve its intended purpose. For example, it can be administered parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, transdermally, orally, intrathecally, intracranially, nasally or externally. Alternatively or concurrently, it can be administered orally. The dosage of the drug will be determined based on the patient's age, health and weight, the type of concurrent treatment, the frequency of treatment, and the desired therapeutic benefit.

[0169] The pharmaceutical preparations of the present invention can be manufactured in a known manner. For example, they can be manufactured by conventional mixing, granulation, tableting, dissolution, or freeze-drying processes. When manufacturing oral preparations, solid excipients and active compounds can be combined and the mixture can be selectively ground. After adding appropriate amounts of auxiliary agents as needed or necessary, the granular mixture can be processed to obtain tablets or lozenge cores.

[0170] Suitable adjuvants are in particular fillers, for example sugars such as lactose or sucrose, mannitol or sorbitol; cellulose preparations and / or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate; and binders, for example starch pastes, including corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone. If necessary, disintegrants 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, can be added. Auxiliary agents are in particular 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 can resist gastric juice. For this purpose, concentrated sugar solutions can be applied. This solution may contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. To prepare a coating resistant to gastric juices, suitable cellulose solutions may be used, for example cellulose acetate phthalate or hydroxypropyl methylcellulose phthalate. Dyes or pigments may be added to the coating of the tablet or lozenge core, for example, for identification or to characterize the combination of active ingredient doses.

[0171] Other pharmaceutical preparations for oral administration include press-fit capsules made of gelatin and sealed soft capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The press-fit capsules may contain the active compound in the form of particles, mixed with a filler such as lactose; a binder such as starch; and / or a lubricant such as talc or magnesium stearate, and a stabilizer. In soft capsules, the active compound is preferably dissolved or suspended in a suitable liquid such as a fat or liquid paraffin, to which a stabilizer may be added.

[0172] Preparations 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 may 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 contained.

[0173] According to one aspect of the present invention, the compounds of the present invention are used in topical and parenteral formulations and are useful in the treatment of skin cancer.

[0174] The topical preparation of the present invention can be made into oil, cream, emulsion, ointment, etc. by preferably using a suitable carrier. Suitable carriers include plant or mineral oil, white mineral oil (white soft paraffin), branched fat or grease, animal fat and high molecular alcohol (grease with a concentration 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, as well as agents that impart color or flavor, if desired. In addition, these topical preparations may contain transdermal penetration enhancers. Examples of such enhancers can be found in U.S. Pat. Nos. 3,989,816 and 4,444,762.

[0175] Creams are preferably formulated with 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 cream example includes about 40 parts water, 20 parts beeswax, 40 parts mineral oil and 1 part almond oil.

[0176] Ointments can be prepared by mixing a vegetable oil containing the active ingredient, such as almond oil, with warm soft paraffin, and then allowing the mixture to cool. A typical ointment example includes about 30% by weight of almond oil and 70% by weight of white soft paraffin.

[0177] The present invention also relates to the use of the compounds of the present invention to prepare drugs for treating clinical conditions that are effective in inhibiting USP1 activity. These drugs may include the above-mentioned pharmaceutical composition.

[0178] The following examples are illustrative, rather than limiting, methods and preparations of the present invention. Other suitable modifications and improvements to various conditions and parameters that are apparent to those skilled in the art and that are typically encountered in clinical treatment are within the spirit and scope of the present invention.

[0179] Example

[0180] General Notes

[0181] All reagents used were of commercial quality, and solvents were dried and purified according to standard methods. Mass spectrometry samples were analyzed using a single quadrupole mass spectrometer (Platform II, Agilent 6110) with electrospray ionization. Brücker Ascend 400 NMR was used to record 1 For H NMR spectra (400 MHz), chemical shifts are reported in ppm downfield from TMS as an internal standard (0.00 ppm), and coupling constants, J values, are reported in Hz.

[0182] Example 1

[0183] 8-(4-(1,4-dimethyl-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-[1,2,4]triazolo[1,5-a]pyridine

[0184] a) Preparation of methyl 2-(2-isopropylphenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate: methyl 2-aminonicotinate (0.6 g, 3.9 mmol) was dissolved in 1,4-dioxane (50 mL). Under nitrogen protection, 2,4,6-trimethylbenzenesulfonic acid aza (1.0 g, 4.7 mmol, dissolved in 10 mL DCM) was added to the above solution and reacted at room temperature for 2 hours. Then, 2-isopropylbenzaldehyde (0.7 g, 4.7 mmol) was added to the reaction solution and reacted at 100°C for 2 hours. The reaction solution was cooled to room temperature, and KOH (10 mL, 1N MeOH solution) was added and stirred at room temperature for 1 hour. Water was added to the reaction solution and then extracted with EtOAc (30 mL×3). The combined organic phases were washed with water and saturated brine in turn, and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the crude target product (600 mg, white solid, yield 51.5%), which was used directly in the next step without purification. MS (ESI, m / z): 296.1 [M+H] + .

[0185] b) Preparation of (2-(2-isopropylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)methanol: 2-(2-isopropylphenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid methyl ester (600.0 mg, 2.0 mmol) was dissolved in dry THF (60 mL), and LiAlH4 (1.6 mL, 4.0 mmol, 2.5 M toluene solution) was slowly added at 0°C. After the addition, the temperature was raised to room temperature for reaction. After the reaction was complete, water (20 mL) was added to quench the reaction, and then extracted with EtOAc (20 mL×3). The combined organic phases were dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to obtain the crude target product (500 mg, white solid, yield 92.1%), which was used directly in the next step without purification. MS (ESI, m / z): 268.1 [M+H] + .

[0186] c) Preparation of 8-(bromomethyl)-2-(2-isopropylphenyl)-[1,2,4]triazolo[1,5-a]pyridine: (2-(2-isopropylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)methanol was dissolved in dry DCM (40 mL), PBr3 (485 mg, 1.7 mmol) was slowly added at 0°C, and the mixture was reacted at room temperature for 2 hours. Saturated NaHCO3 solution (20 mL) was added to quench the reaction, and then extracted with DCM (20 mL×3). The combined organic phases were dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE:EtOAc=10:1) to obtain the target product (270 mg, white solid, yield 54.6%), MS (ESI, m / z): 330.0[M+H] + . 1 H NMR (300MHz, DMSO-d6): δ8.99(dd,J=6.8,1.1Hz,1H),7.91-7.79(m,2H),7.55–7.40(m,2H), 7.38–7.26(m,1H),7.23-7.18(m,1H),5.01(s,2H),3.97–3.82(m,1H),1.22(d,J=6.9Hz,6H).

[0187] d) Preparation of 8-(4-(1,4-dimethyl-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-[1,2,4]triazolo[1,5-a]pyridine: 8-(bromomethyl)-2-(2-isopropylphenyl)-[1,2,4]triazolo[1,5-a]pyridine (200 mg, 0.6 mmol), 1,4-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazole (181 mg, 0.6 mmol), Na2CO3 (193 mg, 1.8 mmol) and Pd(PPh3)2Cl2 (43 mg, 0.06 mmol) were mixed in 1,4-dioxane (20 mL) and water (7 mL), and the mixture was reacted at 60°C under nitrogen for 2 hours. After the reaction is complete, water (30 mL) is added to dilute, and then extracted with EtOAc (30 mL × 3). The combined organic phases are dried over anhydrous sodium sulfate. The desiccant is filtered off, and the filtrate is concentrated under reduced pressure to obtain a crude product. The crude product is purified by preparative high-performance liquid chromatography (acetonitrile / water = 25% / 75%, 0.1% formic acid) to obtain the target compound (30 mg, white solid, yield 11.7%).

[0188] Examples 2 to 9 were synthesized using a method similar to that of Example 1.

[0189]

[0190]

[0191] Example 10

[0192] 2-(2-isopropylphenyl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine

[0193] a) Preparation of [[(6-methyl-2-pyridyl)amino]thiomethyl]-carbamic acid ethyl ester: Ethyl isothiocyanate (6.0 g, 45.8 mmol) was added to 6-methylpyridin-2-amine (5.0 g, 46.2 mmol) in 1,4-dioxane (50 mL). The reaction solution was stirred at room temperature overnight. The reaction solution was concentrated and washed with EtOAc (30 mL) to obtain the target product (11 g, yellow solid, yield 99.6%). MS (ESI, m / z): 240.1 [M+H] + .

[0194] b) Preparation of 5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine: To ethyl [[(6-methyl-2-pyridyl)amino]thiomethyl]-carbamate (11.0 g, 46.0 mmol) in EtOH (50 mL) and MeOH (50 mL) were added NH2OH·HCl (16.0 g, 231.0 mmol) and DIEA (17.8 g, 137.7 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and washed with EtOAc (30 mL) to give the desired product (4 g, off-white solid, yield 58.8%). MS (ESI, m / z): 149.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ7.38-7.32(m,1H),7.20(d,J=8.8Hz,1H),7.79-7.72(m,1H),5.96(brs,2H),2.46(s,3H).

[0195] c) Preparation of 2-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyridine: NaNO2 (559.2 mg, 8.1 mmol) was added to acetonitrile (20 mL) of 5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-amine (1.0 g, 6.8 mmol) at 0°C. Then concentrated hydrochloric acid (1 mL) was added dropwise, and the reaction solution was stirred at 0°C for 15 minutes. Then concentrated hydrochloric acid was added until the solid was dissolved. The reaction solution was stirred at 80°C for 2 hours. Ice water was added to the reaction solution, and it was extracted with DCM (50 mL×3). The organic phases were combined, washed with saturated brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (n-hexane: ethyl acetate = 20:1) to obtain the target product (480 mg, off-white solid, yield 42.4%). MS (ESI, m / z): 168.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ7.68-7.62(m,2H),7.16-7.12(m,1H),2.66(s,3H).

[0196] d) Preparation of 5-(bromomethyl)-2-chloro-[1,2,4]triazolo[1,5-a]pyridine: NBS (613.8 mg, 3.4 mmol) and AIBN (47 mg, 0.3 mmol) were added to CCl4 (10 mL) of 2-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyridine (480 mg, 2.8 mmol). The mixture was refluxed overnight under nitrogen protection. The reaction was quenched by adding water (50 mL), extracted with EtOAc (30 mL × 3), and the organic phases were combined and dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10:1) to obtain the target product (460 mg, white solid, yield 64.9%). MS (ESI, m / z): 246.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ7.86–7.82(m,1H),7.78–7.74(m,1H),7.48-7.46(m,1H),5.07(s,2H).

[0197] e) Preparation of 2-chloro-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine: To a solution of 5-(bromomethyl)-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (230 mg, 0.94 mmol) in dioxane (5 mL), (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)boric acid (255 mg, 0.94 mmol), Pd(PPh3)2Cl2 (66 mg, 0.09 mmol) and Na2CO3 (300 mg, 2.8 mmol) were added. The mixture was reacted at 60°C for 4 hours under nitrogen protection. The reaction was quenched by adding water (50 mL), extracted with EtOAc (30 mL×3), and the organic phases were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2:1) to obtain the target product (250 mg, yellow solid, yield 68.5%). MS (ESI, m / z): 246.0 [M+H] + .

[0198] f) Preparation of 2-(2-isopropylphenyl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine: To a solution of 2-chloro-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine (140 mg, 0.35 mmol) in toluene (5 mL), (2-isopropylphenyl)boronic acid (56 mg, 0.53 mmol), cataCXium A Pd G3 (26 mg, 0.03 mmol) and Cs2CO3 (349 mg, 1.0 mmol) were added. The mixture was reacted at 120°C for 4 hours under nitrogen protection. The reaction was quenched by adding water (30 mL), extracted with EtOAc (20 mL×3), and the organic phase was concentrated. The crude product was purified by preparative HPLC (ACN / 0.1% formic acid solution = 10%) to give the target product (11.3 mg, white solid, yield 6.6%).

[0199] Examples 11 to 17 were synthesized using a method similar to that of Examples 1 and 10.

[0200]

[0201] Embodiment 18

[0202] 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazine

[0203] a) Preparation of 3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrazin-2-amine: Zn (202.0 mg, 3.1 mmol) and I2 (20.0 mg, 0.08 mmol) were mixed in DMF (10 mL) and stirred at 30°C for 10 minutes under nitrogen protection. TMSCl (8.0 mg, 0.08 mmol) was added and stirring continued for 45 minutes, and then a DMF (1 mL) solution of 2-(4-(bromomethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (95 mg, 0.26 mmol) was added and stirred at 45°C for 1 hour. Pd(PPh3)4 (30.0 mg, 0.026 mmol) and 3-bromopyrazin-2-amine (45 mg, 0.26 mmol) were added to the reaction solution and stirred at 60°C for 2 hours under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with EA (40 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thin layer plate (DCM: MeOH = 10: 1) to obtain the target product (40.0 mg, white solid, yield: 46%). MS (ESI): 334.25 [M + H] + .

[0204] b) Preparation of 1,2-diamino-3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrazin-1-ium 2,4,6-trimethylbenzenesulfonate: 3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrazin-2-amine (40 mg, 0.12 mmol) and 2-[(aminooxy)sulfonyl]-1,3,5-trimethylbenzene (51.6 mg, 0.24 mmol) were dissolved in DCM (5 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the solvent was removed by rotary evaporation to obtain the crude target product (50.5 mg, yellow solid) which was used directly in the next step. MS (ESI): 349.30 [M+H] + .

[0205] c) Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazine: 1,2-diamino-3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrazin-1-ium 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.12 mmol) was dissolved in dioxane (5 mL), and 4-cyclopropyl-6-methoxypyrimidine-5-carboxaldehyde (43 mg, 0.24 mmol) and Cs2CO3 (117 mg, 0.36 mmol) were added. The reaction solution was stirred at 90°C for 2 hours. After the reaction was complete, water (50 mL) was added to dilute it and extracted with EA (20 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to obtain the target product (5.0 mg, white solid, 2-step yield: 9%).

[0206] Examples 19 to 47 were synthesized using a method similar to Example 18.

[0207]

[0208]

[0209]

[0210]

[0211] Embodiment 48

[0212] The inhibitory effect of the compounds of the present invention on USP1 / UAF1 enzyme activity was determined by using the ubiquitin-rhodamine 110 assay

[0213] The ubiquitin-rhodamine 110 method was used to detect the inhibitory effect of compounds on USP1 / UAF1 enzyme activity. 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.

[0214]

[0215] IC 50 The values ​​were fitted with the S-shaped dose-response curve equation using XL Fit software. The curve equation is: Y = 100 / (1+10^(LogC-LogIC 50 )), C is the concentration of the compound.

[0216] Table 1 summarizes the inhibitory activity data of compounds against USP1 / UAF1 enzyme (IC 50 ).

[0217] Table 1

[0218] Example <![CDATA[IC 50 (nM)]]> Example <![CDATA[IC 50 (nM)]]> Example <![CDATA[IC 50 (nM)]]> 4 66.62 24 11.82 37 9.53 5 39.10 25 11.64 38 5.44 6 460.42 26 39.46 39 18.83 14 30.65 27 77.46 40 19.91 15 17.93 28 25.98 41 34.20 16 15.79 29 34.56 42 731.82 18 11.21 30 41.38 43 38.90 19 138.10 31 57.45 44 78.29 21 16.06 32 111.16 45 99.72 22 146.71 33 94.50 23 175.12 34 242.50

[0219] Therefore, as determined by the ubiquitin-rhodamine 110 detection method, the compounds of the present invention have a good inhibitory effect on the USP1 / UAF1 enzyme.

[0220] Embodiment 49

[0221] Determination of the inhibitory effect of the compounds of the present invention on human breast cancer cells MDA-MB-436

[0222] After cell recovery, complete medium (DMEM medium + 10% FBS + insulin + glutathione) was used for culture and passage. When the cell confluence reaches about 80%, use a 1mL pipette to gently blow the cells off from the bottom of the culture dish, collect the cell suspension, and centrifuge at 500rpm for 3min; discard the supernatant, add complete medium to resuspend the cells, inoculate them into the culture dish according to the appropriate proportion, and place them in a 37℃, 5% CO2 incubator for static culture. The cells were cultured and passaged until they were in good growth state and the confluence was about 80%, and then they were used for experiments. Use a 1mL pipette to gently blow off the cells in the logarithmic growth phase, centrifuge at 500rpm for 3min, discard the supernatant, resuspend them with fresh medium, disperse them into single cells, count them, and inoculate them into a 96-well cell culture plate (the first column is empty) at a density of 3000 cells per well, and place them in a 37℃, 5% CO2 incubator for overnight culture. The next day, the compound stock solution was serially diluted with DMSO at a ratio of 1:3 for a total of 8 concentrations. 5 μL of each concentration was added to 120 μL of culture medium (25-fold dilution), and a DMSO control well was made at the same time, and the mixture was shaken. The cells were removed from the CO2 incubator, the old culture medium in the well was discarded, 195 μL of fresh culture medium was added to each well, and then 5 μL of the compound containing the corresponding concentration diluted in the culture medium was added to the corresponding wells, and then the culture plate was placed in a 37°C, 5% CO2 incubator for a total of 7 days, and the drug was changed once on the 4th day.

[0223] CTG detection method: After 7 days, add 100 μL CellTiter-Glo reagent to each well and shake on an orbital shaker for 2 minutes to fully lyse the cells. Then incubate at room temperature for 10 minutes and read the chemiluminescence value with a plate reader.

[0224] The inhibitory activity of the compound on cell proliferation is plotted with the compound inhibition rate and compound concentration as coordinates. Cell inhibition rate (%) = (Lum 待测药 -Lum DMSO对照孔 ) / (Lum 培养液对照 -Lum DMSO对照孔 )×100%, where Lum refers to the chemiluminescence value.

[0225] XL Fit software was used to fit the data to obtain a dose-effect curve by nonlinear S-curve regression, and the IC was calculated from this. 50 The curve equation is: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)×slope)), where Y is the cell inhibition rate, X is the compound concentration, Bottom refers to the lowest inhibition rate, and Top refers to the highest inhibition rate.

[0226] Table 2 summarizes the inhibitory effect data (IC 50 ).

[0227] Table 2

[0228] Example <![CDATA[IC 50 (nM)]]> Example <![CDATA[IC 50 (nM)]]> 1 160.56 27 157.50 2 >1000 28 40.61 3 57.61 40 21.09 14 21.65 41 55.31 22 226.53 23 496.15

[0229] CCK-8 detection method: After 7 days, add 20 μL CCK-8 to each well and shake it, then continue to culture. After 4 hours, shake it for 5 minutes and place it on a multifunctional reader to read the absorbance values ​​at 450nm and 650nm wavelengths (OD value = absorbance value 450nm -Absorbance 650nm ).

[0230] The data were analyzed using GraphPad Prism 6.0 software, and the inhibitory activity of the compounds on cell proliferation was plotted using cell survival rate and compound concentration as coordinates. Cell survival rate % = (OD 化合物 -OD 背景 ) / (OD DMSO -OD 背景 )×100. IC 50 The values ​​were fitted with an S-shaped dose-response curve equation: Y = 100 / (1+10^(LogC-LogIC 50 )), C is the concentration of the compound.

[0231] Table 3 summarizes the inhibitory effect data of compounds on human breast cancer MDA-MB-436 cells determined by CCK-8 assay (IC 50 ).

[0232] Table 3

[0233] Example <![CDATA[IC 50 (nM)]]> Example <![CDATA[IC 50 (nM)]]> 3 111.17 14 26.36 4 25.53 15 10.26 5 38.82 16 13.24 6 28.31 17 39.45 9 1172.2 19 44.77 10 225.94

[0234] Therefore, the compounds of the present invention have a good inhibitory effect on the growth of human breast cancer cells MDA-MB-436.

[0235] Although the present invention has been fully described, it will be appreciated by those skilled in the art that the same implementation can be performed in a wide range of and equivalent conditions, formulations and other parameter ranges without affecting the scope of the present invention or any embodiment thereof. All patents, patent applications and publications cited herein are incorporated herein by reference in their entirety.

Claims

1. A compound of formula IIIa or IIIb, or a stereoisomer of a compound of formula IIIa or IIIb, or a pharmaceutically acceptable salt thereof, or a mixture thereof: IIIa IIIb in, B3, B4 and B5 are each independently selected from N and CR2; R2 is selected from hydrogen, halogen, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and amino groups; Cy1 is selected from optionally substituted 6-14 membered aryl and optionally substituted 5-10 membered heteroaryl, Cy1 is optionally selected from halogen, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Alkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted amino and cyano substituents, said C 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 The cycloalkyl group is optionally substituted by 1-5 groups selected from halogen, hydroxy, C 1-4 Alkyl and -NR a R b wherein R a and R b Independently H or C 1-4 Alkyl, the amino group is optionally replaced by 1 or 2 C 1-4 Alkyl substitution; Cy2 is optionally substituted with 1 to 5 groups selected from halogen, 1-4 Alkyl, optionally substituted C 1-4 Alkoxy and C 3-6 The 5-10 membered nitrogen-containing heteroaryl group substituted by the cycloalkyl substituent, the C 1-4 Alkyl and C 1-4 Each alkoxy group is optionally substituted by 1 to 5 groups selected from halogen, hydroxy and -NR a R b wherein R a and R b Independently H or C 1-4 alkyl.

2. The compound of formula IIIa or IIIb, or a stereoisomer of a compound of formula IIIa or IIIb, or a pharmaceutically acceptable salt thereof, or a mixture thereof as claimed in claim 1, characterized in that: B3, B4 and B5 are each independently selected from N and CR2, wherein R2 is H, halogen, C 1-4 Alkyl or C 1-4 Alkoxy.

3. The compound of formula IIIa or IIIb, or a stereoisomer of a compound of formula IIIa or IIIb, or a pharmaceutically acceptable salt thereof, or a mixture thereof as claimed in claim 1, characterized in that: B3, B4 and B5 are each independently N or CH; or, B3, B4 and B5 are all CR2, wherein R2 is each independently H, halogen or C 1-4 alkyl.

4. The compound of formula IIIa or IIIb, or a stereoisomer of a compound of formula IIIa or IIIb, or a pharmaceutically acceptable salt thereof, or a mixture thereof as claimed in claim 1, characterized in that: B3 is N, B4 and B5 are CR2, wherein R2 is H, halogen or C 1-4 Alkyl; or B4 is N, B3 and B5 are CR2, wherein R2 is independently H, halogen or C 1-4 Alkyl; or B5 is N, B3 and B4 are CR2, wherein R2 is independently H, halogen or C 1-4 alkyl.

5. The compound of formula IIIa or IIIb, or a stereoisomer of a compound of formula IIIa or IIIb, or a pharmaceutically acceptable salt thereof, or a mixture thereof according to claim 1, characterized in that: The fused heteroaromatic bicyclic ring containing B3, B4 and B5 is selected from the following groups: , , , , , , and ; Wherein, *1 and *2 represent the connection positions of the group to compound Cy1 and the rest of the compound, respectively.

6. The compound of formula IIIa or IIIb, or a stereoisomer of a compound of formula IIIa or IIIb, or a pharmaceutically acceptable salt thereof, or a mixture thereof according to claim 1, characterized in that: Cy1 is optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted tetrahydrofuranyl, optionally substituted pyrrolidinyl or optionally substituted pyrazolyl, and Cy1 is optionally selected from halogen, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Alkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted amino and cyano substituents, said C 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 The cycloalkyl group is optionally substituted by 1-5 groups selected from halogen, hydroxy, C 1-4 Alkyl and -NR a R b wherein R a and R b Independently H or C 1-4 Alkyl, the amino group is optionally replaced by 1 or 2 C 1-4 Alkyl substitution.

7. The compound of formula IIIa or IIIb, or a stereoisomer of a compound of formula IIIa or IIIb, or a pharmaceutically acceptable salt thereof, or a mixture thereof as claimed in claim 1, characterized in that: Cy2 is a five-membered nitrogen-containing heteroaryl group.

8. The compound of formula IIIa or IIIb, or a stereoisomer of a compound of formula IIIa or IIIb, or a pharmaceutically acceptable salt thereof, or a mixture thereof according to claim 1, characterized in that: Cy2 is an optionally substituted imidazolyl or an optionally substituted pyrazolyl, and Cy2 is optionally substituted by 1-5 groups selected from halogen, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Alkoxy and C 3-6 The cycloalkyl group is substituted with a substituent, the C 1-4 Alkyl and C 1-4 Each alkoxy group is optionally substituted by 1 to 5 groups selected from halogen, hydroxy and -NR a R b wherein R a and R b Independently H or C 1-4 alkyl.

9. The compound of formula IIIa or IIIb, or a stereoisomer of a compound of formula IIIa or IIIb, or a pharmaceutically acceptable salt thereof, or a mixture thereof according to claim 1, characterized in that: Cy2 is selected from 1-3 C 1-4 Alkyl, C 3-6 Cycloalkyl and halogenated C 1-4 The alkyl group is substituted with a substituent.

10. The compound of formula IIIa or IIIb, or a stereoisomer of a compound of formula IIIa or IIIb, or a pharmaceutically acceptable salt thereof, or a mixture thereof according to claim 1, characterized in that: Cy2 is C which may be optionally substituted 1-4 an alkyl-substituted imidazolyl group or an optionally substituted C 1-4 Alkyl-substituted pyrazolyl, the C 1-4 The alkyl group is optionally substituted by 1 to 5 groups selected from halogen, hydroxy and -NR a R b wherein R a and R b Independently H or C 1-4 alkyl.

11. The compound of formula IIIa or IIIb, or a stereoisomer of a compound of formula IIIa or IIIb, or a pharmaceutically acceptable salt thereof, or a mixture thereof according to claim 1, characterized in that: Cy2 is an imidazole group substituted by two substituents, the substituents are selected from C 1-4 Alkyl, C 3-6 Cycloalkyl and halogenated C 1-4 Alkyl, one of the nitrogen atoms is replaced by a C 1-4 Alkyl substitution.

12. The compound of formula IIIa or IIIb, or a stereoisomer of a compound of formula IIIa or IIIb, or a pharmaceutically acceptable salt thereof, or a mixture thereof according to claim 1, characterized in that: Wherein the compound is selected from: 8-(4-(1,4-dimethyl-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-[1,2,4]triazolo[1,5-a]pyridine; 8-(4-(1,4-dimethyl-1H-imidazol-2-yl)benzyl)-2-(2-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine; 2-(2-isopropylphenyl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine; 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine; 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine; 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine; 2-(2-isopropylphenyl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazine; 2-(2-isopropylphenyl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-c]pyrimidine; 2-(2-isopropylphenyl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-b]pyridazine; 2-(2-isopropylphenyl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine; 2-(2-isopropylphenyl)-7-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrimidine; 2-(2-isopropylphenyl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazine; 2-(2-isopropylphenyl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-c]pyrimidine; 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine; 2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine; 2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine; 2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-b]pyridazine; 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazine; 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-c]pyrimidine; 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-b]pyridazine; 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-c]pyrimidine; 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazine; 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrimidine; 8-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-a]pyridine; 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine; 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-fluoro-5-methoxybenzyl)-[1,2,4]triazolo[1,5-a]pyridine; 2-(4,6-dimethoxypyrimidin-5-yl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine; 2-(4-cyclobutyl-6-methoxypyrimidin-5-yl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine; 8-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-a]pyrazine; 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazine; 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3,5-difluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazine; 8-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-c]pyrimidine; 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-c]pyrimidine; 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3,5-difluorobenzyl)-[1,2,4]triazolo[1,5-c]pyrimidine; 2-(4-cyclopropyl-6-cyanopyrimidin-5-yl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine; 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-[1,2,4]triazolo[1,5-a]pyridine; 5-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-a]pyridine; 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine; 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-fluoro-5-methoxybenzyl)-[1,2,4]triazolo[1,5-a]pyridine; 5-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-c]pyrimidine; 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-c]pyrimidine; 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3,5-difluorobenzyl)-[1,2,4]triazolo[1,5-c]pyrimidine; 5-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-a]pyrazine; 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazine; 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3,5-difluorobenzyl)-[1,2,4]triazolo[1,5-a]pyrazine; 2-(4-cyclopropyl-6-cyanopyrimidin-5-yl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine; 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-[1,2,4]triazolo[1,5-a]pyridine.

13. Use of the compound according to any one of claims 1 to 12 or its stereoisomer, pharmaceutically acceptable salt or mixture thereof in the preparation of a medicament for treating or preventing a disease associated with USP1 regulation.

14. The use according to claim 13, characterized in that The disease is cancer.

15. The method of claim 14, wherein the cancer is liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, non-small cell lung cancer, small cell lung cancer, gastric cancer, colon cancer, cancer, malignant pancreatic insulinoma, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi sarcoma, genitourinary neoplasia, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, essential thrombocythemia, adrenocortical carcinoma, skin cancer, and prostate cancer.

16. The use of claim 13, wherein the medicament is used in combination with radiation therapy.

17. The use of claim 13, wherein the drug further comprises at least one known anticancer drug, or a pharmaceutically acceptable salt of the anticancer drug.

18. The use according to claim 17, characterized in that The anticancer 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, methylhydroxyellipticine, mingtopop, 5-azacytidine, gemcitabine, 5-fluorouracil, methotrexate, 5-fluoro-2'-deoxyuridine, fludarabine, nelarabine, a Cytosine, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, monoclonal antibody, panitumumab, necrotizumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab tiuxetan, tositumomab, brentuximab, daratumumab, elotuzumab, T-DM1, Ofatumumab, Dinutuximab, Blinatumomab, Ipilimumab, Avastin, Herceptin, Rituximab, Imatinib, Gefitinib, Erlotinib, Osimertinib, Afatinib, Ceritinib, Alectinib, Crizotinib, Erlotinib, Lapatinib, Sorafenib, Regorafenib, Vemurafenib, Dabrafenib, Aflibercept, Sunitinib, Nilotinib, Dasatinib, Bosutinib, Pratinib, Ibrutinib, Cabozantinib, Lenvatinib, Vandetanib, Trametinib, Cobimetinib, Axitinib, Temsirolimus, Idela lisib, pazopanib, tebuconazole, everolimus, tamoxifen, letrozole, fulvestrant, mitoguanidine, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegi, denosumab, thalidomide, lenalidomide, venetoclax, aldesleukin (recombinant human interleukin-2), sipueucel-T (prostate cancer vaccine), olaparib, niraparib, rucaparib, talazoparib, and senaparib.

19. A pharmaceutical composition comprising the compound according to any one of claims 1 to 12 or its stereoisomer, pharmaceutically acceptable salt or mixture thereof and a pharmaceutically acceptable carrier.

20. The pharmaceutical composition of claim 19, further comprising at least one known anticancer drug, or a pharmaceutically acceptable salt of the anticancer drug.

21. The pharmaceutical composition according to claim 20, characterized in that The at least one known anticancer 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, methylhydroxyellipticine, mingtopop, 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 antibody, panitumumab, necrotizumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab tiuxetan, tositumomab, brentuximab, daratumumab, elotuzumab, T-DM1, Ofatumumab, Dinutuxi mab, Blinatumomab, Ipilimumab, Avastin, Herceptin, Rituximab, Imatinib, Gefitinib, Erlotinib, Osimertinib, Afatinib, Ceritinib, Alectinib, Crizotinib, Erlotinib, Lapatinib, Sorafenib, Regorafenib, Vemurafenib, Dabrafenib, Aflibercept, Sunitinib, Nilotinib, Dasatinib, Bosutinib, Pratinib, Ibrutinib, Cabozantinib, Lenvatinib, Vandetanib, Trametinib, Cobimetinib, Axitinib, Temsirolimus, Idelalisib, Sunitinib, Nilotinib Locitabine, dasatinib, pazopanib, temozolomide, everolimus, tamoxifen, letrozole, fulvestrant, mitoguanidine, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegi, denosumab, thalidomide, lenalidomide, venetoclax, aldesleukin (recombinant human interleukin-2), sipueucel-T (prostate cancer vaccine), olaparib, niraparib, rucaparib, talazoparib, and senaparib.

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