Substituted triazoloheteroaryl compounds as USP1 inhibitors and their applications

Abstract

The present invention provides substituted triazoloheteroaryl compounds represented by formula I and their applications: JPEG2024540921000029.jpg53149A1, A2, B1, B2, B3, B4, B5, D1, D2, D3, D4, L, Cy1 and Cy2 are defined herein. Compounds of formula I are USP1 inhibitors. Thus, the compounds of the present invention can be used to treat diseases, disorders and conditions associated with USP1 regulation, such as cancer.

Description

[Technical field]

[0001] The present invention relates to the field of medicinal chemistry. In particular, the present invention relates to substituted triazoloheteroaryl compounds and the application of these compounds as therapeutically effective USP1 inhibitors and anti-cancer agents. [Background technology]

[0002] Ubiquitin is a long peptide of 76 amino acids that covalently binds to proteins to regulate their stability, localization, or function. Target protein degradation by ubiquitination is a multi-step process. Ubiquitination occurs through the sequential action of enzymes such as ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin protein ligase (E3). Ubiquitination controls multiple cellular activities as thousands of cellular proteins are ubiquitinated. Ubiquitination is a reversible process. The balance between ubiquitination and deubiquitination affects the degree of ubiquitination of intracellular proteins. Deubiquitinating enzymes (DUBs) contribute significantly to deubiquitination, and DUBs act on ubiquitinated substrates to catalyze the removal of the ubiquitin moiety. Thus, the ubiquitination state is a dynamic regulatory mechanism. Ubiquitination also plays a regulatory role in gene expression, cell cycle progression, apoptosis, DNA repair and cell motility, among others (Garcia-Sanstisteban (2013) Mol Cancer 12: 91-103).

[0003] More and more studies have revealed that protein ubiquitination is a key regulatory mechanism underlying DNA damage response (Huang D', Andrea (2006) Mol Cell Biol. 7:323-34). Targeting DDR signaling pathways has become an attractive approach in oncology, and enzymes involved in DNA damage-induced ubiquitination and deubiquitination may be potential targets for anticancer therapy.

[0004] There are 100 genes encoding deubiquitinating enzymes in humans (Garcia-Sanstisteban (2013) Mol Cancer 12: 91-103). One of the best identified DUBs is USP1 (ubiquitin-specific protease 1), which encodes a protein of 785 amino acids with a predicted molecular mass of 88.2 KDa. USP1 is a key regulator in DNA repair processes, mainly in the Fanconi anemia (FA) and translesion synthesis (TLS) pathways. USP1 regulates DNA repair via the Fanconi anemia (FA)-BRCA pathway by deubiquitinating the DNA repair protein FANCD2-Ub (Nijman et al. (2005) Mol Cell 17: 331-39). Loss of USP1 function leads to accumulation of FANCD2, inhibits the FA-BRCA-mediated DNA damage repair pathway, and increases the sensitivity of cancer cells to DNA cross-linking agents such as mitomycin C and cisplatin. PCNA (proliferating cell nuclear antigen) is another ubiquitination substrate of USP1, and its ubiquitination is important for DNA translesion synthesis (Huang et al. (2006) Nature Cell Biol. 8(4): 339-47). Inhibition of USP1 activity by inhibitors may increase the sensitivity of cancer cells to DNA cross-linking agents and PARP inhibitors.

[0005] USP1 inhibitors can be used for cancer treatment, alone or in combination with other DNA damaging agents. Inhibition of USP1 can impair DNA damage repair pathways. One of the characteristics of tumor cells is genetic instability, which makes them more sensitive to DNA damage repair. Some studies have revealed that USP1 inhibitors can not only be used as anticancer drugs, but also increase sensitivity to radiation therapy. With the advancement of USP1 inhibitors, it has become clear that USP1 inhibitors can also be used in combination with targeted drugs such as PARP inhibitors to treat cancers with synthetic lethality mechanisms.

[0006] Thomas S. et al. found through screening that ML323 and related N-benzyl-2-phenylpyrimidin-4-amine derivatives exhibited excellent inhibitory activity against USP1 / UAF1 (Thomas S. et al. (2014) J. Med. Chem. 57: 8099-8110). The results showed that the IC 50 There was a strong correlation between the levels of USP1 and activity in non-small cell lung cancer cells, specifically increasing monoubiquitinated PCNA (Ub-PCNA) levels and decreasing cell survival, establishing the druggability of the USP1 / UAF1 deubiquitinase complex and its potential as a molecular target for anti-cancer therapy.

[0007] Various USP1 inhibitors have been disclosed, for example, WO2014105952, WO2016034675, US20170145012, WO2020139988, WO2020132269, WO2021163530, and WO2022174184A1. Summary of the Invention

[0008] The present invention provides substituted triazoloheteroaryl compounds and analogs of Formula I (including Formula IIa / b and Formula IIIa / b) that can be used as USP1 inhibitors.

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

[0010] In a specific embodiment, the pharmaceutical composition may further comprise one or more pharma- ceutically acceptable excipients or carriers or excipients or diluents for the treatment of cancer.

[0011] In a specific embodiment, the pharmaceutical composition may further comprise at least one known anti-cancer agent or a pharma- ceutically acceptable salt thereof for the treatment of cancer.

[0012] The present invention also relates to methods for preparing the novel compounds of formula I (including formula IIa / b and formula IIIa / b). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] It should be understood that the features of the embodiments described herein can be arbitrarily combined to form the technical solution of the present invention. Herein, the definition of each group applies to any of the embodiments described herein. For example, here, the definition of the alkyl substituent applies to any of the embodiments described herein, unless the alkyl substituent is explicitly defined in the embodiment.

[0014] Specifically, the present invention relates to a compound of formula I

[0015] [ka]

[0016] or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, provided that A1 and A2 are each independently selected from the group consisting of N and CR1; B1 and B2 are each independently selected from the group consisting of N and C, and at most one of B1 and B2 is N; B3, B4 and B5 are each independently selected from the group consisting of N and CR2; D1, D2, D3 and D4 are each independently selected from the group consisting of N and CR3; L is selected from the group consisting of NR6, O, S, SO, SO2, C=O and alkylene optionally substituted with R4 and / or R5; Cy1 is selected from the group consisting of optionally substituted carbocyclic groups, optionally substituted heterocyclic groups, optionally substituted aryl and optionally substituted heteroaryl; Cy2 is selected from the group consisting of optionally substituted carbocyclic groups, optionally substituted heterocyclic groups, optionally substituted aryl and optionally substituted heteroaryl; R1, R2, and R3 are each independently selected from the group consisting of hydrogen, halogen, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted carbocyclic group, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted amino; R4 and R5 are each independently selected from the group consisting of halogen, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted carbocyclic group, optionally substituted alkenyl, and optionally substituted alkynyl; or R4 and R5 together with the C to which they are attached form a ring; R6 is selected from the group consisting of hydrogen and optionally substituted alkyl.

[0017] Preferably, in the above group definitions of formula I, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl and optionally substituted alkynyl are each independently selected from halogen, hydroxyl, NR a R b , C 1-4 Alkoxy, halogenated C 1-4 R is optionally substituted with 1 to 5 substituents selected from the group consisting of alkoxy, carboxyl, and cyano. a and R b are independently H or C 1-4 More preferably, the groups are halogen, hydroxyl and NR a R b and wherein R is optionally substituted with 1 to 5 substituents selected from the group consisting of a and R b are independently H or C 1-4 It is an alkyl.

[0018] Preferably, in the above group definitions of formula I, the optionally substituted carbocyclic group, the optionally substituted aryl group, the optionally substituted heteroaryl group and the optionally substituted heterocyclic group each are selected from the group consisting of halogen, hydroxyl, NR a R b , C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxyl substituted C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 R is optionally substituted with 1 to 5 substituents selected from the group consisting of alkoxy, carboxyl, and cyano. a and R b are independently H or C 1-4 More preferably, the optionally substituted carbocyclic, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic groups are selected from the group consisting of 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 and wherein R is optionally substituted with 1 to 5 substituents selected from the group consisting of a and R b are independently H or C 1-4 Preferably, the carbocyclic group is C 3-8 Preferably, the aryl is C 6-14 Preferably, heteroaryl is C 5-10 Heteroaryl, more preferably C containing 1-3 nitrogen atoms in the ring 5-10 Heteroaryl. Preferably, the heterocyclic group is C 4-10 and preferably containing 1-3 heteroatoms selected from the group consisting of O, N and S.

[0019] In one or more embodiments of the compound of formula I, both A 1 and A 2 are N.

[0020] In one or more 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.

[0021] In one or more embodiments of the compound of Formula I, B3, B4, and B5 are each independently selected from the group consisting of N and CR2, where 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, and R2 is each independently H, halogen or C. 1-4 In some embodiments, B3 is N, B4 and B5 are both CR2, and R2 is each independently H, halogen or C. 1-4 In some embodiments, B4 is N, B3 and B5 are both CR2, and each R2 is independently H, halogen, or C. 1-4 In some embodiments, B5 is N, B3 and B4 are both CR2, and each R2 is independently H, halogen, or C. 1-4 Preferably, each R2 is H.

[0022] In one or more embodiments of the compound of formula I, the fused heteroaromatic bicyclic ring comprising A1, A2, B1, B2, B3, B4 and B5 is selected from the group consisting of:

[0023] [ka]

[0024] *1 and *2 refer to the attachment positions of the groups to Cy1 and L of the compound, respectively.

[0025] In one or more embodiments of the compound of formula I, L is an alkylene group, NH, NC 1-3 alkyl or O, preferably C 1-3 It is an alkylene group, and more preferably a methylene group or a -CH(CH3)- group.

[0026] In one or more embodiments of the compound of formula I, D1, D2, D3 and D4 are CR3. Preferably, R3 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl and optionally substituted alkoxy. The optionally substituted alkyl and optionally substituted alkoxy are preferably each optionally substituted C 1-4 Alkyl and optionally substituted C 1-4 Preferably, said alkyl or said alkoxy is selected from halogen, hydroxyl and NR a R b and wherein R is optionally substituted with 1 to 5 substituents selected from the group consisting of a and R b are each independently H or C 1-4 In some preferred embodiments, D1 and D4 are CH, D2 and D3 are CR3, and R3 is hydrogen, halogen, or C. 1-4 Preferably, in some embodiments, at least one of R3 is a non-hydrogen substituent, i.e., halogen or C 1-4In some preferred embodiments, D1, D2, D3 and D4 are alkoxy. In some preferred embodiments, D1, D2, D3 and D4 are CH. In some preferred embodiments, D1, D2, D3 and D4 are independently N or CH. In some preferred embodiments, at most two of D1, D2, D3 and D4 are N. In some preferred embodiments, only two of D1, D2, D3 and D4 are N. Preferably, the aryl or heteroaryl comprising D1, D2, D3 and D4 is an optionally substituted phenyl, an optionally substituted pyridyl, an optionally substituted pyrimidinyl or an optionally substituted pyrazinyl. Preferably, when the aryl or heteroaryl is substituted, the substituents are selected from the groups described for R3, where halogen, or halogen, hydroxyl and -NR a R b C optionally substituted with 1-5 substituents selected from the group consisting of 1-4 Alkyl or C 1-4 The R groups include, but are not limited to, alkoxy. a and R b are independently H or C 1-4 It is an alkyl.

[0027] In one or more embodiments of the compound of formula I, Cy1 is optionally substituted C 3-8 cycloalkyl, an optionally substituted 4-10 membered heterocyclic group, an optionally substituted 6-14 membered aryl group or an optionally substituted 5-10 membered heteroaryl group. In some further preferred embodiments, the 5-10 membered heteroaryl group is a nitrogen-containing monocyclic heteroaryl group. Preferably, Cy1 is an optionally substituted phenyl, an optionally substituted pyridyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted pyridazinyl, an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted tetrahydrofuranyl, an optionally substituted pyrrolidinyl or an optionally substituted pyrazolyl. Preferably, when Cy1 is substituted, the substituent is selected from halogen, an optionally substituted C 1-4 Alkyl, optionally substituted C 1-4Alkoxy, optionally substituted C 3-6 Preferably, said C is selected from the group consisting of cycloalkyl, optionally substituted amino and cyano. 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 Cycloalkyl is halogen, hydroxyl, and -NR a R b C replaced with 1-4 alkyl, a and R b are independently H or C 1-4 alkyl, and the amino is one or two C 1-4 It is optionally substituted with alkyl.

[0028] In one or more embodiments of the compound of Formula I, Cy2 is an optionally substituted 6-14 membered aryl group, an optionally substituted 5-10 membered heteroaryl group, an optionally substituted C 3-8 Preferably, Cy2 is an optionally substituted heteroaryl group, preferably an optionally substituted 5-10 membered nitrogen-containing heteroaryl group, more preferably a 5 membered nitrogen-containing heteroaryl group. In some preferred embodiments, Cy2 is an optionally substituted imidazolyl or an optionally substituted pyrazolyl. Preferably, when Cy2 is substituted, the substituents are halogen, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Alkoxy and optionally substituted C 3-6 Preferably, Cy2 is an optionally substituted C 1-4 Alkyl-substituted imidazolyl or optionally substituted C 1-4 Preferably, the C is a pyrazolyl substituted with an alkyl group. 1-4 Alkyl and C 1-4 Alkoxy is halogen, hydroxyl and -NR a R bC replaced with 1-4 R is optionally substituted with 1 to 5 substituents selected from the group consisting of alkyl, a and R b are independently H or C 1-4 In some further preferred embodiments, Cy2 is C 1-4 Alkyl, C 3-6 Cycloalkyl and halogenated C 1-4 In some further preferred embodiments, Cy2 is substituted with 1-3 groups selected from the group consisting of alkyl. 1-4 Alkyl and halogenated C 1-4 In some embodiments, Cy2 is substituted with 1-3 groups selected from the group consisting of alkyl. 1-4 Alkyl and halogenated C 1-4 In some embodiments, Cy2 is C 1-4 Alkyl, C 3-6 Cycloalkyl and halogenated C 1-4 imidazolyl substituted with two substituents selected from the group consisting of alkyl, one of which is C 1-4 It is substituted with alkyl.

[0029] In one or more embodiments of the compound of formula I, R4 and R5 are each independently selected from halogen and halogenated C 1-4 In some embodiments, R and R together with the C to which they are attached form a 3-5 membered cycloalkyl.

[0030] In one or more embodiments of the compound of formula I, R6 is H or C 1-3 It is an alkyl.

[0031] The present invention relates to compounds of formula IIa and IIb

[0032] [ka]

[0033] or a stereoisomer, tautomer, N-oxide, hydrate, solvate thereof,

[0034] or a pharma- ceutically acceptable salt, or a mixture thereof, or a prodrug thereof, provided that A1, A2, B3, B4, B5, D1, D2, D3, D4, Cy1 and Cy2 are as defined in any embodiment of formula I.

[0035] In one or more embodiments of the compounds of Formula IIa and IIb, both A 1 and A 2 are N.

[0036] In one or more embodiments of the compounds of formula IIa and IIb, B3, B4, and B5 are each independently selected from the group consisting of N and CR2, where 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, and R2 is each independently H, halogen or C. 1-4 In some embodiments, B3 is N, B4 and B5 are both CR2, and R2 is each independently H, halogen or C. 1-4 In some embodiments, B4 is N, B3 and B5 are both CR2, and each R2 is independently H, halogen, or C. 1-4 In some embodiments, B5 is N, B3 and B4 are both CR2, and each R2 is independently H, halogen, or C. 1-4 Preferably, each R2 is H.

[0037] In one or more embodiments of the compounds of formula IIa and IIb, the fused heteroaromatic bicyclic ring comprising A1, A2, B3, B4 and B5 is selected from the group consisting of:

[0038] [ka]

[0039] *1 and *2 refer to the attachment positions of the groups to Cy1 and L of the compound, respectively.

[0040] In one or more embodiments of the compounds of formula IIa and IIb, D1, D2, D3 and D4 are CR3. Preferably, R3 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl and optionally substituted alkoxy. The optionally substituted alkyl and optionally substituted alkoxy are preferably each optionally substituted C 1-4 Alkyl and optionally substituted C 1-4 Preferably, said alkyl or said alkoxy is selected from halogen, hydroxyl and NR a R b and wherein R is optionally substituted with 1 to 5 substituents selected from the group consisting of a and R b are each independently H or C 1-4 In some preferred embodiments, D1 and D4 are CH, D2 and D3 are CR3, and R3 is hydrogen, halogen, or C. 1-4 Preferably, in some embodiments, at least one of R3 is a non-hydrogen substituent, i.e., halogen or C 1-4In some preferred embodiments, D1, D2, D3 and D4 are alkoxy. In some preferred embodiments, D1, D2, D3 and D4 are CH. In some preferred embodiments, D1, D2, D3 and D4 are independently N or CH. In some preferred embodiments, at most two of D1, D2, D3 and D4 are N. In some preferred embodiments, only two of D1, D2, D3 and D4 are N. Preferably, the aryl or heteroaryl comprising D1, D2, D3 and D4 is an optionally substituted phenyl, an optionally substituted pyridyl, an optionally substituted pyrimidinyl or an optionally substituted pyrazinyl. Preferably, when the aryl or heteroaryl is substituted, the substituents are selected from the groups described for R3, where halogen, or halogen, hydroxyl and -NR a R b C optionally substituted with 1-5 substituents selected from the group consisting of 1-4 Alkyl or C 1-4 The R groups include, but are not limited to, alkoxy. a and R b are independently H or C 1-4 It is an alkyl.

[0041] In one or more embodiments of the compounds of formula IIa and IIb, Cy1 is optionally substituted C 3-8 cycloalkyl, an optionally substituted 4-10 membered heterocyclic group, an optionally substituted 6-14 membered aryl group or an optionally substituted 5-10 membered heteroaryl group. In some further preferred embodiments, the 5-10 membered heteroaryl group is a nitrogen-containing monocyclic heteroaryl group. Preferably, Cy1 is an optionally substituted phenyl, an optionally substituted pyridyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted pyridazinyl, an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted tetrahydrofuranyl, an optionally substituted pyrrolidinyl or an optionally substituted pyrazolyl. Preferably, when Cy1 is substituted, the substituent is selected from halogen, an optionally substituted C 1-4 Alkyl, optionally substituted C1-4 Alkoxy, optionally substituted C 3-6 Preferably, said C is selected from the group consisting of cycloalkyl, optionally substituted amino and cyano. 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 Cycloalkyl is halogen, hydroxyl, and -NR a R b C replaced with 1-4 alkyl, a and R b are independently H or C 1-4 alkyl, and the amino is one or two C 1-4 It is optionally substituted with alkyl.

[0042] In one or more embodiments of the compounds of formula IIa and IIb, Cy2 is an optionally substituted 6-14 membered aryl group, an optionally substituted 5-10 membered heteroaryl group, an optionally substituted C 3-8 Preferably, Cy2 is an optionally substituted heteroaryl group, preferably an optionally substituted 5-10 membered nitrogen-containing heteroaryl group, more preferably a 5 membered nitrogen-containing heteroaryl group. In some preferred embodiments, Cy2 is an optionally substituted imidazolyl or an optionally substituted pyrazolyl. Preferably, when Cy2 is substituted, the substituents are halogen, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Alkoxy and optionally substituted C 3-6 Preferably, Cy2 is an optionally substituted C 1-4 Alkyl-substituted imidazolyl or optionally substituted C 1-4 Preferably, the C is a pyrazolyl substituted with an alkyl group. 1-4 Alkyl and C 1-4 Alkoxy is halogen, hydroxyl and -NRa R b C replaced with 1-4 R is optionally substituted with 1 to 5 substituents selected from the group consisting of alkyl, a and R b are independently H or C 1-4 In some further preferred embodiments, Cy2 is C 1-4 Alkyl, C 3-6 Cycloalkyl and halogenated C 1-4 In some further preferred embodiments, Cy2 is substituted with 1-3 groups selected from the group consisting of alkyl. 1-4 Alkyl and halogenated C 1-4 In some embodiments, Cy2 is substituted with 1-3 groups selected from the group consisting of alkyl. 1-4 Alkyl and halogenated C 1-4 In some embodiments, Cy2 is C 1-4 Alkyl, C 3-6 Cycloalkyl and halogenated C 1-4 imidazolyl substituted with two substituents selected from the group consisting of alkyl, one of which is C 1-4 It is substituted with alkyl.

[0043] In one or more embodiments of the compounds of formula IIa and IIb, Cy1 is optionally substituted phenyl, optionally substituted pyridyl, 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 halogen, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Alkoxy and C 3-6 cycloalkyl, preferably C 1-4 Alkyl, C 1-4 Alkoxy and C 3-6The fused heteroaromatic bicyclic ring comprising A1, A2, B3, B4 and B5 is selected from the group consisting of:

[0044] [ka]

[0045] *1 and *2 refer to the attachment positions of the groups to the Cy1 and methylene groups of the compound, respectively. The aryl or heteroaryl containing D1, D2, D3 and D4 are not halogen, C 1-4 Alkyl or C 1-4 Cy2 is phenyl optionally substituted with 1-2 substituents selected from the group consisting of alkoxy. 1-4 Alkyl, halogenated C 1-4 Alkyl and C 3-6 imidazolyl or pyrazolyl optionally substituted with 1-3 substituents selected from the group consisting of cycloalkyl, and preferably Cy2 is C 1-4 Alkyl, C 3-6 Cycloalkyl and halogenated C 1-4 imidazolyl substituted with two substituents selected from the group consisting of alkyl, one of which is C 1-4 It is substituted with alkyl.

[0046] The present invention relates to compounds of formula IIIa and IIIb

[0047] [ka]

[0048] or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, provided that B3, B4, B5, Cy1 and Cy2 are as defined in any of the embodiments of Formula I or Formula II.

[0049] In one or more embodiments of the compounds of formula IIIa and IIIb, B3, B4, and B5 are each independently selected from the group consisting of N and CR2, where 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, and R2 is each independently H, halogen or C. 1-4 In some embodiments, B3 is N, B4 and B5 are both CR2, and R2 is each independently H, halogen or C. 1-4 In some embodiments, B4 is N, B3 and B5 are both CR2, and each R2 is independently H, halogen, or C. 1-4 In some embodiments, B5 is N, B3 and B4 are both CR2, and each R2 is independently H, halogen, or C. 1-4 Preferably, each R2 is H.

[0050] In one or more embodiments of the compounds of formula IIIa and IIIb, the fused heteroaromatic bicyclic ring comprising B3, B4 and B5 is selected from the group consisting of:

[0051] [ka]

[0052] *1 and *2 refer to the positions of attachment of the groups to Cy1 and the remainder of the compound, respectively.

[0053] In one or more embodiments of the compounds of formula IIIa and IIIb, Cy1 is optionally substituted C 3-8cycloalkyl, an optionally substituted 4-10 membered heterocyclic group, an optionally substituted 6-14 membered aryl group or an optionally substituted 5-10 membered heteroaryl group. In some further preferred embodiments, the 5-10 membered heteroaryl group is a nitrogen-containing monocyclic heteroaryl group. Preferably, Cy1 is an optionally substituted phenyl, an optionally substituted pyridyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted pyridazinyl, an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted tetrahydrofuranyl, an optionally substituted pyrrolidinyl or an optionally substituted pyrazolyl. Preferably, when Cy1 is substituted, the substituent is selected from halogen, an optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Alkoxy, optionally substituted C 3-6 Preferably, said C is selected from the group consisting of cycloalkyl, optionally substituted amino and cyano. 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 Cycloalkyl is halogen, hydroxyl, and -NR a R b C replaced with 1-4 alkyl, a and R b are independently H or C 1-4 alkyl, and the amino is one or two C 1-4 It is optionally substituted with alkyl.

[0054] In one or more embodiments of the compounds of Formula IIIa and IIIb, Cy2 is an optionally substituted 6-14 membered aryl group, an optionally substituted 5-10 membered heteroaryl group, an optionally substituted C 3-8Preferably, Cy2 is an optionally substituted heteroaryl group, preferably an optionally substituted 5-10 membered nitrogen-containing heteroaryl group, more preferably a 5 membered nitrogen-containing heteroaryl group. In some preferred embodiments, Cy2 is an optionally substituted imidazolyl or an optionally substituted pyrazolyl. Preferably, when Cy2 is substituted, the substituents are halogen, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Alkoxy and optionally substituted C 3-6 Preferably, Cy2 is an optionally substituted C 1-4 Alkyl-substituted imidazolyl or optionally substituted C 1-4 Preferably, the C is a pyrazolyl substituted with an alkyl group. 1-4 Alkyl and C 1-4 Alkoxy is halogen, hydroxyl and -NR a R b C replaced with 1-4 R is optionally substituted with 1 to 5 substituents selected from the group consisting of alkyl, a and R b are independently H or C 1-4 In some further preferred embodiments, Cy2 is C 1-4 Alkyl, C 3-6 Cycloalkyl and halogenated C 1-4 In some further preferred embodiments, Cy2 is substituted with 1-3 groups selected from the group consisting of alkyl. 1-4 Alkyl and halogenated C 1-4 In some embodiments, Cy2 is substituted with 1-3 groups selected from the group consisting of alkyl. 1-4 Alkyl and halogenated C 1-4 In some embodiments, Cy2 is C 1-4 Alkyl, C 3-6 Cycloalkyl and halogenated C 1-4imidazolyl substituted with two substituents selected from the group consisting of alkyl, one of which is C 1-4 It is substituted with alkyl.

[0055] In one or more embodiments of the compounds of formula IIIa and IIIb, Cy1 is optionally substituted phenyl, optionally substituted pyridyl, 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 halogen, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Alkoxy and C 3-6 cycloalkyl, preferably C 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 The fused heteroaromatic bicyclic ring comprising B3, B4 and B5 is selected from the group consisting of:

[0056] [ka]

[0057] *1 and *2 refer to the attachment positions of the groups to Cy1 and methylene of the compound, respectively. The aryl or heteroaryl containing D1, D2, D3 and D4 are not halogen, C 1-4 Alkyl or C 1-4 Cy2 is phenyl optionally substituted with 1-2 substituents selected from the group consisting of alkoxy. 1-4 Alkyl, halogenated C 1-4 Alkyl and C 3-6 imidazolyl or pyrazolyl optionally substituted with 1-3 substituents selected from the group consisting of cycloalkyl, and preferably Cy2 is C 1-4 Alkyl, C 3-6 Cycloalkyl and halogenated C1-4 imidazolyl substituted with two substituents selected from the group consisting of alkyl, one of which is C 1-4 It is substituted with alkyl.

[0058] In one or more of the foregoing embodiments, preferred compounds of Formula I (including Formula IIa / b and Formula IIIa / b) include, but are not limited to, the following: 8-(4-(1,4-dimethyl-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-[1,2,4]triazolo[1,5-a]pyridine (Example 1); 8-(4-(1,4-dimethyl-1H-imidazol-2-yl)benzyl)-2-(2-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine (Example 2); 2-(2-isopropylphenyl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine (Example 3); 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); 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); 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); 2-(2-isopropylphenyl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazine (Example 7); 2-(2-isopropylphenyl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-c]pyrimidine (Example 8); 2-(2-isopropylphenyl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-b]pyridazine (Example 9); 2-(2-isopropylphenyl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine (Example 10); 2-(2-isopropylphenyl)-7-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrimidine (Example 11); 2-(2-isopropylphenyl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyrazine (Example 12); 2-(2-isopropylphenyl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-c]pyrimidine (Example 13); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate, or pharma- ceutically acceptable salt thereof, or a mixture thereof or a prodrug thereof.

[0059] As used herein, the term “hydrogen (H)” includes its isotopes D and T.

[0060] The term "alkyl" as used herein refers to alkyl itself or to a straight or branched chain radical of up to ten carbons. Useful alkyl groups include straight or branched C 1-10 Alkyl groups, preferably C 1-6 In some embodiments, the alkyl group is C 1-4 In some embodiments, the alkyl group is a C 1-3 In some embodiments, the alkyl group is a deuterated C 1-3 It is an alkyl group. Typical C 1-10 Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl (including 3-pentyl), hexyl, and octyl groups, and may be optionally substituted.

[0061] The term "alkenyl" as used herein, unless the chain length is limited thereto, refers to a straight or branched chain radical of 2-10 carbon atoms and at least one double bond between any two carbon atoms in the chain. 2-6Exemplary alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl.

[0062] The term "alkynyl" as used herein, unless the chain length is limited thereto, refers to a straight or branched chain radical of 2-10 carbon atoms and at least one triple bond between any two carbon atoms in the chain. 2-6 Exemplary alkynyl groups include ethynyl, 1-propynyl, 1-methyl-2-propynyl, 2-propynyl, 1-butynyl and 2-butynyl.

[0063] Useful alkoxy groups include those listed above. 1-10 Alkyl groups, preferably C 1-6 Alkyl group or C 1-4 Included are oxygen substituted with alkyl groups, such as methoxy, ethoxy, etc. The alkyl in the alkoxy group may be substituted. The alkoxy group substituents include, but are not limited to, halogen, morpholinyl, amino (alkylamino and dialkylamino), and carboxyl (including esters thereof).

[0064] Useful amino and optionally substituted amino groups include -NH, -NHR' and -NR'R'', where -NHR' and -NR'R'' are each independently hydrogen, optionally substituted C 1-10 Alkyl (preferably C 1-4 alkyl), optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl. In some embodiments, -NHR' and -NR'R'' together with the N to which they are attached form an optionally substituted 4-7 membered cyclic amino group, optionally containing one or more (e.g., 2, 3) additional heteroatoms selected from O, N and S.

[0065] The term "aryl group" as used herein alone or as part of another substituent refers to a monocyclic, bicyclic, or tricyclic aromatic group containing 6-14 carbon atoms. Aryl groups may be optionally substituted with one or more substituents described herein.

[0066] Useful aryl groups include C 6-14 Aryl groups, preferably C 6-10 Contains aryl groups. Typical C 6-14 The aryl group includes a phenyl group, a naphthalene group, a phenanthryl group, an anthracyl group, an indenyl group, an azuryl group, a biphenyl group, a biphenylene group and a fluorenyl group.

[0067] As used herein, the term "carbocyclic group" includes cycloalkyl and partially saturated carbocyclic groups. Useful cycloalkyl groups include C 3-8 Cycloalkyl. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Carbocyclic groups may be substituted with one or more substituents described herein.

[0068] Useful partially saturated carbocyclic groups include C 3-8 Cycloalkenyl groups are included, ie, cycloalkenyl groups such as cyclopentenyl, cycloheptenyl and cyclooctenyl.

[0069] Useful halogens or halogen groups include fluoro, chloro, bromo and iodo.

[0070] The term "heterocyclic group" as used herein refers to a saturated or partially saturated 3-7 membered monocyclic or 7-10 membered bicyclic group consisting of carbon atoms and 1-4 heteroatoms independently selected from O, N, S. The nitrogen and / or sulfur heteroatoms may be optionally oxidized and the nitrogen may be optionally quaternized. The term also includes any bicyclic ring system in which any of the heterocycles defined above are fused to a benzene ring. The heterocycle may be substituted at a carbon or nitrogen atom if a stable compound is obtained. The heterocyclic group may be substituted with one or more of the substituents described herein. The above mentioned heterocyclic groups also include 5-8 membered heterocycloalkyl groups, i.e., heterocyclic groups in which one or more ring C atoms in the cycloalkyl group are substituted with a heteroatom selected from N, O and S.

[0071] 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, oxadiazolyl, oxazolyl, and tetramoyl, each of which may be optionally substituted with one or more substituents described herein.

[0072] The term "heteroaryl" as used herein refers to groups having 5-14 ring atoms, preferably 5-10 ring atoms, in which 6, 10, or 14 electrons are shared in a cyclic arrangement. The ring atoms are carbon atoms and 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur. Heteroaryl groups may be optionally substituted with one or more substituents described herein.

[0073] Useful heteroaryl groups include thienyl (thiophenyl), benzo[d]isothiazol-3-yl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (furanyl), pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl (including but not limited to pyridinyl: 2-pyridyl, 3-pyridyl, and 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinozalinyl, and the like. These include aryl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, tetrahydrocyclopenta[c]pyrazol-3-yl, benzoisoxazolyl, such as 1,2-benzisoxazol-3-yl, benzimidazolyl, 2-oxindolyl, thiadiazolyl, 2-oxobenzisoxazole, imidazopyridazinyl, imidazopyridyl, triazolopyridazinyl, pyrazolopyrimidinyl, pyrrolopyrimidinyl, pyrrolopyridyl, pyrrolopyrazinyl or triazolopyrazinyl. When the heteroaryl group contains a nitrogen atom in a ring, the nitrogen atom may be an N-oxide, for example, pyridyl-N-oxide, pyrazinyl-N-oxide, and pyrimidinyl-N-oxide.

[0074] In the present invention, unless otherwise stated, when substituted, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, heterocycle, aryl or heteroaryl as described in any embodiment herein can be substituted with halogen, amino, cyano, C 1-6 Alkoxy, C 1-6 Alkyl, C 6-10 Aryl, C 3-8 Cycloalkyl, C 2-6 Chain alkenyl, C 2-6The alkyl group may be substituted with one or more (e.g., 1, 2, 3, or 4) substituents selected from alkynyl, heterocyclic, heteroaryl, etc., and the one or more substituents may themselves be substituted. Preferred substituents include cyano, halogenated C 1-6 Alkyl, halogen, amino, halogenated C 1-6 Alkoxy, C 1-6 Alkyl and C 3-8 Includes, but is not limited to, cycloalkyl.

[0075] It should be understood that in embodiments, when a substituent is a cyano, cycloalkyl, heterocyclic, aryl or heteroaryl group, the number will typically be one.

[0076] 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 those stereoisomers, as well as the individual enantiomers that can be separated according to methods known to those skilled in the art.

[0077] Examples of pharma- ceutically acceptable salts include inorganic and organic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate, and oxalate salts; inorganic and organic base salts formed with bases such as sodium hydroxy, tris(hydroxymethyl)aminomethane (TRIS, tromethamine), and N-methyl-glucamine.

[0078] Examples of prodrugs of the compounds of the invention include simple esters of carboxylic acid-containing compounds (e.g., C, 1-4 esters of hydroxy-containing compounds (e.g., those obtained by condensation with alcohols); 1-4 Carboxylic acid, C 3-6 diacids or their anhydrides, such as those obtained by condensation with succinic anhydride and fumaric anhydride; imines of amino-containing compounds (e.g., C according to methods known in the art); 1-4carbamates of amino-containing compounds, such as those described by Leu, et al., (J. Med. Chem. 42:3623-3628 (1999)) and Greenwald, et al., (J. Med. Chem. 42:3657-3667 (1999)); and acetals and ketals of alcohol-containing compounds, such as those obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether according to methods known in the art.

[0079] The compounds of the present invention can be prepared by methods known to those skilled in the art or by the novel methods of the present invention. In particular, the compounds of formula I (including formula IIa / b and formula IIIa / b) of the present invention can be prepared according to the reaction illustrated in Scheme 1. The reaction of methyl 2-aminonicotinate with O-(mesitylsulfonyl)hydroxylamine produced 1,2-diamino-3-(methoxycarbonyl)pyridin-1-ium·2,4,6-trimethylbenzenesulfonate. The reaction of 1,2-diamino-3-(methoxycarbonyl)pyridin-1-ium·2,4,6-trimethylbenzenesulfonate with 2-isopropylbenzaldehyde under KOH catalysis produced methyl 2-(2-isopropylphenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate. The reaction of methyl 2-(2-isopropylphenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate with LiAlH4 gave (2-(2-isopropylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)methanol. The reaction of (2-(2-isopropylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)methanol with PBr3 gave 8-(bromomethyl)-2-(2-isopropylphenyl)-[1,2,4]triazolo[1,5-a]pyridine. Suzuki coupling reaction of 8-(bromomethyl)-2-(2-isopropylphenyl)-[1,2,4]triazolo[1,5-a]pyridine with 1,4-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazole under Pd(PPh3)2Cl2 catalysis afforded the target compound 8-(4-(1,4-dimethyl-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-[1,2,4]triazolo[1,5-a]pyridine.

[0080] [ka]

[0081] Other related compounds can be prepared similarly. For example, when 2-isopropylbenzaldehyde is replaced 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 is produced. When 1,4-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazole was replaced with 1-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)-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 was produced.

[0082] The compounds of the present invention can be prepared according to the reactions illustrated in Scheme 2. The reaction of 6-methylpyridin-2-amine with O-ethyl carboisothiocyanatidate produced carbamic acid, [[(6-methyl-2-pyridinyl)amino]thioxomethyl]-ethyl ester. The reaction of carbamic acid, [[(6-methyl-2-pyridinyl)amino]thioxomethyl]-ethyl ester and hydroxylamine hydrochloride produced 5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine. The Sandmeyer reaction of 5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine with NaNO2 / HCl produced 2-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyridine. The reaction of 2-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyridine with N-bromosuccinimide (NBS) under the catalysis of 2,2'-azobis(2-methylpropionitrile) (AIBN) afforded 5-(bromomethyl)-2-chloro-[1,2,4]triazolo[1,5-a]pyridine. Suzuki coupling reaction of 5-(bromomethyl)-2-chloro-[1,2,4]triazolo[1,5-a]pyridine with (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)boronic acid under Pd(PPh3)2Cl2 catalysis afforded 2-chloro-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine. Suzuki coupling reaction of 2-chloro-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine with (2-isopropylphenyl)boronic acid catalyzed by methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane (cataCXium A Pd G3) afforded 2-(2-isopropylphenyl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine.

[0083] [ka]

[0084] Other related compounds can be prepared similarly. For example, when (2-isopropylphenyl)boronic acid is replaced with (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid, 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 is generated. When (2-isopropylphenyl)boronic acid is replaced with (1-isopropyl-4-methyl-1H-pyrazol-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 is generated.

[0085] The compounds of the present invention can be prepared according to the reaction illustrated in Scheme 3. Negishi cross-coupling reaction of 3-bromopyrazin-2-amine with 2-(4-(bromomethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole under Pd(PPh3)4 catalysis afforded 3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrazin-2-amine. Reaction of 3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrazin-2-amine with O-(mesitylsulfonyl)hydroxylamine afforded 1,2-diamino-3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrazin-1-ium·2,4,6-trimethylbenzenesulfonate. 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-a]pyrazine) was produced by the reaction of 1,2-diamino-3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrazin-1-ium·2,4,6-trimethylbenzenesulfonate with 4-cyclopropyl-6-methoxypyrimidine-5-carbaldehyde under Cs2CO3 catalysis.

[0086] [ka]

[0087] Other related compounds can be prepared similarly. For example, when 3-bromopyrazine-2-amine is replaced with 5-bromopyrimidin-4-amine, 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 is produced. When 3-bromopyrazine-2-amine is replaced with 2-bromopyrimidin-4-amine, 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 is produced. When 3-bromopyrazine-2-amine was replaced with 6-bromopyrazine-2-amine, 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]pyrazine was produced. When 3-bromopyrazine-2-amine was replaced with 4-bromopyrimidin-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-c]pyrimidine was produced.

[0088] One important aspect of the present invention is the discovery that the compounds of formula I (including the compounds of formula IIa / b and formula IIIa / b described herein) are USP1 inhibitors. Thus, the compounds of formula I (including the compounds of formula IIa / b and formula IIIa / b described herein) can be used to treat or prevent diseases associated with USP1 regulation, such as cancer. Or can be used to prepare a medicament for treating or preventing diseases associated with USP1 regulation, such as cancer. USP1-modulated or USP1-mediated diseases are diseases in which USP1 is involved in the development and progression of the disease, and diseases that benefit from the inhibition of USP1 activity.

[0089] The present invention also includes a method for treating or preventing diseases associated with USP1 regulation, in particular a method for treating or preventing diseases associated with USP1 regulation and a method for treating or preventing diseases caused by a deficiency in DDR function, comprising administering to a subject (particularly a mammal, more particularly a human) in need thereof an effective amount of a compound of formula I (including the compounds of formula IIa / b and formula IIIa / b described herein) or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate or pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula I (including the compounds of formula IIa / b and formula IIIa / b described herein) or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate or pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof.

[0090] In the present invention, the disease associated with USP1 regulation includes cancer.Preferably, the cancer associated with USP1 regulation is defective in DDR function.Diseases associated with USP1 regulation that can be treated or prevented by the method or pharmaceutical composition of the present invention include liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, non-small cell lung cancer, and the like. Cancer, small cell lung cancer, gastric cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinomatous carcinoma, choriocarcinoma, fungal mycosis, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary tumors, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, multiple erythrocytosis, idiopathic thrombocytemia, adrenocortical carcinoma, skin cancer and prostate cancer.

[0091] The present invention also includes methods for the treatment or prevention of other diseases caused by excessive or abnormal cell proliferation, including proliferative or hyperproliferative diseases such as myeloproliferative diseases, particularly proliferative or hyperproliferative diseases caused by excessive or abnormal cell proliferation associated with USP1 regulation. Thus, the present invention also includes compounds of formula I (including compounds of formula IIa / b and formula IIIa / b described herein) for the treatment or prevention of other diseases caused by excessive or abnormal cell proliferation, particularly proliferative or hyperproliferative diseases caused by excessive or abnormal cell proliferation associated with USP1 regulation.

[0092] In carrying out the treatment method, an effective amount of a pharmaceutical preparation is administered to an individual who exhibits one or more symptoms of these disorders. The pharmaceutical preparation contains a therapeutically effective concentration of a compound of formula I, formula IIa / b or formula IIIa / b and is applied for oral, intravenous, local or topical administration for the treatment of cancer and other diseases. The amount is effective to improve or eliminate one or more symptoms of the disorder. An effective amount of a compound for treating a particular disease is an amount sufficient to improve or in some way alleviate symptoms associated with the disease. The amount may be administered as a single dose or according to an effective regimen. The amount may be administered to improve symptoms of the disease, although it may cure the disease. Repeated administration is usually required to achieve the desired improvement in symptoms.

[0093] In another embodiment, there is provided a pharmaceutical composition comprising a compound of Formula I, Formula IIa / b or Formula IIIa / b, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharma- ceutically acceptable salt thereof as a USP1 inhibitor and one or more pharma- ceutically acceptable excipients or carriers.

[0094] Another embodiment of the present invention relates to a pharmaceutical composition effective for treating cancer, comprising a compound of formula I, formula IIa / b or formula IIIa / b as a USP1 inhibitor, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or a pharmaceutically acceptable salt or a prodrug thereof, in combination with at least one known anticancer drug or a pharmaceutically acceptable salt thereof. In particular, the compound herein can be combined with other anticancer drugs related to DNA damage and repair mechanisms, including PARP inhibitors such as olaparib, niraparib, rucaparib, talazoparib, pamiparib, fluzovalib and senaparib; HDAC inhibitors such as Volinota, Romididesin, Papiseta and Bailesta, and the like. The compound herein can also be combined with other anticancer drugs related to cell division detection sites, including Chk1 / 2 inhibitors, CDK4 / 6 inhibitors such as paposinib, ATM inhibitors, Wee1 inhibitors, ATR inhibitors, Myt1 inhibitors, DNA-PK inhibitors, and the like. It can also be used in combination with other targeted anticancer drugs, including PRMT5 inhibitors, Polθ inhibitors, and RAD51 inhibitors.Other known anti-cancer agents that can be used in the anti-cancer combination therapy include alkylating agents, such as busulfan, melphalan, chloroambucil, 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, aclacinomycin, mitoxantrone, elliptinium, and etoposide; RNA / DNA antimetabolites, such as 5-azacytidine, gemcitabine, 5-fluorouracil, capecitabine and methotrexate;DNA antimetabolites, such as 5-fluoro-2'-deoxyuridine, fludarabine, nelarabine, cytarabine, pralatrexate, pemetrexed, hydroxycarbamide and thioguanine;mitotic inhibitors, such as colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel and docetaxel;antibodies, such as mAb, panitum Mab, necitumumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab, tositumomab, brentuximab, daratumumab, elotuzumab, ofatumumab, dinutuximab, blinatumomab, ipilimumab, Avastin, Herceptin, MabThera; antibody-drug conjugates (ADCs), e.g. T-DM1, trastuzumab deruxtecan, trastuzumab emtansine, datos potamab deruxtecan, gemtuzumab ozogamicin, brentuximab vedotin, inotuzumab ozogamicin, sacituzumab govitecan, enfortumab vedotin, belantamab mafodotin; kinase inhibitors, such as imatinib, gefitinib, erlotinib, osimertinib, afatinib, ceritinib, alectinib, crizotinib, erlotinib, lapatinib, sorafenib, sunitinib, nilotinib, dasatinib, pazopanib, torisel, and everolimus.Other known anticancer drugs that can be used in the anticancer combination therapy include tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide, venetoclax, aldesleukin (recombinant human interleukin-2), and sipuecel-T (a prostate cancer therapeutic vaccine).

[0095] In carrying out the method of the present invention, the compound of the present invention may be administered together with at least one known anti-cancer drug in a single pharmaceutical composition. The compound of the present invention may also be administered separately from at least one known anti-cancer drug. In one embodiment, the compound of the present invention and at least one known anti-cancer drug are administered substantially simultaneously, i.e., all drugs are administered simultaneously or sequentially, so that the compounds reach therapeutic concentrations in the blood at the same time. In another embodiment, the compound of the present invention and at least one known anti-cancer drug are administered according to individual dosing schedules so that the compounds reach therapeutic concentrations in the blood.

[0096] Another embodiment of the present invention relates to a bioconjugate comprising a compound described herein and functioning as a USP1 inhibitor effective in inhibiting tumors. The tumor inhibiting bioconjugate comprises a compound described herein and at least one known therapeutically useful antibody, such as trastuzumab or rituximab, or a growth factor, such as EGF or FGF, or a cytokine, such as IL-2 or IL-4, or any molecule capable of binding to a cell surface. Antibodies and other molecules can deliver the compounds described herein to their target, making them effective anti-cancer agents. The bioconjugate can also enhance the anti-cancer effect of therapeutically useful antibodies, such as trastuzumab or rituximab.

[0097] Another embodiment of the present invention relates to a pharmaceutical composition comprising a USP1 inhibitor of formula I (including formula IIa / b and formula IIIa / b), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or a pharma- ceutically acceptable salt or prodrug thereof, which is effective for inhibiting tumors in combination with radiation therapy. In this embodiment, the compound of the present invention can be administered simultaneously with radiation therapy or at different times.

[0098] Yet another embodiment of the present invention relates to a pharmaceutical composition comprising a USP1 inhibitor of formula I, formula IIa / b or formula IIIa / b, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or a pharma- ceutically acceptable salt or prodrug thereof, effective for the post-operative treatment of cancer. The present invention also relates to a method of treating cancer by treating a mammal with the pharmaceutical composition described herein after surgical removal of a tumor.

[0099] The pharmaceutical composition of the present invention includes all pharmaceutical formulations containing the compound of the present invention in an amount effective to achieve its intended purpose. Although individual needs vary, determining the optimal amount of each component in a pharmaceutical formulation is within the skill of one of ordinary skill in the art. Typically, the compound or its pharma- ceutically acceptable salt can be orally administered to a mammal at a dose of about 0.0025-50 mg per kilogram of body weight per day. Preferably, it is orally administered at about 0.01 mg / kg to about 10 mg / kg of body weight. If a known anti-cancer agent is also administered, it is administered in an amount effective to achieve its intended purpose. The optimal amount of the known anti-cancer agent is well known to those of ordinary skill in the art.

[0100] A unit oral dose may contain from about 0.01 to about 50 mg, preferably from about 0.1 to about 10 mg, of a compound of the invention. The unit dose may be administered one or more times daily in one or more tablets, each tablet containing from about 0.1 to about 50 mg, preferably from about 0.25 to 10 mg, of a compound of the invention or a solvate thereof.

[0101] In a topical formulation, the compounds of the invention may be present in a concentration of about 0.01 to 100 mg per gram of carrier.

[0102] The compounds of the present invention can be administered as raw chemicals. They may also be administered as part of suitable pharmaceutical preparations that contain pharma- ceutically acceptable carriers (including excipients and auxiliaries) that facilitate processing of the compounds into pharma- ceutically acceptable preparations. Preferably, pharmaceutical preparations, especially oral preparations such as tablets, dragees, and capsules, as well as those used for preferred administration, and solutions suitable for injection or oral administration, contain about 0.01% to 99%, preferably about 0.25% to 75%, of one or more active compounds, and one or more excipients.

[0103] Also included within the scope of the present invention are non-toxic pharmaceutically acceptable salts of the compounds of the present invention. Acid addition salts are formed by mixing a solution of a compound of the present invention with a solution of a pharmaceutically acceptable non-toxic acid, such as, 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 solution of one or more compounds of the present invention with a solution of a pharmaceutically acceptable non-toxic base, such as, for example, sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, tris(hydroxymethyl)aminomethane, N-methylglucamine, etc.

[0104] The pharmaceutical formulations of the present invention can be administered to any mammalian subject so long as the therapeutic effect of the compounds of the present invention can be obtained, most importantly, however, human and veterinary animals, without the intention of limiting the invention thereto.

[0105] The pharmaceutical preparation of the present invention can be administered by any means that achieves its intended purpose.For example, administration can be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal or topical route.Alternatively or additionally, administration can be by oral route.The dosage depends on the age, health and weight of the recipient, the type of concurrent treatment, the frequency of treatment, and the nature of the desired effect.

[0106] The pharmaceutical preparations of the present invention are prepared in a known manner, for example by conventional mixing, granulation, sugar-making, dissolving or lyophilization. Pharmaceutical preparations for oral use are obtained by combining the active compound with a solid excipient, grinding the resulting mixture if necessary, and processing the mixture of granules to obtain tablets or dragees, after adding suitable auxiliaries as required and as required.

[0107] Suitable excipients are in particular fillers, such as sugars, for example lactose or sucrose, mannitol or sorbitol; cellulose preparations and / or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate; binders, for example starch pastes, including corn starch, for example wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone. If necessary, disintegrants, such as the above-mentioned starches and carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, for example sodium alginate, can be added. Auxiliaries are in particular flow regulators and lubricants, for example silica, talc, stearic acid or a salt thereof, for example magnesium stearate or calcium stearate, and / or polyethylene glycol. Dragee cores are provided with suitable coatings, if necessary, resistant to gastric juices. For this purpose, gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions and concentrated sugar solutions, which may contain suitable organic solvents or solvent mixtures, can be used. To produce coatings that are resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, are used. Dyes or pigments can be added to the tablet or dragee coating, for example for identification or to characterize dose combinations of active compounds.

[0108] Other pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and plasticizers, such as glycerol or sorbitol. Push-fit capsules may contain the active compound in granular form, which can be mixed with fillers such as lactose; binders such as starch; and / or lubricants such as talc or magnesium stearate; and stabilizers. In soft capsules, the active compound is preferably dissolved or suspended in a suitable liquid, such as fatty oils or liquid paraffin. Stabilizers can also be added.

[0109] Suitable formulations for parenteral administration include aqueous solutions of the active compound, for example aqueous solutions of water-soluble salts and alkaline solutions. In addition, suspensions of the active compound can be administered as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate, triglycerides, or polyethylene glycol-400, or cremophor, or cyclodextrin. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, and / or dextran. Suspension stabilizers may also be included as needed.

[0110] According to one aspect of the invention, the compounds of the invention are provided in a topical parenteral formulation and used to treat skin cancer.

[0111] The topical formulations of the present invention are preferably formulated as oils, creams, lotions, ointments, etc., by selection of an appropriate carrier. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched oils, animal fats, and high molecular weight alcohols (C 12The preferred carriers include those in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants and antioxidants may also be included, as well as agents to impart color or fragrance, if desired. Additionally, these topical formulations may include transdermal penetration enhancers. Examples of such enhancers include those described in U.S. Patents 3,989,816 and 4,444,762.

[0112] Creams are preferably formulated from a mixture of mineral oil, self-emulsifying beeswax and water, mixed with the active ingredient dissolved in a small amount of oil, such as almond oil, A typical example of such a cream would include about 40 parts water, about 20 parts beeswax, about 40 parts mineral oil and about 1 part almond oil.

[0113] Ointments can be formulated by mixing a solution of the active ingredient in a vegetable oil (e.g., almond oil) with warm soft paraffin and then cooling the mixture. A typical example of such an ointment would be one that contains about 30% almond oil and about 70% white ointment by weight.

[0114] The present invention also includes the use of the compounds of the present invention for the preparation of a medicament for the treatment or prevention of a clinical condition responsive to the effects of inhibiting the activity of USP1. The medicament may include a pharmaceutical composition as described above.

[0115] The following examples are illustrative of the methods and compositions of the present invention, but are not intended to be limiting thereof. Other suitable modifications and adjustments of the various conditions and parameters normally encountered in clinical therapy and which are obvious to those skilled in the art are within the spirit and scope of the invention. EXAMPLES

[0116] Overview All reagents were of commercial quality. Solvents were dried and purified by standard methods. Mass spectral analyses were recorded on a Platform II (Agilent 6110) single quadrupole mass spectrometer equipped with an electrospray interface. 1H NMR spectra were recorded at 400 MHz on a Brucker Ascend 400 instrument. Chemical shifts are reported in parts per million (ppm) downfield from TMS (0.00 ppm) and J coupling constants are reported in Hertz (Hz).

[0117] Example 1 8-(4-(1,4-dimethyl-1H-imidazol-2-yl)benzyl)-2-(2-isopropylphenyl)-[1,2,4]triazolo[1,5-a]pyridine a) Preparation of methyl-2-(2-isopropylphenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate: To a stirred solution of methyl 2-aminonicotinate (0.6 g, 3.9 mmol) in dioxane (50 mL) under N2, O-(mesitylsulfonyl)hydroxylamine (1.0 g, 4.7 mmol in 10 mL DCM) was added and the mixture was stirred at room temperature for 2 h. Then, 2-isopropylbenzaldehyde (0.7 g, 4.7 mmol) was added and the mixture was stirred at 100° C. for 2 h. The reaction was cooled to room temperature, then KOH (1N in MeOH, 10 mL) was added and stirred at room temperature for 1 h. Water was added to the mixture and the mixture was extracted with ethyl acetate (30 mL×3). The combined organic layer was washed twice with water and then with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (600 mg, white solid, 51.5% yield), which was used in the next step without further purification. MS (ESI, m / z): 296.1 [M+H] + .

[0118] b) Preparation of (2-(2-isopropylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)methanol: To a solution of methyl 2-(2-isopropylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-8-carboxylate (600.0 mg, 2.0 mmol) in dry THF (60 mL) was added LiAlH4 (1.6 mL, 4.0 mmol, 2.5 M in toluene) over 10 min at 0 °C. The reaction mixture was allowed to warm to room temperature. After completion of the reaction, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give the title compound (500 mg, white solid, 92.1% yield) which was carried on to the next step without further purification. MS (ESI, m / z): 268.1 [M+H] + .

[0119] c) Preparation of 8-(bromomethyl)-2-(2-isopropylphenyl)-[1,2,4]triazolo[1,5-a]pyridine: To a solution of (2-(2-isopropylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)methanol (400 mg, 1.5 mmol) in dry DCM (40 mL) was added PBr3 (485 mg, 1.7 mmol) at 0° C., and the mixture was stirred at room temperature for 2 h. The reaction was then quenched with saturated NaHCO3 solution (20 mL) and extracted with DCM (20 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate=10:1) to give the title compound (270 mg, white solid, 54.6% yield). MS (ESI, m / z): 330.0 [M+H] + . 1 H NMR (300 MHz, DMSO-d6): δ 8.99 (dd, J = 6.8, 1.1 Hz, 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 = 6.9 Hz, 6H).

[0120] 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), Na2CO3 (193 mg, 1. A solution of 1,4-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazole (181 mg, 0.6 mmol) and Pd(PPh3)2Cl2 (43 mg, 0.06 mmol) in 1,4-dioxane (20 mL) and water (7 mL) was stirred at 60 °C under N2 for 2 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3), the organic layer was dried over Na2SO4, filtered, concentrated and purified by preparative HPLC (ACN / water = 25% / 75%, 0.1% FA as additive) to give the target compound (30 mg, white solid, 11.7%).

[0121] The following compounds, Examples 2-9, were prepared using synthetic methods similar to those described in Example 1.

[0122] [Table 1]

[0123] [Table 2]

[0124] Example 10 2-(2-isopropylphenyl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-[1,2,4]triazolo[1,5-a]pyridine a) Preparation of carbamic acid, [[(6-methyl-2-pyridinyl)amino]thioxomethyl]ethyl ester: To a mixture of 6-methylpyridin-2-amine (5.0 g, 46.2 mmol) in 1,4-dioxane (50 mL) was added O-ethyl carboisothiocyanatidate (6.0 g, 45.8 mmol). The mixture was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum and washed with EtOAc (30 mL) to give the title compound (11 g, yellow solid, 99.6% yield). MS (ESI, m / z): 240.1 [M+H] + .

[0125] b) Preparation of 5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine: To a mixture of carbamic acid, [[(6-methyl-2-pyridinyl)amino]thioxomethyl]ethyl ester (11.0 g, 46.0 mmol) in EtOH (50 mL) and MeOH (50 mL) was added NH2OH·HCl (16.0 g, 231.0 mmol) and DIEA (17.8 g, 137.7 mmol). The mixture was stirred at room temperature overnight. The mixture was then concentrated under vacuum and washed with EtOAc (30 mL) to give the title compound (4 g, off-white solid, 58.8% yield). MS (ESI, m / z): 149.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 7.38 - 7.32 (m, 1H), 7.20 (d, J = 8.8 Hz, 1H), 7.79 - 7.72 (m, 1H), 5.96 (brs, 2H), 2.46 (s, 3H).

[0126] c) Preparation of 2-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyridine: To a solution of 5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine (1.0 g, 6.8 mmol) in ACN (20 mL) was added NaNO2 (559.2 mg, 8.1 mmol) at 0° C. Concentrated HCl (1 mL) was then added dropwise and the reaction mixture was stirred at 0° C. for 15 min. Additional concentrated HCl was then added until the mixed solids dissolved. The resulting mixture was stirred at 80° C. for 2 h. The mixture was added to ice water and extracted with DCM (50 mL×3), and the combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, concentrated in vacuo, and then purified by silica gel chromatography (hexane:EtOAc=20:1) to give the title compound (480 mg, off-white solid, 42.4% yield). MS (ESI, m / z): 168.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 7.68 - 7.62 (m, 2H), 7.16 - 7.12 (m, 1H), 2.66 (s, 3H).

[0127] d) Preparation of 5-(bromomethyl)-2-chloro-[1,2,4]triazolo[1,5-a]pyridine: To a mixture of 2-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyridine (480 mg, 2.8 mmol) in CCl4 (10 mL) was added NBS (613.8 mg, 3.4 mmol) and AIBN (47 mg, 0.3 mmol). The mixture was stirred at reflux overnight under nitrogen atmosphere. The resulting mixture was quenched with water (50 mL) and extracted with EtOAc (30 mL x 3), and the organic layer was dried over MgSO4, filtered, and concentrated. The concentrated residue was purified by silica gel chromatography (hexane / EtOAc = 10:1) to give the title compound (460 mg, white solid, 64.9% yield). MS (ESI, m / z): 246.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 7.86 - 7.82 (m, 1H), 7.78 - 7.74 (m, 1H), 7.48 - 7.46 (m, 1H), 5.07 (s, 2H).

[0128] 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 mixture of 5-(bromomethyl)-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (230 mg, 0.94 mmol) in dioxane (5 mL) was added (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)boronic acid (255 mg, 0.94 mmol), Pd(PPh3)2Cl2 (66 mg, 0.09 mmol) and Na2CO3 (300 mg, 2.8 mmol). The mixture was stirred at 60 °C under nitrogen atmosphere for 4 h. The resulting mixture was quenched with water (50 mL) and extracted with EtOAc (30 mL×3), and the organic layer was dried over Na2SO4, filtered, and concentrated. The concentrated residue was purified by silica gel chromatography (hexane / EtOAc=2:1) ​​to give the title compound (250 mg, yellow solid, 68.5% yield). MS (ESI, m / z): 246.0 [M+H] + .

[0129] 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 mixture 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) was added (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). The mixture was stirred at 120° C. for 4 hours under nitrogen atmosphere in a microwave reaction. The resulting mixture was quenched with water (30 mL), extracted with EtOAc (20 mL×3), and the organic layer was concentrated. The crude product was purified by preparative HPLC (ACN / 0.1% FA aq=10%) to give the target compound (11.3 mg, white solid, 6.6% yield).

[0130] The following compounds, Examples 11-17, were prepared using synthetic methods similar to those described in Examples 1 and 10.

[0131] [Table 3]

[0132] Example 18 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 a) Preparation of 3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrazin-2-amine: A solution of Zn (202.0 mg, 3.1 mmol), I2 (20.0 mg, 0.08 mmol) in DMF (10 mL) was stirred at 30° C. for 10 min under N2. TMSCl (8.0 mg, 0.08 mmol) was then added and stirred at 30° C. for 45 min, followed by addition of a solution of 2-(4-(bromomethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (95 mg, 0.26 mmol) in DMF (1 mL) and stirring at 45° C. for 1 h. The mixture was added to a system of Pd(PPh3)4 (30.0 mg, 0.026 mmol) and 3-bromopyrazin-2-amine (45 mg, 0.26 mmol), which was stirred under N2 at 60° C. for 2 h. After completion, the mixture was cooled to room temperature, water (100 mL) was added to the mixture, and extracted with EA (40 mL×3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH=10:1) to give the title compound (40.0 mg, white solid, 46% yield). MS(ESI): 334.25 [M+H] + .

[0133] b) Preparation of 1,2-diamino-3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrazin-1-ium·2,4,6-trimethylbenzenesulfonate: A solution of 3-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrazin-2-amine (40 mg, 0.12 mmol) and O-(mesitylsulfonyl)hydroxylamine (51.6 mmol, 0.24 mmol) in DCM (5 mL) was stirred at room temperature for 16 h. After completion, the solvent was evaporated to give the title compound (50.5 mg, yellow solid, crude) which was used directly in the next step. MS(ESI): 349.30 [M+H] + .

[0134] 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: 4-cyclopropyl-6-methoxypyrimidin-5-carbaldehyde (43 mg, 0.24 mmol) and Cs2CO3 (117 mg, 0.36 mmol) were added to a solution of 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) in dioxane (5 mL). The mixture was stirred at 90 °C for 2 h. After completion, the mixture was poured into water (50 mL) and extracted with EA (20 mL×3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative HPLC to give the target compound (5.0 mg, white solid, two-step yield: 9%).

[0135] The following compounds, Examples 19-47, were prepared using synthetic methods similar to those described in Example 18.

[0136] [Table 4]

[0137] [Table 5]

[0138] [Table 6]

[0139] [Table 7]

[0140] Example 48 USP1 / UAF1 activity USP1 / UAF1 activity was measured using the ubiquitin-rhodamine 110-glycine (Ub-Rho; Boston Biochem) assay. Enzymatic reactions were performed in assay buffer (50 mM Tris-HCl, pH 7.8, 0.5 mM EDTA, 100 mM NaCl, 1 mM DTT, 0.01 BSA and 0.01% Tween-20) containing 0.1 nM USP1 / UAF1. Each individual compound was tested at 10 concentrations ranging from 0.0005-10 μM. The plate was incubated for 15 min until equilibrium was reached, after which the enzymatic reaction was initiated by dispensing 10 μL of Ub-Rho solution (final concentration 100 nM). After 120 min of treatment with Ub-Rho solution, rhodamine fluorescence was acquired using a 480 nm excitation / 540 nm emission filter set using an Envision instrument. The USP1 / UAF1 enzyme activity inhibition rate of the compound was calculated according to the following formula.

[0141]

number

[0142] I C 50 The values ​​are obtained by fitting a sigmoidal dose-response curve equation using XL software. The equation of the curve is Y=100 / (1+10^(logC-logIC 50 )) where C is the compound concentration.

[0143] Table 1 shows the USP1 / UAF1 activity (IC 50 ) is summarized.

[0144] [Table 8]

[0145] Thus, the compounds of the present invention disclosed herein have good inhibitory effects on USP1 / UAF1 enzyme activity as measured by the ubiquitin-rhodamine 110-glycine assay.

[0146] Example 49 Growth inhibition assay against BRCA-mutated human breast cancer MDA-MB-436 cell line Cells were cultured in complete medium (DMEM medium + 10% FBS + insulin + glutathione). When the confluence reached approximately 80%, the cells were digested and gently dispensed from the bottom of the dish with a 1 mL pipette. The cell suspension was collected and centrifuged at 500 rpm for 3 min. The supernatant was discarded and the cell pellet was resuspended in complete medium. Cells were seeded in culture dishes at appropriate ratios and cultured at 37°C in a 5% CO2 incubator. The assay was performed when the cells were in optimal condition and had reached 80% confluence. Cells in logarithmic growth phase were centrifuged and the culture supernatant was removed. Cells were resuspended in refresh complete medium and counted. The resuspended cells were seeded at 3000 cells / well in a 96-well plate and incubated overnight at 37°C in a 5% CO2 incubator. Compounds were prepared as follows: 1000x dilutions of test compound solutions were prepared to 40x test compound solutions by adding 5 μL of 1000x compound solution to 120 μL of medium (25-fold dilution). The solutions were mixed by shaking. 0.1% DMSO was used as a control.

[0147] The next day, the 96-well plate seeded with cells was removed from the incubator and the culture supernatant was removed. Then, 195uL / well of fresh medium and 5uL / well of the above 40(test compound solution) were added to the 96-well plate, respectively. Finally, the plate was incubated in a 37℃, 5% CO2 incubator for 7 days. The medium containing the compound was replaced on the fourth day.

[0148] CTG method: After 7 days, 100μL Celltiter-Glo reagent was added to each well, and then the plate was shaken for 2 minutes to dissolve completely.Then, the plate was incubated at room temperature for 10 minutes, and the chemiluminescence value was read by a plate reader.

[0149] The inhibitory activity of the compounds against cell proliferation was plotted as cell viability versus compound concentration. Cell Inhibition % = (Lum Compound - Lum DMSO ) / (Lum medium-Lum DMSO ) x 100. Lum refers to the chemiluminescence value.

[0150] The XL Fit software was used to fit the data to a nonlinear S-curve regression to obtain dose-effect curves, from which the IC 50 The value was calculated: Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X) × slope), Y is the cell inhibition rate, X is the compound concentration, the bottom is the lowest inhibition rate, and the top is the highest inhibition rate.

[0151] Table 2 shows the inhibitory effect data (IC) of compounds on the proliferation of human breast cancer cells MDA-MB-436 measured by the CTG method. 50 ) is a compilation of

[0152] [Table 9]

[0153] CCK method: After 7 days, 20 μL of CCK-8 was added to each well, gently shaken, and cultured for 4 hours. After incubation, the plate was shaken for 5 minutes. The absorbance values ​​at wavelengths of 450 nm or 650 nm were recorded, respectively, using a multifunction reader (OD = absorbance at 450 nm - absorbance at 650 nm).

[0154] The data was analyzed by the software GraphPad Prism 6.0. The inhibitory activity of the compounds on cell proliferation was plotted as the coordinate of cell viability against compound concentration. Cell viability % = (OD compound - OD background) / (OD DMSO -OD background) x 100. IC 50 Values ​​are fitted by a sigmoidal dose-response curve equation: Y=100 / (1+10^(logC-logIC50)), where C is the compound concentration.

[0155] Table 3 shows the inhibitory effect data (IC) of compounds on the proliferation of human breast cancer cells MDA-MB-436 measured by the CCK-8 method. 50 ) is a compilation of

[0156] [Table 10]

[0157] Therefore, the compounds herein have good inhibitory effects on the proliferation of human breast cancer cells MDA-MB-436.

[0158] Now that the invention has been fully described, those skilled in the art will appreciate that the same may be practiced within a broadly equivalent range of conditions, compositions and other parameters without affecting the scope of the invention or its embodiments. All patents, patent applications and publications cited herein are incorporated by reference in their entirety.

Claims

1. Compounds of Formula I: 【Chemistry 1】 or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharma- ceutically acceptable salt thereof, or a mixture thereof or a prodrug thereof, provided that A 1 and A 2 are N and CR independently 1 Selected from the group consisting of: B 1 and B. 2 are each independently selected from the group consisting of N and C; B 1 and B. 2 At most one of is N; B 3 , B 4 and B. 5 are N and CR independently 2 Selected from the group consisting of: D 1 , D 2 , D 3 and D. 4 are N and CR independently 3 Selected from the group consisting of: L is NR 6 , O, S, SO, SO 2 , C=O and R 4 and / or R 5 alkylene optionally substituted with Cy 1 is selected from the group consisting of optionally substituted carbocyclic groups, optionally substituted heterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups; Cy 2 is selected from the group consisting of optionally substituted carbocyclic groups, optionally substituted heterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups; R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen, halogen, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted carbocyclic group, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted amino; R 4 and R 5 are each independently selected from the group consisting of halogen, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted carbocyclic, optionally substituted alkenyl, and optionally substituted alkynyl; or R 4 and R 5 forms a ring together with the attached C; R 6 is selected from the group consisting of hydrogen and optionally substituted alkyl.

2. A compound of formula I according to claim 1, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or a pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, having the following characteristics: A 1 is N and A 2 is N; and / or B 1 is N and B 2 is C or B 1 is C and B 2 is N; and / or L is C 1-3 Alkylene group, NH, NC 1-3 Alkyl or O, preferably methylene group or -CH(CH 3 )-groups; and / or R 6 is H or C 1-3 It is an alkyl.

3. A compound of formula I according to claim 1, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or a pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, having the following characteristics: 3 , B 4 and B. 5 are independently N and CR 2 R 2 H, halogen, C 1-4 Alkyl or C 1-4 is alkoxy; Preferably, B 3 , B 4 and B. 5 are each independently N or CH; or B 3 , B 4 and B. 5 All are CR 2 and R 2 are each independently H, halogen or C 1-4 alkyl, preferably B 3 , B 4 and B. 5 are all CH; or B 3 is N and B 4 and B. 5 Both are CR 2 and R 2 are each independently H, halogen or C 1-4 alkyl, preferably R 2 are each H; or B 4 is N and B 3 and B. 5 Both are CR 2 and R 2 are each independently H, halogen or C 1-4 alkyl, preferably R 2 are each H; or B 5 is N and B 3 and B. 4 is CR 2 and R 2 are each independently H, halogen or C 1-4 alkyl, preferably R 2 are H, respectively; Preferably, A 1 , A 2 , B 1 , B 2 , B 3 , B 4 and B. 5 The fused heteroaromatic bicyclic ring comprising is selected from the group consisting of: 【Chemistry 2】 *1 and *2 are the Cy of the compound, respectively. 1 and L; preferably, A 1 , A 2 , B 1 , B 2 , B 3 , B 4 and B. 5 The fused heteroaromatic bicyclic ring comprising is selected from the group consisting of: 【Chemistry 3】

4. A compound of formula I according to claim 1, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or a pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, having the following characteristics: 1 , D 2 , D 3 and D. 4 is CR 3 is; Preferably, R 3 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl and optionally substituted alkoxy; preferably, said alkyl or said alkoxy is selected from the group consisting of halogen, hydroxy and NR a R b wherein R is optionally substituted with 1 to 5 substituents selected from the group consisting of a and R b are each independently H or C 1-4 is alkyl; Preferably, D 1 and D. 4 is CH and D 2 and D. 3 is CR 3 and R 3 are hydrogen, halogen or C 1-4 Alkoxy; preferably, R 3 At least one of the substituents is a non-hydrogen substituent, i.e., halogen or C 1-4 Alkoxy; more preferably, D 1 , D 2 , D 3 and D. 4 is CH.

5. A compound of formula I according to claim 1, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or a pharma- ceutically acceptable salt, or a mixture thereof, or a prodrug thereof, having the following characteristics: Cy 1 is an optionally substituted C 3-8 cycloalkyl, an optionally substituted 4-10 membered heterocyclic group, an optionally substituted 6-14 membered aryl group, or an optionally substituted 5-10 membered heteroaryl group; Preferably, Cy 1 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; more preferably, Cy is 1 is an optionally substituted pyrimidinyl; Preferably, Cy 1 is halogen, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Alkoxy, optionally substituted C 3-6 Optionally substituted with a substituent selected from the group consisting of cycloalkyl, optionally substituted amino and cyano; 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 Cycloalkyl is halogen, hydroxyl, and -NR a R b C replaced with 1-4 alkyl, a and R b are independently H or C 1-4 alkyl; the amino is one or two C 1-4 It is optionally substituted with alkyl.

6. A compound of formula I according to claim 1, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or a pharma- ceutically acceptable salt, or a mixture thereof, or a prodrug thereof, having the following characteristics: Cy 2 is an optionally substituted 6-14 membered aryl group, an optionally substituted 5-10 membered heteroaryl group, an optionally substituted C 3-8 cycloalkyl or an optionally substituted 4-10 membered heterocyclic group; Preferably, Cy 2 is an optionally substituted 5-10 membered nitrogen-containing heteroaryl group, more preferably a 5 membered nitrogen-containing heteroaryl group; more preferably, Cy 2 is optionally substituted imidazolyl or optionally substituted pyrazolyl; Preferably, Cy 2 is halogen, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Alkoxy and optionally substituted C 3-6 cycloalkyl, and preferably, 1-4 Alkyl and C 1-4 Alkoxy is halogen, hydroxyl and -NR a R b C replaced with 1-4 alkyl, a and R b are independently H or C 1-4 is preferably Cy 2 is C 1-4 Alkyl, C 3-6 Cycloalkyl and halogenated C 1-4 and is substituted with 1-3 substituents selected from the group consisting of alkyl; more preferably, Cy 2 is C 1-4 Alkyl and halogenated C 1-4 substituted with 1-3 substituents selected from the group consisting of alkyl; More preferably, Cy 2 is an optionally substituted C 1-4 Alkyl-substituted imidazolyl or optionally substituted C 1-4 is preferably Cy 2 is C 1-4 Alkyl, C 3-6 Cycloalkyl and halogenated C 1-4 imidazolyl substituted with two substituents selected from the group consisting of alkyl, one of which is C 1-4 It is substituted with alkyl.

7. The compound of claim 1, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or a pharma- ceutically acceptable salt, or a mixture thereof, or a prodrug thereof, having the following characteristics: Compounds of formula I are compounds of formula IIa or IIb 【Chemistry 4】 or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, 1 , A 2 , B 3 , B 4 , B 5 , D 1 , D 2 , D 3 , D 4 , Cy 1 and Cy 2 is as defined in claims 1-6.

8. The compound of claim 1, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or a pharma- ceutically acceptable salt, or a mixture thereof, or a prodrug thereof, having the following characteristics: Compounds of formula I are compounds of formula IIIa or IIIb 【Chemistry 5】 or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, comprising B 3 , B 4 , B 5 , Cy 1 and Cy 2 is as defined in claims 1, 3, 5 and 6.

9. The compound according to claim 1, selected from the group consisting of: 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; or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharma- ceutically acceptable salt thereof, or a mixture thereof or a prodrug thereof.

10. The use of a compound according to any one of claims 1-9 in the manufacture of a medicament for the treatment or prevention of a disease related to USP1 regulation; preferably, the disease is cancer.

11. Cancers include liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, non-small cell lung cancer, small cell lung cancer, gastric cancer, colon cancer, and malignant pancreatic islet tumors.

11. The application according to claim 10, wherein the cancer is selected from the group consisting of cancers of the following cancer types: malignant carcinoma, malignant carcinoma, choriocarcinoma, mycotic mycosis, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary tract tumors, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, multiple erythrocytic carcinoma, idiopathic thrombocytemia, adrenocortical carcinoma, skin cancer and prostate cancer.

12. The application of claim 11 , wherein the pharmaceutical agent is used in combination with radiation therapy.

13. The application of claim 11, wherein the medicament further comprises at least one known anti-cancer agent or a pharma- ceutically acceptable salt thereof. Preferably, the anticancer agent is selected from the group consisting of busulfan, melphalan, chloroambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, methylhydroxyellipticine, etoposide, 5-azacytidine, gemcitabine, 5-fluorouracil, capecitabine, methotrexate, 5-fluoro-2'-deoxyuridine, fludara. vin, nelarabine, cytarabine, pralatrexate, pemetrexed, hydroxycarbamide, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, mAb, panitumumab, necitumumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab, tositumomab, brentuximab, daratumumab, elotuzumab, Fatumumab, dinutuximab, blinatumomab, ipilimumab, Avastin, Herceptin, MabThera, T-DM1, trastuzumab deruxtecan, trastuzumab emtansine, datopotamab deruxtecan, gemtuzumab ozogamicin, brentuximab vedotin, inotuzumab ozogamicin, sacituzumab govitecan, enfortumab vedotin, belantamab mafodotin, imatinib, gefitinib, erlotinib, osimertinib, afatinib, ceritinib, alectinib, crizotinib, erlotinib, lapatinib, sorafenib sunitinib, nilotinib, dasatinib, pazopanib, toricel, everolimus, vorinostat, romidepsin, panobinostat, belinostat, tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenic trioxide, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide, venetoclax, aldesleukin (recombinant human interleukin-2), sipuecel-T (prostate cancer treatment vaccine), palbociclib,Olaparib, Niraparib, Rucaparib, Talazoparib and Senaparib.

14. A pharmaceutical composition comprising a compound according to any one of claims 1-9 and a pharma- ceutically acceptable carrier.

15. The pharmaceutical composition of claim 14, further comprising at least one known anti-cancer drug or a pharma- ceutical acceptable salt thereof; preferably, the anti-cancer drug is selected from the group consisting of busulfan, melphalan, chloroambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, methylhydroxyellipticine, etoposide, 5-azacytidine, gemcitabine, cefotaxime ... Citabine, 5-fluorouracil, capecitabine, methotrexate, 5-fluoro-2'-deoxyuridine, fludarabine, nelarabine, cytarabine, pralatrexate, pemetrexed, hydroxycarbamide, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, mAb, panitumumab, necitumumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab , rituximab, alemtuzumab, ibritumomab, tositumomab, brentuximab, daratumumab, elotuzumab, ofatumumab, dinutuximab, blinatumomab, ipilimumab, Avastin, Herceptin, MabThera, T-DM1, trastuzumab deruxtecan, trastuzumab emtansine, datopotamab deruxtecan, gemtuzumab ozogamicin, brentuximab vedotin, inotuzumab ozogamicin, sacituzumab govitecan, enfortumab vedotin, belantamab mafodotin, imatinib, gefitinib, erlotinib , osimertinib, afatinib, ceritinib, alectinib, crizotinib, erlotinib, lapatinib, sorafenib, sunitinib, nilotinib, dasatinib, pazopanib, toricel, everolimus, vorinostat, romidepsin, panobinostat, belinostat, tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenic trioxide, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide, venetoclax,Aldesleukin (recombinant human interleukin-2), Sipuecel-T (prostate cancer treatment vaccine), palbociclib, olaparib, niraparib, rucaparib, talazoparib and senaparib.

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