WO2024083237A1

WO2024083237A1 - Substituted heteroaryl bicyclic compounds as usp1 inhibitors and the use thereof

Info

Publication number: WO2024083237A1
Application number: PCT/CN2023/125724
Authority: WO
Inventors: Sui Xiong Cai; Ye Edward Tian; Xiaozhu WANG; Letian ZHANG
Original assignee: Impact Therapeutics (Shanghai) , Inc
Priority date: 2022-10-20
Filing date: 2023-10-20
Publication date: 2024-04-25

Abstract

The disclosure provides substituted heteroaryl bicyclic compounds as represented in Formula I and the use thereof, wherein, A1, A2, B1, B2, B3, ring Z, L, Cy1 and Cy2 are defined herein. The compounds of Formula I can be used to prevent or treat diseases, disorders and conditions associated with USP1 regulation, such as cancer. The disclosure also provides uses of compounds of Formula I in the preparation of medicaments for treating or preventing diseases associated with USP1 modulation, and compositions containing compounds of Formula I.

Description

SUBSTITUTED HETEROARYL BICYCLIC COMPOUNDS AS USP1 INHIBITORS AND THE USE THEREOF

Field of the Disclosure

This disclosure is in the field of medicinal chemistry. In particular, the disclosure relates to substituted heteroaryl bicyclic compounds, and the use of these compounds as therapeutically effective USP1 inhibitors and anticancer drugs.

Background of the Invention

Ubiquitin is a 76 amino acid long peptide, which is covalently attached to proteins to modulate their stability, localization, or function. The degradation of a target protein by ubiquitination is a multistep process. The ubiquitination is acted through the sequential action of enzymes such as a ubiquitin activating enzyme (E1) , a ubiquitin-conjugating enzyme (E2) , and a ubiquitin protein-ligase (E3) . Ubiquitination regulates multiple cellular activities as thousands of cellular proteins are ubiquitinated. Ubiquitination is a reversible process. The balance of ubiquitination and deubiquitination is responsible for degree of intracellular protein ubiquitination. Deubiquitinating enzymes (DUBs) greatly contribute to deubiquitination, and DUBs act on ubiquitinated substrates to catalyze the removal of ubiquitin moieties. Thus, the ubiquitination status 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 (García-Sanstisteban (2013) Mol Cancer 12: 91-103) .

Increasing number of studies revealed that protein ubiquitination is emerging as a critical regulatory mechanism underlying DNA damage response (Huang D', Andrea (2006) Mol Cell Biol. 7: 323-34) . As targeting DDR signaling pathways has become an attractive strategy in oncology, enzymes involved in DNA-damage-induced ubiquitination and deubiquitination could be a potential target for anticancer therapy.

There are 100 genes encoding for deubiquitinases in human. (García-Sanstisteban (2013) Mol Cancer 12: 91-103) . One of the best-characterized DUBs is USP1 (ubiquitin-specific protease 1) , which encodes a 785 amino acid protein with a predicted molecular weight of 88.2 KDa. USP1 has been identified as a key regulator in the DNA repair processes, mainly in FA (Fanconi Anemia) pathway and Translesion Synthesis (TLS) pathway. USP1 regulates DNA repair through Fanconi anemia (FA) -BRCA pathway by deubiquitylating DNA repair proteins, FANCD2-Ub (Nijman et al. (2005) Mol Cell 17: 331-39) . Loss of USP1 function results in an accumulation of FANCD2, which inhibits FA-BRCA-mediated DNA damage repair pathways, leading to elevation of the sensitivity of cancer cells to DNA cross-linking agents, such as mitomycin C and cisplatin. PCNA (Proliferating Cell Nuclear Antigen) is another ubiquitinated substrates of USP1, whose ubiquitination is important for DNA translesion synthesis mechanism (Huang et al. (2006) Nature Cell Biol. 8 (4) : 339-47) . Inhibiting USP1 activity by inhibitor can elevate the sensitivity of cancer cells to DNA cross-linking agents and PARP inhibitors.

USP1 inhibitors can be used in cancer therapy alone or in combination with other DNA damaging agents. The inhibitions of USP1 can impair DNA damage repair pathways. One of the hallmarks of tumor cells is genetic instability, which make tumor cells more sensitive to the DNA damage repairing. Some research reveals that USP1 inhibitor not only can be used as anticancer drugs but also can increase sensitivity to radiotherapy. Further support for advancing USP1 inhibitors shows that USP1 inhibitor also can be used to treat cancer by synthetic lethal mechanism in combination with targeted drugs, such as PARP inhibitors.

Thomas S. et al found ML323 and related N-benzyl-2-phenylpyrimidin-4-amine derivatives displayed excellent inhibitory activity toward USP1/UAF1 by screening (Thomas S. et al. (2014) J. Med. Chem. 57: 8099-8110) . The results indicated a strong correlation between compound IC₅₀ values for USP1/UAF1 inhibition and activity in non-small cell lung cancer cells, specifically increased monoubiquitinated PCNA (Ub-PCNA) levels and decreased cell survival. The results established the druggability of the USP1/UAF1 deubiquitinase complex and its potential as a molecular target for anticancer therapies.

Various USP1 inhibitors have been disclosed. For example, WO2014105952, WO2016034675, US20170145012, WO2020139988, WO2020132269, WO2021163530, WO2022174184, WO2022214053, WO2023083286, WO2023143424 and WO2023066299.

Summary of the Disclosure

The disclosure provides substituted heteroaryl bicyclic compounds and analogues as represented in Formula I (including Formulae II, III, IV and V) , which can be used as USP1 inhibitors.

The disclosure also provides pharmaceutical compositions comprising an effective amount of the compound of Formula I (including Formulae II, III, IV and V) for the treatment of cancer.

In a specific embodiment, the pharmaceutical composition may also contain one or more pharmaceutically acceptable excipients or carriers or excipients or diluents, for the treatment of cancer.

In a specific embodiment, the pharmaceutical composition may also contain at least one known anticancer drug or pharmaceutically acceptable salts thereof, for the treatment of cancer.

The disclosure is also directed to methods for the preparation of novel compounds of Formula I (including Formulae II, III, IV and V) .

Detailed Description of the Disclosure

It should be understood that the characteristics of the embodiments described herein can be arbitrarily combined to form the technical solution of this disclosure. The definition of each group herein can apply to any of the embodiments described herein. For example, the definitions of the substituents of alkyl herein apply to any of the embodiments described herein unless the substituents of alkyl are clearly defined in the embodiment.

Specifically, the disclosure provides compounds represented by Formula I:

or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-substituted derivatives, or pharmaceutically acceptable salts thereof, or mixtures thereof, or prodrugs thereof, wherein:

A₁ and A₂ are each independently selected from a group consisting of N, NR₁, O and S;

B₁, B₂ and B₃ are each independently selected from a group consisting of N and CR₂;

ring Z is selected from a group consisting of an optionally substituted carbocyclic group, an optionally substituted heterocyclic group, an optionally substituted aryl and an optionally substituted heteroaryl;

L is selected from a group consisting of NR₆, O, S, SO, SO₂, C=O and an alkylene optionally substituted with R₄ and/or R₅;

Cy₁ is selected from a group consisting of an optionally substituted carbocyclic group, an optionally substituted heterocyclic group, an optionally substituted aryl and an optionally substituted heteroaryl;

Cy₂ is selected from a group consisting of an optionally substituted carbocyclic group, an optionally substituted heterocyclic group, an optionally substituted aryl and an optionally substituted heteroaryl; or ring Z and Cy₂ together form an optionally substituted 11-14 membered heterocyclic group;

R₁ is selected from a group consisting of hydrogen and an optionally substituted alkyl;

R₂ is selected from a group consisting of hydrogen, halogen, cyano, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted carbocyclic group, an optionally substituted alkenyl, an optionally substituted alkynyl, and an optionally substituted amino;

R₄ and R₅ are each independently selected from a group consisting of halogen, cyano, hydroxyl, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted carbocyclic group, an optionally substituted alkenyl and an optionally substituted alkynyl; or R₄ and R₅ together with the attached C atom form a ring;

R₆ is selected from a group consisting of hydrogen and an optionally substituted alkyl.

Preferably, in the definition of the above groups of Formula I, the optionally substituted alkyl, the optionally substituted alkoxy, the optionally substituted alkenyl and the optionally substituted alkynyl each are optionally substituted by 1-5 substituents selected from a group consisting of halogen, hydroxyl, -NR_aR_b, C_1-4 alkoxy, halogenated C_1-4 alkoxy, carboxyl and cyano, wherein the said R_a and R_b are independently H or C_1-4 alkyl. More preferably, the said groups can be optionally substituted by 1-5 substituents selected from a group consisting of halogen, hydroxyl and -NR_aR_b, wherein the said R_a and R_b are independently H or C_1-4 alkyl.

Preferably, the optionally substituted amino involved in Formula I is represented as -NR_aR_b, wherein the said R_a and R_b are each independently H, C_1-4 alkyl or halogenated C_1-4 alkyl.

Preferably, in the definition of the above groups of Formula I, the optionally substituted carbocyclic group, the optionally substituted aryl, the optionally substituted heteroaryl and the optionally substituted heterocyclic group each are optionally substituted by 1-5 substituents selected from the group of halogen, hydroxyl, -NR_aR_b, C_1-4 alkyl, halogenated C_1-4 alkyl, C_1-4 alkyl substituted by hydroxyl, C_3-6 cycloalkyl, C_1-4 alkoxy, halogenated C_1-4 alkoxy, carboxyl and cyano, wherein the said R_a and R_b are independently H or C_1-4 alkyl. More preferably, the said optionally substituted carbocyclic group, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic group can be optionally substituted by 1-5 substituents selected from a group consisting of halogen, C_1-4 alkyl, C_3-6 cycloalkyl, C_1-4 alkoxy, halogenated C_1-4 alkyl, halogenated C_1-4 alkoxy, hydroxyl and -NR_aR_b, wherein the said R_a and R_b are independently H or C_1-4 alkyl.

In one or more embodiments of the compound of Formula I, A₂ is N, A₁ is O, S or NR₁, wherein R₁ is hydrogen or C_1-4 alkyl, preferably methyl. In some embodiments, A₂ is N, A₁ is O or S. In some embodiments, A₂ is N, A₁ is O. In some embodiments, A₁ is N, A₂ is O or S, preferably O. It should be understood that the position of the double bond in the 5-membered ring containing A₁ and A₂ is different according to the selection of A₁ and A₂, but the bond valence theory should be satisfied.

In one or more embodiments of the compound of Formula I, B₁, B₂ and B₃ are each independently selected from a group consisting of N and CR₂, wherein R₂ is H, halogen, C_1-4 alkyl or C_1-4 alkoxy. Preferably, B₁, B₂ and B₃ are each independently N or CH, and at most one of B₁, B₂ and B₃ is N. In some embodiments, both of B₁ and B₂ are CH, B₃ is N. In some embodiments, all of B₁, B₂ and B₃ are CH.

In one or more embodiments of the compound of Formula I, the fused heteroaromatic bicyclic ring containing A₁, A₂, B₁, B₂ and B₃ is selected from the following groups:

preferably:

more preferably:

wherein, *1 and *2 refer to the position of attachment of the group to Cy₁ and L of the compound, respectively.

In one or more embodiments of the compound of Formula I, L is an alkylene group, NH, N-C_1-3 alkyl or O, preferably L is a C_1-3 alkylene group, more preferably a methylene group.

In one or more embodiments of the compound of Formula I, ring Z is an optionally substituted C_3-8 cycloalkyl group, 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 embodiments, the C_3-8 cycloalkyl group is a C_5-8 cycloalkyl group. Preferably, the said C_5-8 cycloalkyl group is a bridged cycloalkyl group, a cubic alkyl group or a spiro cycloalkyl group. In some embodiments, the 6-14 membered aryl group is phenyl. In some embodiments, the 4-10 membered heterocyclic group is a heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, such as azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, tetrahydrofuranyl and tetrahydropyranyl, etc. In some embodiments, the 5-10 membered heteroaryl group is a heteroaryl group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, such as imidazolyl, pyrazolyl, triazolyl, pyridyl and pyridyl, etc. Preferably, when ring Z is substituted, the substituents may be 1 or 2 groups selected from a group consisting of halogen, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl group, optionally substituted alkenyl group, optionally substituted alkynyl group and optionally substituted amino group, the said optionally substituted alkyl group and optionally substituted alkoxy group are preferably an optionally substituted C_1-4 alkyl or an optionally substituted C_1-3 alkoxy, the said optionally substituted cycloalkyl is preferably an optionally substituted C_3-8 cycloalkyl, the said optionally substituted alkenyl and optionally substituted alkynyl group are each preferably an optionally substituted C_2-4 alkenyl group or an optionally substituted C_2-4 alkynyl group, respectively, and the said optionally substituted amino group is -NR_aR_b, wherein R_a and R_b are each independently H or C_1-4 alkyl; preferably, each of the alkyl, alkoxy, alkenyl, alkynyl and cycloalkyl groups is optionally substituted by 1-5 groups selected from a group consisting of halogen, hydroxyl and -NR_aR_b, the said R_a and R_b are each independently H or C_1-4 alkyl. In some embodiments, the substituents on the Z ring are 1 or 2 substituents selected from halogen and C_1-3 alkoxy.

In one or more embodiments of the compound of Formula I, ring Z and Cy₂ together form an optionally substituted 11-14 membered heterotricyclic group containing 2, 3 or 4 heteroatoms selected from nitrogen and oxygen, such as benzimidazoloxazinyl, dihydrobenzimidazoloxazepine, dihydrobenzimidazodiazepine and benziimidazooxazepine, etc. When the 11-14 membered heterocyclic group is substituted, the substituents may be 1 or 2 groups selected from a group consisting of halogen, optionally substituted alkyl and optionally substituted alkoxy. The said optionally substituted alkyl and the optionally substituted alkoxy group are preferably an optionally substituted C_1-4 alkyl group and an optionally substituted C_1-3 alkoxy group; preferably, the alkyl group and the alkoxy group are optionally substituted by 1-5 groups selected from halogen, hydroxyl and -NR_aR_b, wherein the said R_a and R_b are each independently H or C_1-4 alkyl. In some embodiments, the substituent is halogen or halogenated C_1-4 alkyl.

In one or more embodiments of the compound of Formula I, Cy₁ 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. In some further preferred embodiments, the said 4-10 membered heterocyclic group is a heterocyclic group containing nitrogen and/or oxygen. In some further preferred embodiments, the said 5-10 membered heteroaryl group is a nitrogen-containing monocyclic heteroaryl group, such as imidazolyl, pyrazolyl, triazolyl, pyrimidinyl and pyridyl. In some further preferred embodiments, the said aryl group is phenyl. Preferably, Cy₁ is an optionally substituted phenyl, an optionally substituted pyrazolyl, an optionally substituted pyridyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted pyridazinyl, an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted tetrahydrofuranyl, an optionally substituted pyrrolidinyl or an optionally substituted pyrazolyl. More preferably, Cy₁ is optionally substituted pyrimidinyl or optionally substituted pyrazolyl.

Herein, when Cy₁ is substituted, the substituents can be 1, 2 or 3 groups selected from a group consisting of halogen, cyano, an optionally substituted C_1-4 alkyl, an optionally substituted C_1-4 alkoxy, an optionally substituted C_3-6 cycloalkyl and an optionally substituted amino; preferably, the C_1-4 alkyl and C_1-4 alkoxy are optionally substituted by 1-5 groups selected from a group consisting of deuterium, halogen, hydroxyl and -NR_aR_b, and the said C_3-6 cycloalkyl is optionally substituted by 1-5 groups selected from a group consisting of halogen, hydroxyl, -NR_aR_b, C_1-4 alkyl, halogenated C_1-4 alkyl, C_1-4 alkyl substituted with hydroxyl, C_1-4 alkoxy and halogenated C_1-4 alkoxy, and the amino group is optionally substituted by 1 or 2 groups selected from C_1-4 alkyl and halogenated C_1-4, wherein R_a and R_b are each independently H or C_1-4 alkyl. Preferably, when Cy₁ is substituted, the substituent of Cy₁ is one or two groups selected from a group consisting of halogen, C_1-4 alkyl, C_1-4 alkoxy, deuterated C_1-4 alkoxy and C_3-6 cycloalkyl; further preferably, the substituent on Cy₁ is selected from a group consisting of C_1-4 alkoxy, deuterated C_1-4 alkoxy and C_3-6 cycloalkyl. Further preferably, the substituents on Cy₁ are located ortho to the position where the ring containing A₁ and A₂ is connected to Cy₁.

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 cycloalkyl or an optionally substituted 4-10 membered heterocyclic group. In some embodiments, the said 6-14 membered aryl group is phenyl. In some embodiments, the said 4-10 membered heterocyclic group is a heterocyclic group containing 1-3 heteroatoms selected from nitrogen and oxygen, including a partially saturated 8-10 membered nitrogen-and/or oxygen-containing heterocyclic group, such as azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroimidazopyrazinyl and dihydroimidazoxazinyl, etc. In some embodiments, the said 5-10 membered heteroaryl group is a heteroaryl group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, such as imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, etc. Preferably, Cy₂ is an optionally substituted nitrogen-containing 5-10 membered heteroaryl group or an optionally substituted nitrogen-and/or oxygen-containing 8-10-membered heterocyclic group, more preferably a nitrogen-containing five-membered heteroaryl group. In some preferred embodiments, Cy₂ is an optionally substituted imidazolyl or an optionally substituted pyrazolyl. In other embodiments, Cy₂ is an optionally substituted tetrahydroimidazopyrazinyl or an optionally substituted dihydroimidazoxazinyl.

Herein, when Cy₂ is substituted, the substituents can be 1, 2, 3, 4 or 5 substituents selected from a group consisting of halogen, cyano, an optionally substituted C_1-4 alkyl, an optional substituted C_2-4 alkenyl, an optionally substituted C_2-4 alkynyl, an optionally substituted C_3-6 cycloalkyl, an optionally substituted 4-10 membered heterocyclic groups, and an optionally substituted C_1-4 alkoxy. The said C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl and C_1-4 alkoxy groups are optionally substituted by 1-5 groups selected from a group consisting of deuterium, halogen, hydroxyl and -NR_aR_b; the said C_3-6 cycloalkyl and 4-10 membered heterocyclic groups are each optionally substituted by 1-5 groups selected from a group consisting of halogen, hydroxyl, -NR_aR_b, C_1-4 alkyl, halogenated C_1-4 alkyl, C_1-4 alkyl substituted with hydroxyl, C_1-4 alkoxy group and halogenated C_1-4 alkoxy group; wherein R_a and R_b are each independently H or C_1-4 alkyl group. The said 4-10 membered heterocyclic group is preferably a heterocyclic group containing oxygen and/or nitrogen, such as oxetanyl, azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, tetrahydrofuranyl and tetrahydropyranyl, etc. Preferably, the substituents on Cy₂ is 1 or 2 groups selected from a group consisting of halogen, cyano, C_1-4 alkyl, C_2-4 alkynyl, halogenated C_1-4 alkyl, deuterated C_1-4 alkyl, 4-10 membered heterocyclic groups, C_3-6 cycloalkyl and C_1-4 alkoxy; preferably, Cy₂ is imidazolyl or pyrazolyl, optionally substituted by 1 or 2 substituents selected from a group consisting of halogen, cyano, C_1-4 alkyl, C_2-4 alkynyl, halogenated C_1-4 alkyl, deuterated C_1-4 alkyl, 4-10 membered heterocyclic groups, C_3-6 cycloalkyl and C_1-4 alkoxy. In some embodiments, Cy₂ is substituted with 1-3 substituents selected from a group consisting of halogen, cyano, C_1-4 alkyl, C_3-6 cycloalkyl and halogenated C_1-4 alkyl. In some embodiments, Cy₂ has two substituents selected from a group consisting of halogen, C_1-4 alkyl, C_3-6 cycloalkyl and halogenated C_1-4 alkyl. In some embodiments, one of substituents on Cy₂ is located on its ring nitrogen atom.

In one or more embodiments of the compound of Formula I, R₄ and R₅ are each independently selected from a group consisting of C_1-4 alkyl and hydroxyl. In some embodiments, R₄ and R₅ together with the attached C atom form a 3-5 membered cycloalkyl or 3-5 membered heterocyclic group. In some preferred embodiments, L is an alkylene group, and R₄ and R₅ form a 3-5 membered cycloalkyl group with C atom in the connected alkylene group.

In one or more embodiments of the compound of Formula I, R₆ is H or C_1-3 alkyl.

The disclosure provides compounds represented by Formula II:

A₁, A₂, B₁, B₂, B₃, L, Cy₁ and Cy₂ are as defined in any embodiments of Formula I;

D₁, D₂, D₃ and D₄ are each independently selected from a group consisting of N and CR₃;

R₃ is selected from a group consisting of hydrogen, halogen, cyano, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted carbocyclic group, an optionally substituted alkenyl, an optionally substituted alkynyl, and an optionally substituted amino.

In one or more embodiments of the compound of Formula II, A₂ is N, A₁ is O, S or NR₁, wherein R₁ is hydrogen or C_1-4 alkyl, preferably methyl. In some embodiments, A₂ is N, A₁ is O or S. In some embodiments, A₂ is N, A₁ is O. In some embodiments, A₁ is N, A₂ is O or S, preferably O.

In one or more embodiments of the compound of Formula II, B₁, B₂ and B₃ are each independently selected from a group consisting of N and CR₂, wherein R₂ is H, halogen, C_1-4 alkyl or C_1-4 alkoxy. Preferably, B₁, B₂ and B₃ are each independently N or CH, and at most one of B₁, B₂ and B₃ is N. In some embodiments, both of B₁ and B₂ are CH, B₃ is N. In some embodiments, all of B₁, B₂ and B₃ are CH.

In one or more embodiments of the compound of Formula II, the fused heteroaromatic bicyclic ring containing A₁, A₂, B₁, B₂ and B₃ is selected from the following groups:

preferably:

more preferably:

In one or more embodiments of the compound of Formula II, L is an alkylene group, NH, N-C_1-3 alkyl or O, preferably L is a C_1-3 alkylene group, more preferably a methylene group.

In one or more embodiments of the compound of Formula II, D₁, D₂, D₃ and D₄ are CR₃. In some embodiments, D₁, D₃ and D₄ are CR₃, D₂ is N. Preferably, R₃ is selected from a group consisting of hydrogen, halogen, cyano, an optionally substituted C_1-4 alkyl, an optionally substituted C_1-3 alkoxy, an optionally substituted C_3-8 cycloalkyl, an optionally substituted C_2-4 alkenyl, an optionally substituted C_2-4 alkynyl and -NR_aR_b, wherein R_a and R_b are each independently H or C_1-4 alkyl; further preferably, R₃ is each independently selected from a group consisting of halogen, an optionally substituted C_1-4 alkyl and an optionally substituted C_1-3 alkoxy; preferably, the said alkyl, alkoxy, alkenyl, alkynyl and cycloalkyl groups is optionally substituted by 1-5 groups selected from a group consisting of halogen, hydroxyl and -NR_aR_b, wherein R_a and R_b are each independently H or C_1-4 alkyl. In some embodiments, R₃ is selected from a group consisting of H, halogen, and C_1-3 alkoxy. In some embodiments, both of D₁ and D₄ are CH, D₂ and D₃ are each independently CR₃, wherein each R₃ is independently hydrogen, halogen, C_1-3 alkyl, or C_1-3 alkoxy. In some embodiments, all of D₁, D₂, D₃, and D₄ are CH.

In one or more embodiments of the compound of Formula II, the aryl or heteroaryl group containing D₁, D₂, D₃, D₄, and Cy₂ together form an optionally substituted 11-14 membered heterotricyclic group containing 2, 3 or 4 heteroatoms selected from nitrogen and oxygen, such as benzimidazoloxazinyl, dihydrobenzimidazoloxazepine, dihydrobenzimidazodiazepine and benziimidazooxazepine, etc. When the 11-14 membered heterocyclic group is substituted, the substituents may be 1 or 2 groups selected from a group consisting of halogen, an optionally substituted alkyl and an optionally substituted alkoxy. The said optionally substituted alkyl and the optionally substituted alkoxy group are preferably an optionally substituted C_1-4 alkyl group or an optionally substituted C_1-3 alkoxy group; preferably, the alkyl group and the alkoxy group are each optionally substituted by 1-5 groups selected from halogen, hydroxyl and -NR_aR_b, wherein the said R_a and R_b are each independently H or C_1-4 alkyl. In some embodiments, the substituent is halogen or halogenated C_1-4 alkyl.

In one or more embodiments of the compound of Formula II, Cy₁ 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. In some further preferred embodiments, the said 4-10 membered heterocyclic group is a heterocyclic group containing nitrogen and/or oxygen. In some further preferred embodiments, the said 5-10 membered heteroaryl group is a nitrogen-containing monocyclic heteroaryl group, such as imidazolyl, pyrazolyl, triazolyl, pyrimidinyl and pyridyl. In some further preferred embodiments, the said aryl group is phenyl. Preferably, Cy₁ is an optionally substituted phenyl, an optionally substituted pyrazolyl, an optionally substituted pyridyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted pyridazinyl, an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted tetrahydrofuranyl, an optionally substituted pyrrolidinyl or an optionally substituted pyrazolyl. More preferably, Cy₁ is optionally substituted pyrimidinyl or an optionally substituted pyrazolyl.

In one or more embodiments of the compound of Formula II, when Cy₁ is substituted, the substituents can be 1, 2 or 3 groups selected from a group consisting of halogen, cyano, an optionally substituted C_1-4 alkyl, an optionally substituted C_1-4 alkoxy, an optionally substituted C_3-6 cycloalkyl and an optionally substituted amino; preferably, the said C_1-4 alkyl and C_1-4 alkoxy are each optionally substituted by 1-5 groups selected from a group consisting of deuterium, halogen, hydroxyl and -NR_aR_b, and the said C_3-6 cycloalkyl is optionally substituted by 1-5 groups selected from a group consisting of halogen, hydroxyl, -NR_aR_b, C_1-4 alkyl, halogenated C_1-4 alkyl, C_1-4 alkyl substituted with hydroxyl, C_1-4 alkoxy and halogenated C_1-4 alkoxy, and the amino group is optionally substituted by 1 or 2 groups selected from C_1-4 alkyl and halogenated C_1- ₄, wherein R_a and R_b are each independently H or C_1-4 alkyl. Preferably, the substituent of Cy₁ is selected from a group consisting of halogen, C_1-4 alkyl, C_1-4 alkoxy, deuterated C_1-4 alkoxy and C_3- ₆ cycloalkyl; further preferably, the substituent on Cy₁ is selected from a group consisting of C_1-4 alkoxy, deuterated C_1-4 alkoxy and C_3-6 cycloalkyl. Further preferably, the substituents on Cy₁ are located ortho to the position where the ring containing A₁ and A₂ is connected to Cy₁.

In one or more embodiments of the compound of Formula II, Cy₂ 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. In some embodiments, the said 6-14 membered aryl group is phenyl. In some embodiments, the said 4-10 membered heterocyclic group is a heterocyclic group containing 1-3 heteroatoms selected from nitrogen and oxygen, including a partially saturated 8-10 membered nitrogen-and/or oxygen-containing heterocyclic group, such as azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroimidazopyrazinyl and dihydroimidazoxazinyl, etc. In some embodiments, the said 5-10 membered heteroaryl group is a heteroaryl group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, such as imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, etc. Preferably, Cy₂ is an optionally substituted nitrogen-containing 5-10 membered heteroaryl group or an optionally substituted nitrogen-and/or oxygen-containing 8-10-membered heterocyclic group, more preferably a nitrogen-containing five-membered heteroaryl group. In some preferred embodiments, Cy₂ is an optionally substituted imidazolyl or an optionally substituted pyrazolyl. In other embodiments, Cy₂ is an optionally substituted tetrahydroimidazopyrazinyl or an optionally substituted dihydroimidazoxazinyl.

In one or more embodiments of the compound of Formula II, when Cy₂ is substituted, the substituents can be 1, 2, 3, 4 or 5 substituents selected from a group consisting of halogen, cyano, an optionally substituted C_1-4 alkyl, an optional substituted C_2-4 alkenyl, an optionally substituted C_2-4 alkynyl, an optionally substituted C_3-6 cycloalkyl, an optionally substituted 4-10 membered heterocyclic groups, and an optionally substituted C_1-4 alkoxy. The said C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl and C_1-4 alkoxy groups are optionally substituted by 1-5 groups selected from a group consisting of deuterium, halogen, hydroxyl and -NR_aR_b; the C_3-6 cycloalkyl and 4-10 membered heterocyclic groups are each optionally substituted by 1-5 groups selected from a group consisting of halogen, hydroxyl, -NR_aR_b, C_1-4 alkyl, halogenated C_1-4 alkyl, C_1-4 alkyl substituted with hydroxyl, C_1-4 alkoxy group and halogenated C_1-4 alkoxy group; wherein R_a and R_b are each independently H or C_1-4 alkyl group. The 4-10 membered heterocyclic group is preferably a heterocyclic group containing oxygen and/or nitrogen, such as oxetanyl, azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, tetrahydrofuranyl and tetrahydropyranyl, etc. Preferably, when Cy₂ is substituted, the substituent (s) on Cy₂ can be 1 or 2 groups selected from a group consisting of halogen, cyano, C_1-4 alkyl, C_2-4 alkynyl, halogenated C_1-4 alkyl, deuterated C_1-4 alkyl, 4-10 membered heterocyclic groups, C_3-6 cycloalkyl and C_1-4 alkoxy; preferably, Cy₂ is imidazolyl or pyrazolyl, optionally substituted by 1 or 2 substituents selected from a group consisting of halogen, cyano, C_1-4 alkyl, C_2-4 alkynyl, halogenated C_1-4 alkyl, deuterated C_1-4 alkyl, 4-10 membered heterocyclic groups, C_3-6 cycloalkyl and C_1-4 alkoxy. In some embodiments, Cy₂ is substituted with 1-3 substituents selected from a group consisting of halogen, cyano, _1-4 alkyl, C_3-6 cycloalkyl and halogenated C_1-4 alkyl. In some embodiments, Cy₂ has two substituents selected from a group consisting of halogen, C_1-4 alkyl, C_3-6 cycloalkyl and halogenated C_1-4 alkyl. In some embodiments, one of substituents on Cy₂ is located on its ring nitrogen atom.

In one or more embodiments of the compound of Formula II, R₄ and R₅ are each independently selected from a group consisting of C_1-4 alkyl and hydroxyl. In some embodiments, R₄ and R₅ together with the attached C atom form a 3-5 membered cycloalkyl or 3-5 membered heterocyclic group. In some preferred embodiments, L is an alkylene group, and R₄ and R₅ form a 3-5 membered cycloalkyl group with C atom in the connected alkylene group.

In one or more embodiments of the compound of Formula II, R₆ is H or C_1-3 alkyl.

The disclosure provides compounds represented by Formulae IIIa and IIIb:

or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-substituted derivatives, or pharmaceutically acceptable salts thereof, or mixtures thereof, or prodrugs thereof, wherein A₁, A₂, B₂, B₃, L, D₂, D₃, Cy₁ and Cy₂ are as defined in any embodiments of Formula I or Formula II.

In one or more embodiments of the compound of Formula IIIa, A₁ is O, S or NR₁, wherein R₁ is H or C_1-4 alkyl, preferably methyl. Preferably, A₁ is O or S; more preferably, A₁ is O.

In one or more embodiments of the compound of Formula IIIb, A₂ is O or S. In some embodiments, A₂ is O.

In one or more embodiments of the compound of Formulae IIIa and IIIb, B₂ and B₃ are each independently selected from a group consisting of N and CR₂, wherein R₂ is H, halogen, C_1-4 alkyl or C_1-4 alkoxy. Preferably, B₂ and B₃ are each independently N or CH, and at most one of B₂ and B₃ is N. In some embodiments, B₂ is CH, B₃ is N. In some embodiments, both of B₂ and B₃ are CH.

In one or more embodiments of the compound of Formulae IIIa and IIIb, the fused heteroaromatic bicyclic ring containing A₁/A₂, B₂ and B₃ is selected from the following groups:

preferably:

more preferably:

In one or more embodiments of the compound of Formulae IIIa and IIIb, L is an alkylene group, NH, N-C_1-3 alkyl or O, preferably L is a C_1-3 alkylene group, more preferably a methylene group.

In one or more embodiments of the compound of Formulae IIIa and IIIb, both of D₂ and D₃ are CR₃. Preferably, R₃ is selected from a group consisting of hydrogen, halogen, an optionally substituted alkyl and an optionally substituted alkoxy; the said optionally substituted alkyl and optionally substituted alkoxy are preferably an optionally substituted C_1-4 alkyl and an optionally substituted C_1-3 alkoxy, respectively; preferably, the said alkyl and alkoxy are each optionally substituted by 1-5 substituents selected from a group consisting of halogen, hydroxyl and -NR_aR_b, wherein the said R_a and R_b are independently H or C_1-4 alkyl. In some embodiments, one of D₂ and D₃ is CH, the other is CR₃, wherein R₃ is halogen, C_1-3 alkyl or C_1-3 alkoxy, preferably halogen. In some embodiments, D₂ and D₃ are both CH. In some embodiments, one of D₂ and D₃ is N, the other is CR₃, wherein R₃ is hydrogen, halogen, C_1-3 alkyl or C_1-3 alkoxy, preferably hydrogen.

In one or more embodiments of the compound of Formulae IIIa and IIIb, the aryl or heteroaryl group containing D₂, D₃, and Cy₂ together form an optionally substituted 11-14 membered heterotricyclic group containing 2, 3 or 4 heteroatoms selected from nitrogen and oxygen, such as benzimidazoloxazinyl, dihydrobenzimidazoloxazepine, dihydrobenzimidazodiazepine and benziimidazooxazepine, etc. When the 11-14 membered heterocyclic group is substituted, the substituents may be 1 or 2 groups selected from a group consisting of halogen, an optionally substituted alkyl and an optionally substituted alkoxy. The said optionally substituted alkyl and the optionally substituted alkoxy group are preferably an optionally substituted C_1-4 alkyl group and an optionally substituted C_1-3 alkoxy group; preferably, the alkyl group and the alkoxy group are optionally substituted by 1-5 groups selected from halogen, hydroxyl and -NR_aR_b, wherein the said R_a and R_b are each independently H or C_1-4 alkyl. In some embodiments, the substituent is halogen or halogenated C_1-4 alkyl.

In one or more embodiments of the compound of Formulae IIIa and IIIb, Cy₁ 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. In some further preferred embodiments, the said 4-10 membered heterocyclic group is a heterocyclic group containing nitrogen and/or oxygen. In some further preferred embodiments, the said 5-10 membered heteroaryl group is a nitrogen-containing monocyclic heteroaryl group, such as imidazolyl, pyrazolyl, triazolyl, pyrimidinyl and pyridyl. In some further preferred embodiments, the said aryl group is phenyl. Preferably, Cy₁ is an optionally substituted phenyl, an optionally substituted pyrazolyl, an optionally substituted pyridyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted pyridazinyl, an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted tetrahydrofuranyl, an optionally substituted pyrrolidinyl or an optionally substituted pyrazolyl. More preferably, Cy₁ is an optionally substituted pyrimidinyl or an optionally substituted pyrazolyl.

In one or more embodiments of the compound of Formulae IIIa and IIIb, when Cy₁ is substituted, the substituents can be 1, 2 or 3 groups selected from a group consisting of halogen, cyano, an optionally substituted C_1-4 alkyl, an optionally substituted C_1-4 alkoxy, an optionally substituted C_3-6 cycloalkyl and an optionally substituted amino; preferably, the C_1-4 alkyl and C_1-4 alkoxy are each optionally substituted by 1-5 groups selected from a group consisting of deuterium, halogen, hydroxyl and -NR_aR_b, and the said C_3-6 cycloalkyl is optionally substituted by 1-5 groups selected from a group consisting of halogen, hydroxyl, -NR_aR_b, C_1-4 alkyl, halogenated C_1-4 alkyl, C_1-4 alkyl substituted with hydroxyl, C_1-4 alkoxy and halogenated C_1-4 alkoxy, and the amino group is optionally substituted by 1 or 2 groups selected from C_1-4 alkyl and halogenated C_1-4, wherein R_a and R_b are each independently H or C_1-4 alkyl. Preferably, the substituent of Cy₁ is selected from a group consisting of halogen, C_1-4 alkyl, C_1-4 alkoxy, deuterated C_1-4 alkoxy and C_3-6 cycloalkyl; further preferably, the substituent on Cy₁ is selected from a group consisting of C_1-4 alkoxy, deuterated C_1-4 alkoxy and C_3-6 cycloalkyl. Further preferably, the substituents on Cy₁ are located ortho to the position where the ring containing A₁ and A₂ is connected to Cy₁.

In one or more embodiments of the compound of Formulae 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_3-8 cycloalkyl or an optionally substituted 4-10 membered heterocyclic group. In some embodiments, the said 6-14 membered aryl group is phenyl. In some embodiments, the said 4-10 membered heterocyclic group is a heterocyclic group containing 1-3 heteroatoms selected from a group consisting of nitrogen and oxygen, including a partially saturated 8-10 membered nitrogen-and/or oxygen-containing heterocyclic group, such as azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroimidazopyrazinyl and dihydroimidazoxazinyl, etc. In some embodiments, the 5-10 membered heteroaryl group is a heteroaryl group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, such as imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, etc. Preferably, Cy₂ is an optionally substituted nitrogen-containing 5-10 membered heteroaryl group or an optionally substituted nitrogen-and/or oxygen-containing 8-10-membered heterocyclic group, more preferably a nitrogen-containing five-membered heteroaryl group. In some preferred embodiments, Cy₂ is an optionally substituted imidazolyl or an optionally substituted pyrazolyl. In other embodiments, Cy₂ is an optionally substituted tetrahydroimidazopyrazinyl or an optionally substituted dihydroimidazoxazinyl.

In one or more embodiments of the compound of Formulae IIIa and IIIb, when Cy₂ is substituted, the substituents can be 1, 2, 3, 4 or 5 substituents selected from a group consisting of halogen, cyano, an optionally substituted C_1-4 alkyl, an optional substituted C_2-4 alkenyl, an optionally substituted C_2-4 alkynyl, an optionally substituted C_3-6 cycloalkyl, an optionally substituted 4-10 membered heterocyclic groups, and an optionally substituted C_1-4 alkoxy. The said C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl and C_1-4 alkoxy groups are optionally substituted by 1-5 groups selected from a group consisting of deuterium, halogen, hydroxyl and -NR_aR_b; the said C_3-6 cycloalkyl and 4-10 membered heterocyclic groups are each optionally substituted by 1-5 groups selected from a group consisting of halogen, hydroxyl, -NR_aR_b, C_1-4 alkyl, halogenated C_1-4 alkyl, C_1-4 alkyl substituted with hydroxyl, C_1-4 alkoxy group and halogenated C_1-4 alkoxy group; wherein R_a and R_b are each independently H or C_1-4 alkyl group. The said 4-10 membered heterocyclic group is preferably a heterocyclic group containing oxygen and/or nitrogen, such as oxetanyl, azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, tetrahydrofuranyl and tetrahydropyranyl, etc. Preferably, when Cy₂ is substituted, the substituent on Cy₂ is 1 or 2 groups selected from a group consisting of halogen, cyano, C_1-4 alkyl, C_2-4 alkynyl, halogenated C_1-4 alkyl, deuterated C_1-4 alkyl, 4-10 membered heterocyclic groups, C_3-6 cycloalkyl and C_1-4 alkoxy; preferably, Cy₂ is imidazolyl or pyrazolyl, optionally substituted by 1 or 2 substituents selected from a group consisting of halogen, cyano, C_1-4 alkyl, C_2-4 alkynyl, halogenated C_1-4 alkyl, deuterated C_1-4 alkyl, a 4-10 membered heterocyclic group, C_3-6 cycloalkyl and C_1-4 alkoxy. In some embodiments, Cy₂ is substituted with 1-3 substituents selected from a group consisting of halogen, cyano, C_1-4 alkyl, C₃-C₆ cycloalkyl and halogenated C_1-4 alkyl. In some embodiments, Cy₂ has two substituents selected from a group consisting of halogen, C_1-4 alkyl, C₃-C₆ cycloalkyl and halogenated C_1-4 alkyl. In some embodiments, one of substituents on Cy₂ is located on its ring nitrogen atom.

In one or more embodiments of the compound of Formulae IIIa and IIIb, Cy₁ is an optionally substituted pyrimidinyl group, wherein when Cy₁ is substituted, the number of substituents is 1-3, preferably 2, and the substituents are selected from a group consisting of halogen, cyano, an optionally substituted C_1-4 alkyl, an optionally substituted C_3-6 cycloalkyl and an optionally substituted C_1-4 alkoxy, the preferred substituents are C_1-4 alkyl, C_3-6 cycloalkyl and C_1-4 alkoxy. The fused heteroaromatic bicyclic ring containing A₁/A₂, B₂ and B₃ is selected from the following groups:

preferably:

more preferably:

wherein, *1 and *2 refer to the position of attachment of the group to Cy₁ and methylene group of the compound, respectively. The ring containing D₂ and D₃ is a pyridyl group or a phenyl group optionally substituted by 1 or 2 substituents selected from a group consisting of halogen, C_1-4 alkyl and C_1-3 alkoxy; Cy₂ is imidazolyl, pyrazolyl, tetrahydroimidazopyrazinyl or dihydroimidazoxazinyl optionally substituted by 1-3 substituents selected from a group consisting of halogen, cyano, C_1-4 alkyl, C_3-6 cycloalkyl and halogenated C_1-4 alkyl.

The disclosure provides compounds represented by Formulae IVa and IVb:

A₁, A₂, B₂, B₃ and Cy₂ are as defined in any embodiments of Formula I, II or III;

R₇ and R₉ are each independently selected from a group consisting of hydrogen, halogen, cyano, an optionally substituted C_1-4 alkyl, an optionally substituted C_1-4 alkoxy, an optionally substituted C_3-6 cycloalkyl and an optionally substituted amino;

R₈ is selected from a group consisting of hydrogen, halogen and an optionally substituted C_1- ₄ alkyl;

R₁₀ and R₁₁ are each independently selected from a group consisting of hydrogen, halogen, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted cycloalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, and an optionally substituted amino.

In one or more embodiments of the compound of Formula IVa, A₁ is O, S or NR₁, wherein R₁ is H or C_1-4 alkyl, preferably methyl. Preferably, A₁ is O or S; more preferably, A₁ is O.

In one or more embodiments of the compound of Formula IVb, A₂ is O or S. In some embodiments, A₂ is O.

In one or more embodiments of the compound of Formulae IVa and IVb, B₂ and B₃ are each independently selected from a group consisting of N and CR₂, wherein R₂ is H, halogen, C_1-4 alkyl or C_1-4 alkoxy. Preferably, B₂ and B₃ are each independently N or CH, and at most one of B₂ and B₃ is N. In some embodiments, B₂ is CH, B₃ is N. In some embodiments, both of B₂ and B₃ are CH.

In one or more embodiments of the compound of Formulae IVa and IVb, the fused heteroaromatic bicyclic ring containing A₁/A₂, B₂ and B₃ is selected from the following groups:

preferably:

more preferably:

wherein, *1 and *2 refer to the attachment position of the described group to the substituted pyrimidinyl and methylene group of the compound.

In one or more embodiments of the compound of Formulae IVa and IVb, R₇ and R₉ are each independently hydrogen, halogen, cyano, an optionally substituted C_1-4 alkyl, an optionally substituted C_1-4 alkoxy, an optionally substituted C_3-6 cycloalkyl or an optionally substituted amino; Preferably, the said C_1-4 alkyl and C_1-4 alkoxy groups are optionally substituted by 1-5 groups selected from a group consisting of halogen, hydroxyl and -NR_aR_b; the said C_3-6 cycloalkyl group is optionally substituted by 1 -5 groups selected from a group consisting of halogen, hydroxyl, -NR_aR_b, C_1-4 alkyl, halogenated C_1-4 alkyl, C_1-4 alkyl substituted with hydroxy, C_1-4 alkoxy and halogenated C_1-4 alkoxy; the said amino group is optionally substituted by 1 or 2 substituents selected from a group consisting of C_1-4 alkyl and halogenated C_1-4 alkyl, wherein the R_a and R_b are each independently H or C_1-4 alkyl. In one or more embodiments, R₇ and R₉ are each independently hydrogen, cyano, C_1-4 alkyl, C_1-4 alkoxy, deuterated C_1-4 alkoxy or C_3-6 cycloalkyl, and R₇ and R₉ are not hydrogen at the same time; preferably, R₇ and R₉ are each independently C_1- ₄ alkoxy, deuterated C_1-4 alkoxy or C_3-6 cycloalkyl.

In one or more embodiments of the compound of Formulae IVa and IVb, R₈ is hydrogen, halogen or C_1-4 alkyl optionally substituted by 1-5 groups selected from a group consisting of halogen, hydroxyl and -NR_aR_b, where R_a and R_b are each independently H or C_1-4 alkyl. Preferably, R₈ is hydrogen.

In one or more embodiments of the compound of Formulae IVa and IVb, R₁₀ and R₁₁ are each independently hydrogen, halogen, an optionally substituted C_1-4 alkyl or an optionally substituted C_1-4 alkoxy; preferably, the said C_1-4 alkyl and C_1-4 alkoxy are optionally substituted by 1-5 groups selected from a group consisting of halogen, hydroxyl and -NR_aR_b, wherein R_a and R_b are each independently H or C_1-4 alkyl. In some embodiments, one of R₁₀ and R₁₁ is H, and the other is halogen, an optionally substituted C_1-4 alkyl, or an optionally substituted C_1-4 alkoxy.

In one or more embodiments of the compound of Formulae IVa and IVb, Cy₂ 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. In some embodiments, the said 6-14 membered aryl group is phenyl. In some embodiments, the said 4-10 membered heterocyclic group is a heterocyclic group containing 1-3 heteroatoms selected from a group consisting of nitrogen and oxygen, including a partially saturated 8-10 membered nitrogen-and/or oxygen-containing heterocyclic group, such as azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroimidazopyrazinyl and dihydroimidazoxazinyl, etc. In some embodiments, the 5-10 membered heteroaryl group is a heteroaryl group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, such as imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, etc. Preferably, Cy₂ is an optionally substituted nitrogen-containing 5-10 membered heteroaryl group or an optionally substituted nitrogen-and/or oxygen-containing 8-10-membered heterocyclic group, more preferably a nitrogen-containing five-membered heteroaryl group. In some preferred embodiments, Cy₂ is an optionally substituted imidazolyl or an optionally substituted pyrazolyl. In other embodiments, Cy₂ is an optionally substituted tetrahydroimidazopyrazinyl or an optionally substituted dihydroimidazoxazinyl.

In one or more embodiments of the compound of Formulae IVa and IVb, when Cy₂ is substituted, the substituents can be 1, 2, 3, 4 or 5 substituents selected from a group consisting of halogen, cyano, an optionally substituted C_1-4 alkyl, an optional substituted C_2-4 alkenyl, an optionally substituted C_2-4 alkynyl, an optionally substituted C_3-6 cycloalkyl, an optionally substituted 4-10 membered heterocyclic group, and an optionally substituted C_1-4 alkoxy. The said C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl and C_1-4 alkoxy groups are optionally substituted by 1-5 groups selected from a group consisting of deuterium, halogen, hydroxyl and -NR_aR_b; the C_3-6 cycloalkyl and 4-10 membered heterocyclic groups are each optionally substituted by 1-5 groups selected from a group consisting of halogen, hydroxyl, -NR_aR_b, C_1-4 alkyl, halogenated C_1-4 alkyl, C_1-4 alkyl substituted with hydroxyl, C_1-4 alkoxy group and halogenated C_1-4 alkoxy group; wherein R_a and R_b are each independently H or C_1-4 alkyl group. The said 4-10 membered heterocyclic group is preferably a heterocyclic group containing oxygen and/or nitrogen, such as oxetanyl, azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, tetrahydrofuranyl and tetrahydropyranyl, etc. Preferably, when Cy₂ is substituted, the substituent on Cy₂ is 1 or 2 groups selected from a group consisting of halogen, cyano, C_1-4 alkyl, C_2-4 alkynyl, halogenated C_1-4 alkyl, deuterated C_1-4 alkyl, 4-10 membered heterocyclic groups, C_3-6 cycloalkyl and C_1-4 alkoxy; preferably, Cy₂ is imidazolyl or pyrazolyl, optionally substituted by 1 or 2 substituents selected from a group consisting of halogen, cyano, C_1-4 alkyl, C_2-4 alkynyl, halogenated C_1-4 alkyl, deuterated C_1-4 alkyl, 4-10 membered heterocyclic groups, C_3-6 cycloalkyl and C_1-4 alkoxy. In some embodiments, Cy₂ is substituted with 1-3 substituents selected from a group consisting of halogen, cyano, C_1-4 alkyl, C_3-6 cycloalkyl and halogenated C_1-4 alkyl. In some embodiments, Cy₂ has two substituents selected from a group consisting of halogen, C_1-4 alkyl, C_3-6 cycloalkyl and halogenated C_1-4 alkyl. In some embodiments, one of substituents on Cy₂ is located on its ring nitrogen atom.

The disclosure provides compounds represented by Formula V:

A₁, A₂, B₂ and B₃ are as defined in any embodiments of Formula I, II or III; R₇, R₉, R₁₀ and R₁₁ are as defined in any embodiments of Formulae IVa and IVb.

R₁₂ is selected from a group consisting of hydrogen, an optionally substituted C_1-4 alkyl, an optionally substituted C_3-6 cycloalkyl and an optionally substituted C_4-6 heterocyclic group; alternatively, R₁₁ and R₁₂ are connected to form an optionally substituted 6-7 membered heterocyclic group;

R₁₃ is selected from a group consisting of hydrogen, halogen, an optionally substituted C_1-4 alkyl and an optionally substituted C_1-4 alkoxy; alternatively, R₁₂ and R₁₃ are connected to form an optionally substituted 5-7 membered heterocyclic group;

R₁₄ is selected from a group consisting of hydrogen, cyano, halogen and an optionally substituted C_1-4 alkyl.

In one or more embodiments of the compound of Formula V, A₁ is O, S or NR₁, wherein R₁ is H or C_1-4 alkyl, preferably methyl. Preferably, A₁ is O or S; more preferably, A₁ is O.

In one or more embodiments of the compound of Formula V, B₂ and B₃ are each independently selected from a group consisting of N and CR₂, wherein R₂ is H, halogen, C_1-4 alkyl or C_1-4 alkoxy. Preferably, B₂ and B₃ are each independently N or CH, and at most one of B₂ and B₃ is N. In some embodiments, B₂ is CH, B₃ is N. In some embodiments, both of B₂ and B₃ are CH.

In one or more embodiments of the compound of Formula V, the fused heteroaromatic bicyclic ring containing A₁, B₂ and B₃ is selected from the following groups:

preferably:

In one or more embodiments of the compound of Formula V, R₇ and R₉ are each independently hydrogen, halogen, cyano, an optionally substituted C_1-4 alkyl, an optionally substituted C_1-4 alkoxy, an optionally substituted C_3-6 cycloalkyl or an optionally substituted amino; Preferably, the said C_1-4 alkyl and C_1-4 alkoxy groups are optionally substituted by 1-5 groups selected from a group consisting of halogen, hydroxyl and -NR_aR_b, and the C_3-6 cycloalkyl group is optionally substituted by 1 -5 groups selected from a group consisting of halogen, hydroxyl, -NR_aR_b, C_1-4 alkyl, halogenated C_1-4 alkyl, C_1-4 alkyl substituted with hydroxy, C_1-4 alkoxy and halogenated C_1-4 alkoxy, the amino group is optionally substituted by 1 or 2 substituents selected from a group consisting of C_1-4 alkyl and halogenated C_1-4 alkyl, wherein the R_a and R_b are each independently H or C_1-4 alkyl. In one or more embodiments, R₇ and R₉ are each independently hydrogen, cyano, C_1-4 alkyl, C_1-4 alkoxy, deuterated C_1-4 alkoxy or C_3-6 cycloalkyl, and R₇ and R₉ are not hydrogen at the same time; preferably, R₇ and R₉ are each independently C_1-4 alkoxy, deuterated C_1-4 alkoxy or C_3-6 cycloalkyl.

In one or more embodiments of the compound of Formula V, R₁₀ and R₁₁ are each independently hydrogen, halogen, an optionally substituted C_1-4 alkyl or an optionally substituted C_1-4 alkoxy; preferably, the said C_1-4 alkyl and C_1-4 alkoxy are optionally substituted by 1-5 groups selected from a group consisting of halogen, hydroxyl and -NR_aR_b, wherein R_a and R_b are each independently H or C_1-4 alkyl. In some embodiments, one of R₁₀ and R₁₁ is H, and the other is halogen, an optionally substituted C_1-4 alkyl, or an optionally substituted C_1-4 alkoxy.

In one or more embodiments of the compound of Formula V, R₁₂ is selected from a group consisting of hydrogen, an optionally substituted C_1-4 alkyl, an optionally substituted C_1-4 alkoxy, an optionally substituted C_2-4 alkenyl, an optionally substituted C_2-4 alkynyl, an optionally substituted C_3-6 cycloalkyl and an optionally substituted C_4-6 heterocyclic group; preferably, the optionally substituted C_4-6 heterocyclic group is an nitrogen-or oxygen-containing heterocyclic group, such as oxetanyl, nitrogen heterocyclobutanyl, pyrrolidinyl, piperidinyl and piperazinyl, etc. The substituent of R₁₂ may be 1-3 substituents selected from a group consisting of halogen, hydroxyl and -NR_aR_b, wherein R_a and R_b are each independently H or C_1-4 alkyl. Preferably, R₁₂ is C_1-4 alkyl, deuterated C_1-4 alkyl, C_1-4 alkoxy, C_2-4 alkynyl or C_3-6 cycloalkyl.

In one or more embodiments of the compound of Formula V, R₁₃ is selected from a group consisting of hydrogen, halogen, an optionally substituted C_1-4 alkyl and an optionally substituted C_1-4 alkoxy; preferably, R₁₃ is hydrogen.

In one or more embodiments of the compound of Formula V, R₁₄ is selected from a group consisting of hydrogen, cyano, halogen, an optionally substituted C_1-4 alkyl. The alkyl group is optionally substituted with 1 to 5 substituents selected from a group consisting of hydroxyl and halogen. Preferably, R₁₄ is halogen or halogenated C_1-4 alkyl, such as trifluoromethyl.

In one or more embodiments of the compound of Formula V, R₁₁ and R₁₂ are connected to form an optionally substituted 6-7 membered heterocyclic group, the said heterocyclic group together with the phenyl and imidazolyl groups form a 11-14 membered heterotricyclic group containing 2, 3 or 4 selected from a group consisting of nitrogen and oxygen as described herein, such as benzimidazoloxazinyl, dihydrobenzimidazoloxazepine, dihydrobenzimidazodiazepine and benzimidazoloxazepine.

In one or more embodiments of the compound of Formula V, R₁₂ and R₁₃ are connected to form an optionally substituted 5-7-membered nitrogen-and/or oxygen-containing heterocyclic group, the said heterocyclic group together with the imidazolyl group forms a 7-10 membered nitrogen-and/or oxygen-containing bicyclic heterocyclic group, such as tetrahydroimidazopyrazinyl and dihydroimidazoxazinyl.

In one or more embodiments of the compound of Formula V: A₁ is O; B₂ and B₃ are each independently N or CH, and at most one of B₂ and B₃ is N; R₇ and R₉ are each independently C_1-4 alkyl, C_1-4 alkoxy, deuterated C_1-4 alkoxy or C_3-6 cycloalkyl, preferably, R₇ is C_1-4 alkyl or C_3- ₆ cycloalkyl and R₉ is C_1-4 alkoxy or deuterated C_1-4 alkoxy; R₁₀ and R₁₁ are each independently hydrogen, halogen, or C_1-4 alkoxy; R₁₂ is hydrogen, C_1-4 alkyl, deuterated C_1-4 alkyl, or C_3-6 cycloalkyl; R₁₃ is hydrogen; and R₁₄ is halogen, C_1-4 alkyl or halogenated C_1-4 alkyl.

In one or more of the foregoing embodiments, preferred compounds of Formula I (including Formulae II, III, IV and V) include, without limitation:

or stereoisomers, tautomers, N-oxides, hydrates, isotope-substituted derivatives, solvates or pharmaceutically acceptable salts thereof, or mixtures thereof, or prodrugs thereof.

The term “hydrogen (H) ” as empolyed herein includes its isotopes D and T.

The term “alkyl” as used herein refers to alkyl itself or a straight or branched chain radical of up to ten carbons. Useful alkyl groups include straight-chain, branched C_1-10 alkyl groups, preferably C_1-6 alkyl groups. In some embodiments, alkyl is C_1-4 alkyl. In some embodiments, alkyl is C_1-3 alkyl. In some embodiments, alkyl is deuterated C_1-3 alkyl. Typical C_1-10 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl (such as 3-pentyl) , hexyl and octyl groups, which may be optionally substituted.

The term “alkenyl” as used herein refers to a straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, wherein there is at least one double bond between two of the carbon atoms in the chain; preferably, C_2-6 alkenyl. Typical alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl.

The term “alkynyl” as used herein refers to a straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, wherein there is at least one triple bond between two of the carbon atoms in the chain; preferably, C_2-6 alkynyl. Typical alkynyl groups include ethynyl, 1-propynyl, 1-methyl-2-propynyl, 2-propynyl, 1-butynyl and 2-butynyl.

Useful alkoxy groups include oxygen substituted by the above mentioned C_1-10 alkyl groups, preferred C_1-6 alkyl groups or C_1-4 alkyl groups, e.g., methoxy, ethoxy, etc. The alkyl in the alkoxy groups may be optionally substituted. Substituents of alkoxy groups include, without limitation, halogen, morpholino, amino (including alkylamino and dialkylamino) , and carboxy (including esters thereof) .

Useful amino and optionally substituted amino groups include -NH₂, -NHR' and -NR'R", wherein -NHR' and -NR'R" each are independently hydrogen, an optionally substituted C_1- ₁₀ alkyl (preferably C_1-4 alkyl) , an optionally substituted cycloalkyl, an optionally substituted aryl or an 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, which optionally comprises one or more (such as 2, 3) additional heteroatoms selected from a group consisting of O, N and S.

The term “aryl” as used herein by itself or as part of another group refers to monocyclic, bicyclic or tricyclic aromatic groups containing 6 to 14 carbon atoms. Aryl may be substituted by one or more substituents as described herein.

Useful aryl groups include C_6-14 aryl groups, preferably C_6-10 aryl groups. Typical C_6-14 aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azulyl, biphenyl, biphenylene and fluorenyl.

The term “carbocyclic group” as used herein include cycloalkyl and partially saturated carbocyclic groups. Useful cycloalkyl groups are C_3-8 cycloalkyl. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Carbocyclic group may be substituted by one or more substituents as described herein.

Useful partially saturated carbocyclic groups include cycloalkenyl groups, such as C_3-8 cycloalkenyl groups, e.g., cyclopentenyl, cycloheptenyl and cyclooctenyl.

Useful halo or halogen groups include fluoro, chloro, bromo and iodo.

The term “heterocyclic group” as used herein refers to a saturated or partially saturated 3-7 membered monocyclic, 7-10 membered bicyclic ring, spirocyclic ring or bridged ring system, or 11-14 membered bicyclic ring , spirocyclic ring or bridged ring system, which consists of carbon atoms and one to four heteroatoms independently selected from a group consisting of O, N, and S, wherein the nitrogen and/or sulfur heteroatoms can be optionally oxidized and the nitrogen can be optionally quaternized, and the term also includes any bicyclic ring system in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocycle can be substituted on carbon atom or nitrogen atom if the resulting compound is stable. Heterocyclic group may be substituted by one or more substituents as described herein. The heterocyclic groups mentioned above also include 5-8 membered heterocycloalkyl groups, i.e., heterocyclic groups in which one or more ring C atoms in the cycloalkyl group are replaced by heteroatoms selected from a group consisting of N, O and S.

Useful saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, tetrahydropyranyl, pyranyl, piperidinyl, piperazinyl, oxetanyl, azetidinyl, 1, 4-diazepanyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indoline, isoindolyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidine, pyrazolinyl, Tetrahydroisoquinolyl, tetronoyl, oxadiazolyl, oxazolyl and tetramoyl, which may be optionally substituted by one or more substituents as described herein.

The term “heteroaryl” as used herein refers to a group having 5 to 14 ring atoms, preferably 5 to 10 ring atoms, with 6, 10 or 14 π electrons shared in a cyclic array. Ring atoms are carbon atoms and 1-3 heteroatoms selected from a group consisting of oxygen, nitrogen and sulfur. Heteroaryl may be optionally substituted by one or more substituents as described herein.

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 (pyridinyl, including without limitation 2-pyridyl, 3-pyridyl, and 4-pyridyl) , pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalzinyl, naphthyridinyl, quinozalinyl, 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-benzoisoxazol-3-yl, benzimidazolyl, 2-oxindolyl, thiadiazolyl, 2-oxobenzimidazolyl, imidazopyridazinyl, imidazopyridyl, triazolopyridazinyl, pyrazolopyrimidinyl, pyrrolopyrimidinyl, pyrrolopyridyl, pyrrolopyrazinyl or triazolopyrazinyl. Where the heteroaryl group contains a nitrogen atom in a ring, such nitrogen atom may be in the form of an N-oxide, e.g., a pyridyl N-oxide, pyrazinyl N-oxide and pyrimidinyl N-oxide.

In this disclosure, unless otherwise described, when substituted, the alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, heterocyclic, aryl or heteroaryl as described in any embodiment herein may be substituted by one or more (such as 1, 2, 3, or 4) substituents selected from a group consisting of halogen, amino, cyano, C_1-6 alkoxy, C_1-6 alkyl, C_6-10 aryl, C_3-8 cycloalkyl, C_2-6 chain alkenyl, C_2-6 alkynyl, heterocyclic group, heteroaryl, etc. The substituent itself may also be optionally substituted. Preferred substituents include without limitation cyano, halogenated C_1- ₆ alkyl, halo, amino, halogenated C_1-6 alkoxy, C_1-6 alkyl and C_3-8 cycloalkyl.

In some embodiments, one or more hydrogens in the alkyl, alkoxy, alkenyl and alkynyl groups described herein are replaced by their isotopes deuterium (D) and/or tritium (T) , such as tri-deuterated methyl, tri-deuterated methoxy, etc.

It should be understood that in each embodiment, when the substituent is cyano, cycloalkyl, heterocyclic group, aryl or heteroaryl, the number thereof is usually 1.

Some of the compounds of the present disclosure may exist as stereoisomers including optical isomers. The disclosure includes all stereoisomers and the racemic mixtures of such stereoisomers as well as the individual enantiomers that may be separated according to methods that are well known to those of ordinary skill in the art.

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

Examples of prodrugs of the compounds of the disclosure include the simple esters of carboxylic acid-containing compounds (e.g., those obtained by condensation with a C_1-4 alcohol according to methods known in the art) ; esters of hydroxy containing compounds (e.g., those obtained by condensation with a C_1-4 carboxylic acid, C_3-6 diacid or anhydride thereof, such as succinic anhydride and fumaric anhydride according to methods known in the art) ; imines of amino containing compounds (e.g., those obtained by condensation with a C_1-4 aldehyde or ketone according to methods known in the art) ; carbamate 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 (e.g., those obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether according to methods known in the art) .

The compounds of this disclosure may be prepared using methods known to those skilled in the art, or the novel methods of this disclosure. Specifically, the compounds of this disclosure with Formula I (including Formulae II, III, IV and V) can be prepared as illustrated by the exemplary reaction in Scheme 1. Miyaura borate esterification reaction of 3-bromo-2-methoxyaniline and bis (pinacolato) diboron under the catalysis of [1, 1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (Pd (dppf) Cl₂) and potassium acetate (KOAc) produced 2-methoxy-3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline. Suzuki coupling reaction of 2-methoxy-3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline and 2- (4- (bromomethyl) phenyl) -1-methyl-4- (trifluoromethyl) -1H-imidazole under the catalysis of Pd (dppf) Cl₂ and cesium acetate (Cs₂CO₃) produced 2-methoxy-3- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) aniline. Reaction of 2-methoxy-3- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) aniline and boron tribromide (BBr₃) produced 2-amino-6- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) phenol. Reaction of 2-amino-6- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) phenol and 4-cyclopropyl-6-methoxypyrimidine-5-carbaldehyde under the catalysis of (diacetoxyiodo) benzene (PhI (OAc) ₂) produced the target compound 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) benzo [d] oxazole.

Scheme 1

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

The compounds of this disclosure may be prepared using methods known to those skilled in the art, or the novel methods of this disclosure. Specifically, the compounds of this disclosure with Formula I (including Formulae II, III, IV and V) can be prepared as illustrated by the exemplary reaction in Scheme 2. Reaction of 3-bromobenzene-1, 2-diamine and di-tert-butyl dicarbonate under the catalysis of 4-dimethylaminopyridine (DMAP) produced di-tert-butyl (3-bromo-1, 2-phenylene) dicarbamate. Miyaura borate esterification reaction of di-tert-butyl (3-bromo-1, 2-phenylene) dicarbamate and bis (pinacolato) diboron under the catalysis of Pd (dppf) Cl₂ and KOAc produced di-tert-butyl (3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-phenylene) dicarbamate. Suzuki coupling reaction of di-tert-butyl (3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-phenylene) dicarbamate and 2- (4- (bromomethyl) phenyl) -1-methyl-4- (trifluoromethyl) -1H-imidazole under the catalysis of Pd (dppf) Cl₂ and Cs₂CO₃ produced di-tert-butyl (3- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -1, 2-phenylene) dicarbamate. Deprotection of di-tert-butyl (3- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -1, 2-phenylene) dicarbamate under the catalysis of HCl/dioxane produced 3- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) benzene-1, 2-diamine. Reaction of 3- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) benzene-1, 2-diamine and 4-cyclopropyl-6-methoxypyrimidine-5-carbaldehyde under the catalysis of copper acetate (Cu (OAc) ₂) produced 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -1H-benzo [d] imidazole. Reaction of 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -1H-benzo [d] imidazole and iodomethane (MeI) under the catalysis of K₂CO₃ produced the target compound 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1-methyl-7- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -1H-benzo [d] imidazole.

Scheme 2

The compounds of this disclosure may be prepared using methods known to those skilled in the art, or the novel methods of this disclosure. Specifically, the compounds of this disclosure with Formula I (including Formulae II, III, IV and V) can be prepared as illustrated by the exemplary reaction in Scheme 3. Reaction of 4-amino-2-bromopyridin-3-ol and 4-cyclopropyl-6-methoxypyrimidine-5-carboxylic acid under the catalysis of triethylamine (TEA) and 2- (1H-benzotriazole-1-yl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate (TBTU) produced N- (2-bromo-3-hydroxypyridin-4-yl) -4-cyclopropyl-6-methoxypyrimidine-5-carboxamide. Ring closing reaction of N- (2-bromo-3-hydroxypyridin-4-yl) -4-cyclopropyl-6-methoxypyrimidine-5- carboxamide under the catalysis of hexachloroethane (C₂Cl₆) and triphenylphosphine (PPh₃) produced 4-bromo-2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) oxazolo [5, 4-c] pyridine. Negishi coupling reaction of 4-bromo-2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) oxazolo [5, 4-c] pyridine and 2- (4- (bromomethyl) -2-fluorophenyl) -1-methyl-4- (trifluoromethyl) -1H-imidazole under the catalysis of Zn, I₂, TMSCl and Pd (PPh₃) ₄ produced the target compound 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- (3-fluoro-4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine.

Scheme 3

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

The compounds of this disclosure may be prepared using methods known to those skilled in the art, or the novel methods of this disclosure. Specifically, the compounds of this disclosure with Formula I (including Formulae II, III, IV and V) can be prepared as illustrated by the exemplary reaction in Scheme 4. Negishi coupling reaction of 2-bromo-3-methoxypyridin-4-amine and 2- (4- (bromomethyl) phenyl) -1-methyl-4- (trifluoromethyl) -1H-imidazole under the catalysis of Zn, I₂, TMSCl and Pd (PPh₃) ₄ produced 3-methoxy-2- (4- (1-methyl-4- (trifluoromethyl) - 1H-imidazol-2-yl) benzyl) pyridin-4-amine. Reaction of 3-methoxy-2- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) pyridin-4-amine and BBr₃ produced 4-amino-2- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) pyridin-3-ol. Reaction of 4-amino-2- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) pyridin-3-ol and 4-chloro-1-isopropyl-1H-pyrazole-5-carboxylic acid under the catalysis of HATU and DIEA produced 4-chloro-N- (3-hydroxy-2- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) pyridin-4-yl) -1-isopropyl-1H-pyrazole-5-carboxamide. Ring closing reaction of 4-chloro-N- (3-hydroxy-2- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) pyridin-4-yl) -1-isopropyl-1H-pyrazole-5-carboxamide under the catalysis of C₂Cl₆ and triphenylphosphine PPh₃ produced the target compound 2- (4-chloro-1-isopropyl-1H-pyrazol-5-yl) -4- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine.

Scheme 4

Other related compounds can be prepared using similar methods. For example, replacement of 4-chloro-1-isopropyl-1H-pyrazole-5-carboxylic acid with 4-methoxy-6-methylpyrimidine-5-carboxylic acid produced the target compound 2- (4-methoxy-6-methylpyrimidin-5-yl) -4- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine. Replacement of 4-chloro-1-isopropyl-1H-pyrazole-5-carboxylic acid with 4-isopropylpyrimidine-5-carboxylic acid produced the target compound 2- (4-isopropylpyrimidin-5-yl) -4- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine.

Replacement of 4-chloro-1-isopropyl-1H-pyrazole-5-carboxylic acid with 4, 6-dimethoxypyrimidine-5-carboxylic acid produced the target compound 2- (4, 6-dimethoxypyrimidin-5-yl) -4- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine.

One important aspect of the present disclosure is the finding that the compounds of Formula I (including Formulae II, III, IV and V as described herein) are USP1 inhibitors. Therefore, the compounds of Formula I (including Formulae II, III, IV and V as described herein) can be used to treat or prevent diseases associated with USP1 regulation or be used to prepare medicaments for the treatment or prevention of diseases associated with USP1 regulation.

In the disclosure, the diseases associated with USP1 regulation include cancers. Preferably, the cancers associated with USP1 regulation have defects in DDR function. The diseases associated with USP1 regulation that can be treated or prevented by the methods or pharmaceutical compositions of the disclosure include, but are not limited to, 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 lung cancer, small cell lung cancer, gastric cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi’s sarcoma, urogenital tumors, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocythemia, adrenocortical carcinoma, skin cancer, and prostate cancer.

Therefore, in some embodiments, this disclosure provides compounds of Formula I (including Formulae II, III, IV and V as described herein) or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-substituted derivatives or pharmaceutically acceptable salts, or mixtures thereof, or the use of pharmaceutical compositions thereof in the preparation of medicaments for the treatment of diseases related to USP1 regulation or USP1-mediated diseases, and in the treatment of diseases associated with USP1 regulation. Compounds of Formula I (including Formulae II, III, IV and V as described herein) or stereoisomers, isomers, tautomers, N-oxides, hydrates, solvates, isotope-substituted derivatives or pharmaceutically acceptable salts, or mixtures thereof, or pharmaceutical compositions thereof used in methods of USP1 modulation-related diseases or USP1-mediated diseases.

The present disclosure also includes methods for the treatment or prevention of diseases associated with USP1 regulation, especially, methods of the treatment or prevention of diseases associated with USP1 regulation and methods of treatment or prevention of diseases caused by defects in DDR function, comprising administering to a subject (especially mammal, more specifically human) in need thereof an effective amount of the compound of Formula I (including Formulae II, III, IV and V as described herein) or stereoisomers, tautomers, N-oxides, hydrates, isotope-substituted derivatives, solvates or pharmaceutically acceptable salts thereof, or mixtures thereof, or prodrugs thereof, or a pharmaceutical composition comprising an effective amount of the compound of Formula I (including Formulae II, III, IV and V as described herein) or stereoisomers, tautomers, N-oxides, hydrates, isotope-substituted derivatives, solvates or pharmaceutically acceptable salts thereof, or mixtures thereof, or prodrugs thereof.

In some embodiments, the present disclosure further provides a method for treatment or prevention of other diseases caused by excessive or abnormal cell proliferation, including proliferative or hyperproliferative diseases, such as myeloproliferative diseases, especially excessive or abnormal cells associated with USP1 regulation, comprising administering to a subject in need thereof (especially a mammal, more specifically a human) an effective amount of a compound of Formula I (including Formulae II, III, IV and V as described herein) or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-substituted derivatives or pharmaceutically acceptable salts, or mixtures thereof, or containing an effective amount of a compound of Formula I (including Formulae II, III, IV and V as described herein) or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-substituted derivatives or pharmaceutically acceptable salts thereof , or pharmaceutical compositions of mixtures thereof.

In practicing the therapeutic methods, effective amounts of pharmaceutical preparations are administered to an individual exhibiting the symptoms of one or more of these disorders. The pharmaceutical preparations comprise therapeutically effective concentrations of the compounds of Formula I (including Formulae II, III, IV and V as described herein) formulated for oral, intravenous, local or topical application, for the treatment of cancer and other diseases. The amounts are effective to ameliorate or eliminate one or more symptoms of the disorders. An effective amount of a compound for treating a particular disease is an amount that is sufficient to ameliorate or in some manner reduce the symptoms associated with the disease. Such amount may be administered as a single dosage or may be administered according to an effective regimen. The amount may cure the disease but, typically, is administered in order to ameliorate the symptoms of the disease. Typically, repeated administration is required to achieve the desired amelioration of symptom.

In another embodiment, there is provided a pharmaceutical composition comprising a compound of Formula I (including Formulae II, III, IV and V as described herein) as an USP1 inhibitor, or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-substituted derivatives, or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients or carriers.

Another embodiment of the present disclosure is directed to a pharmaceutical composition effective to treat cancer comprising a compound of Formula I (including Formulae II, III, IV and V as described herein) as an USP1 inhibitor, or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-substituted derivatives, or pharmaceutically acceptable salts thereof or prodrugs thereof, in combination with at least one known anticancer agent or a pharmaceutically acceptable salt thereof. In particular, the compound herein can be combined with other anticancer drugs related to the mechanism of DNA damage and repair, including PARP inhibitors, such as olaparib, niraprib, rucaparib, talazoparib, pamiparib, fluzoparib and senaparib; HDAC inhibitors such as Volinota, Romididesin, Papiseta and Bailesta; and so on. And the compound herein can 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 so on. And combination with other targeted anti-cancer drugs, including PRMT5 inhibitors, Polθ inhibitors, RAD51 inhibitors, and so on. Other known anticancer agents which may be used for anticancer combination therapy include, but are not limited to alkylating agents, such as busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cis-platin, 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'-deoxy-uridine, fludarabine, nelarabine, ara-C, pralatrexate, pemetrexed, hydroxyurea and thioguanine; antimitotic agent such as colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel and docetaxel; antibodies such as 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 and mabthera; Antibody–Drug Conjugates (ADC) such as T-DM1, Trastuzumab Deruxtecan, Trastuzumab Emtansine, Datopotamab 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, regorafenib, vemurafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, ponatinib, ibrutinib, cabozantinib, lenvatinib, vandetanib, trametinib, cobimetinib, axitinib, temsirolimus, Idelalisib, pazopanib, Torisel and everolimus. Other known anticancer agents which may be used for anticancer combination therapy include tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, Ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide, Venetoclax, Aldesleukin and Sipueucel-T.

In practicing the methods of the present disclosure, the compound of the disclosure may be administered together with at least one known anticancer agent in a unitary pharmaceutical composition. Alternatively, the compound of the disclosure may be administered separately from at least one known anticancer agent. In one embodiment, the compound of the disclosure and at least one known anticancer agent are administered substantially simultaneously, i.e. all agents are administered at the same time or one after another, provided that compounds reach therapeutic levels in the blood at the same time. In another embodiment, the compound of the disclosure and at least one known anticancer agent are administered according to individual dose schedule, provided that the compounds reach therapeutic levels in the blood.

Another embodiment of the present disclosure is directed to a bioconjugate, which functions as a USP1 inhibitor, that comprises a compound described herein and is effective to inhibit tumor. The bioconjugate that inhibits tumor consists of the compound described herein and at least one known therapeutically useful antibody, such as trastuzumab or rituximab, or growth factor, such as EGF or FGF, or cytokine, such as IL-2 or IL-4, or any molecule that can bind to cell surface. The antibodies and other molecules could deliver the compound described herein to its targets, making it an effective anticancer agent. The bioconjugates could also enhance the anticancer effect of the therapeutically useful antibodies, such as trastuzumab or rituximab.

Another embodiment of the present disclosure is directed to a pharmaceutical composition effective to inhibit tumor comprising the USP1 inhibitor of Formula I (including Formulae II, III, IV and V as described herein) , or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-substituted derivatives, or pharmaceutically acceptable salts thereof or prodrugs thereof, in combination with radiation therapy. In this embodiment, the compound of the disclosure may be administered at the same time as the radiation therapy or at a different time.

Yet another embodiment of the present disclosure is directed to a pharmaceutical composition effective for post-surgical treatment of cancer, comprising the USP1 inhibitor of Formula I (including Formulae II, III, IV and V as described herein) or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-substituted derivatives, or pharmaceutically acceptable salts thereof or prodrugs thereof. The disclosure also relates to a method of treating cancer by surgically removing tumor and then treating the mammal with the pharmaceutical composition described herein.

Pharmaceutical compositions of this disclosure include all pharmaceutical preparations which contain the compounds of the present disclosure in an amount that is effective to achieve its intended purpose. While individual needs vary, determination of optimal amounts of each component in the pharmaceutical preparations is within the skill of the art. Typically, the compounds or the pharmaceutically acceptable salt thereof may be administered to mammals, orally at a dose of about 0.0025 to 50 mg per kg body weight per day. Preferably, from approximately 0.01 mg/kg to approximately 10 mg/kg body weight is orally administered. If a known anticancer agent is also administered, it is administered in an amount that is effective to achieve its intended purpose. The optimal amounts of such known anticancer agents are well known to those skilled in the art.

The unit oral dose may comprise from approximately 0.01 to approximately 50 mg, preferably approximately 0.1 to approximately 10 mg of the compound of the disclosure. The unit dose may be administered one or more times, with one or more tablets daily, each containing from approximately 0.1 to approximately 50 mg, conveniently approximately 0.25 to 10 mg of the compound of the disclosure or its solvates.

In a topical formulation, the compound of the disclosure may be present at a concentration of approximately 0.01 to 100 mg per gram of carrier.

The compound of the disclosure may be administered as a raw chemical. The compounds of the disclosure may also be administered as part of a suitable pharmaceutical preparation containing pharmaceutically acceptable carriers (comprising excipients and auxiliaries) , which facilitate the processing of the compounds into pharmaceutically acceptable preparations. Preferably, the pharmaceutical preparations, particularly oral preparations and those used for the preferred administration, such as tablets, dragees, and capsules, as well as solutions suitable for injection or oral administration, contain from approximately 0.01%to 99%, preferably from approximately 0.25%to 75%of active compound (s) , together with excipient (s) .

Also included within the scope of the present disclosure are the non-toxic pharmaceutically acceptable salts of the compounds of the present disclosure. Acid addition salts are formed by mixing a solution of the compounds of the present disclosure with a solution of a pharmaceutically acceptable non-toxic acid, such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, and the like. Base addition salts are formed by mixing a solution of the compounds of the present disclosure with a solution of a pharmaceutically acceptable non-toxic base, such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, tris (hydroxymethyl) aminomethane, N-methyl-glucamine and the like.

The pharmaceutical preperations of the disclosure may be administered to any mammal, so long as they may experience the therapeutic effects of the compounds of the disclosure. Foremost among such mammals are humans and veterinary animals, although the disclosure is not intended to be so limited.

The pharmaceutical preperations of the present disclosure may be administered by any means that achieve their intended purpose. For example, administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal or topical routes. Alternatively or concurrently, administration may be by oral route. The dosage administered will be dependent upon the age, health, and weight of the recipient, type of concurrent treatment, frequency of treatment, and the nature of the effect desired.

The pharmaceutical preparations of the present disclosure are manufactured in a known manner, e.g., by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes. Pharmaceutical preparations for oral use may be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture, processing the mixture of granules after adding suitable auxiliaries if desired or necessary, thereby obtaining tablets or dragee cores.

Suitable excipients are, in particular, fillers, such as saccharides, e.g. lactose or sucrose, mannitol or sorbitol; cellulose preparations and/or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate; as well as binders, such as starch paste, including, e.g., maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, disintegrating agents may be added, such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are, in particular, flow-regulating agents and lubricants, e.g., silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, are used. Dyes or pigments may be added to the tablets or dragee coatings, e.g., for identification or in order to characterize combinations of active compound doses.

Other pharmaceutical preparations, which may be used orally, include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules may contain the active compounds in the form of granules, which may be mixed with fillers, such as lactose; binders, such as starches; and/or lubricants, such as talc or magnesium stearate and stabilizers. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin. In addition, stabilizers may be added.

Suitable formulations for parenteral administration include aqueous solutions of the active compounds, e.g., aqueous solutions and alkaline solutions of water-soluble salts. In addition, suspensions of the active compounds as appropriate oily injection suspensions may be administered. Suitable lipophilic solvents or vehicles include fatty oils, e.g., sesame oil, or synthetic fatty acid esters, e.g., ethyl oleate or triglycerides or polyethylene glycol-400, or cremophor, or cyclodextrins. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, e.g., sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, suspension stabilizers may also be contained.

In accordance with one aspect of the present disclosure, compounds of the disclosure are employed in topical and parenteral formulations and are used for the treatment of skin cancer.

The topical formulations of this disclosure are formulated preferably as oils, creams, lotions, ointments and the like by choice of appropriate carriers. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin) , branched chain fats or oils, animal fats and high molecular weight alcohol (greater than C₁₂) . The preferred carriers are those in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants and antioxidants may also be included, as well as agents imparting color or fragrance, if desired. Additionally, transdermal penetration enhancers may be employed in these topical formulations. Examples of such enhancers are found in U.S. Patent Nos. 3,989,816 and 4,444,762.

Creams are preferably formulated from a mixture of mineral oil, self-emulsifying beeswax and water in which the active ingredient, dissolved in a small amount of an oil, such as almond oil, is admixed. A typical example of such a cream is one which includes approximately 40 parts water, approximately 20 parts beeswax, approximately 40 parts mineral oil and approximately 1 part almond oil.

Ointments may be formulated by mixing a solution of the active ingredient in a vegetable oil, such as almond oil, with warm soft paraffin and allowing the mixture to cool. A typical example of such an ointment is one which includes approximately 30%almond oil and approximately 70%white soft paraffin by weight.

The present disclosure also involves use of the compounds of the disclosure for the preparation of a medicament for the treatment or prevention of clinical symptoms in response to the effect of inhibiting the activity of USP1. The medicament may include the above-mentioned pharmaceutical compositions.

The following examples are illustrative, but not limiting, of the method and compositions of the present disclosure. Other suitable modifications and adaptations of the variety of 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 disclosure.

EXAMPLES

General remarks

All reagents were of commercial quality. Solvents were dried and purified by standard methods. Mass spectrum analyses were recorded on a Platform II (Agilent 6110) quadrupole mass spectrometer fitted with an electrospray interface. ¹H NMR spectra was recorded at 400 MHz, on a Brücker Ascend 400 apparatus. Chemical shifts were recorded in parts per million (ppm) downfield from TMS (0.00 ppm) , and J coupling constants were reported in hertz (Hz) .

Example 1

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) benzo [d] oxazole

a) Preparation of 2-methoxy-3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline: To a solution of 3-bromo-2-methoxyaniline (1.5 g, 7.3 mmol) in 1, 4-dioxane (10 mL) was added bis (pinacolato) diboron (2.8 g , 11.1 mmol) , KOAc (2.2 g, 22.2 mmol) and Pd (dppf) Cl₂ (150 mg, 0.18 mmol) . The reaction was heated at 100 ℃ overnight under N₂. The reaction was cooled to room temperature. The mixture diluted with water (30 mL) and extracted with EA (30 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 column over silica gel (PE/EA=5/1) to give the title compound. (1.3 g, white solid, yield: 70%) . MS (ESI) : 250.10 [M+H] ⁺.

b) Preparation of 2-methoxy-3- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) aniline: To a solution of 2-methoxy-3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (1.3 g, 5.2 mmol) in dioxane/H₂O (10 mL, v/v= 1/1) was added 2- (4- (bromomethyl) phenyl) -1-methyl-4- (trifluoromethyl) -1H-imidazole (2.5 g, 7.8 mmol) , Cs₂CO₃ (5.07 g, 15.6 mmol) and Pd (dppf) Cl₂ (570 mg, 0.78 mmol) at room temperature. The mixture was stirred at 90 ℃ overnight under N₂ atmosphere. The mixture was cooled slowly to room temperature, The resulting reaction mixture was partitioned by adding with water (50 mL) and extracted with EA (50 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 column over silica gel (PE/EA=10/1) to give the title compound (800 mg, white solid, yield: 44 %) . MS (ESI) : 362.25 [M+H] ⁺.

c) Preparation of 2-amino-6- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) phenol: To a stirred solution of 2-methoxy-3- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) aniline (400 mg, 1.1 mol) in DCM (10 mL) was added BBr₃ (5.5 ml, 5.5 mmol, 1 M in DCM) dropwise at 0 ℃. The mixture was warmed slowly to room temperature and stirred for 3 h. After the reaction was completed, the reaction mixture was quenched with MeOH (3 mL) and concentrated under vacuum. The residue was purified by Pre-HPLC to give the title compound (310 mg, white solid, yield: 80 %) . MS (ESI) : 348.05 [M+H] ⁺.

d) Preparation of 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) benzo [d] oxazole: To a solution of 2-amino-6- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) phenol (310 mg, 0.89 mmol) in EtOH (5 mL) was added 4-cyclopropyl-6-methoxypyrimidine-5-carbaldehyde (158 mg, 0.89 mmol) at room temperature for 30 min. The mixture was added PhI (OAc) ₂ (311 mg, 1.35) at room temperature for 30 min. After the reaction was completed. The reaction was cooled to room temperature. The mixture diluted with water (20 mL) and extracted with EA (20 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 column over silica gel (PE/EA=3/1) to give the target compound (41.68 mg, white solid, yield: 28.6 %) .

The following compounds of Examples 2-8 were prepared using a synthesis method similar to that described in Example 1.

Example 9

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) benzo [d] thiazole

a) Preparation of 2- (4- (2-fluoro-3-nitrobenzyl) phenyl) -1-methyl-4- (trifluoromethyl) -1H-imidazole: To a solution of 2- (2-fluoro-3-nitrophenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (3.0 g, 11.23 mmol) in dioxane/H₂O (30 mL, v/v = 5/1) was added 2- (4- (bromomethyl) phenyl) -1-methyl-4- (trifluoromethyl) -1H-imidazole (3.6 g, 11.23 mmol) , Cs₂CO₃ (7.3 g, 22.47 mmol) and Pd (dppf) Cl₂ (822 mg, 1.1 mmol) at room temperature. The mixture was stirred in sealed tube at 90 ℃ overnight under N₂ atmosphere. After the reaction was completed, the mixture was cooled to room temperature, the resulting reaction mixture was extracted with EA (50 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 column over silica gel (PE/EA=10/1-5/1) to afford the title compound (1.8 g, yellow solid, yield: 42.3%) . MS (ESI) : 380.09 [M+H] ⁺ .

b) Preparation of 2- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6-nitrobenzenethiol: To a stirred solution of 2- (4- (2-fluoro-3-nitrobenzyl) phenyl) -1-methyl-4- (trifluoromethyl) -1H-imidazole (800 mg, 2.11 mmol) in DMSO (8 mL) was added dropwise sodium bisulfide (NaHS, 608 mg, 7.60 mmol) at 0 ℃. The mixture was warmed to room temperature and stirred for 2 hrs. After the reaction was completed, the PH of the mixture was adjusted to ～2 with HCl (1.0 M) , the resulting reaction mixture was extracted with EA (50 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 Pre-TLC to give the title compound (240 mg, white solid, yield: 28.9 %) . MS (ESI) : 394.08 [M+H] ⁺.

c) Preparation of 2-amino-6- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) benzenethiol: To a stirred solution of 2- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6-nitrobenzenethiol (140 mg, 0.36 mmol) in acetic acid (4 mL) was added Zn (116 mg, 1.78 mmol) at room temperature and the mixture was stirred at 70 ℃ for 2 hours. After the reaction was completed, the mixture was diluted with water (5 mL) , and the mixture was extracted with EA (50 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 Pre-TLC to afford the title compound (100 mg, white solid, yield: 77.2 %) .

d) Preparation of 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) benzo [d] thiazole: To a solution of 2-amino-6- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) benzenethiol (20 mg, 0.06 mmol) in ethanol (5 mL) was added 4-cyclopropyl-6-methoxypyrimidine-5-carbaldehyde (15 mg, 0.08 mmol) and 1drop of acetic acid at room temperature, after 30 mins, the mixture was added PhI (OAc) ₂ (26 mg, 0.08 mmol) at room temperature, the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was cooled to room temperature. The mixture was diluted with water (20 mL) and extracted with EA (20 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 Pre-HPLC to afford the target compound (3.2 mg, white solid, yield: 11.2 %) . MS (ESI) : 522.15 [M+H] ⁺. ¹H NMR (400MHz, CDCl₃) : δ 8.63 (s, 1H) , 8.03 (d, J = 8.0 Hz, 1H) , 7.58-7.56 (m, 2H) , 7.50-7.48 (m, 1H) , 7.38 (d, J = 8.0 Hz, 2H) , 7.29 (s, 1H) , 7.25 (s, 1H) , 4.30 (s, 2H) , 3.96 (s, 3H) , 3.75 (s, 3H) , 2.20 –2.16 (m, 1H) , 1.26 –1.23 (m, 2H) , 1.02 –0.98 (m, 2H) .

Example 10

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine

The compound was prepared using a synthesis method similar to that described in Example 11.MS (ESI) : 507.25 [M+H] ⁺. ¹H NMR (400MHz, CDCl₃) : δ 8.69 (s, 1H) , 8.53 (d, J = 4.0 Hz, 1H) , 7.65 (d, J = 4.0 Hz, 1H) , 7.55-7.49 (m, 4H) , 7.26 (s, 1H) , 4.51 (s, 2H) , 4.01 (s, 3H) , 3.71 (s, 3H) , 2.27 –2.23 (m, 1H) , 1.31 –1.28 (m, 2H) , 1.06 –1.02 (m, 2H) .

Example 11

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- (3-fluoro-4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine

a) Preparation of N- (2-bromo-3-hydroxypyridin-4-yl) -4-cyclopropyl-6-methoxypyrimidine-5-carboxamide: To a solution of 4-amino-2-bromopyridin-3-ol (500 mg, 1.4 mmol) in DMF (10 mL) was added 4-cyclopropyl-6-methoxypyrimidine-5-carboxylic acid (335 mg, 1.7 mmol) , TBTU (692mg, 2.2 mmol) and TEA (436 mg, 4.31 mmol) at room temperature, the mixture was stirred at room temperature for overnight. After the reaction was completed, the mixture was diluted with water (20 mL) and extracted with EA (20 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 column over silica gel (DCM/MeOH=20/1) to afford the title compound (370 mg, yellow solid, yield: 49 %) . MS (ESI) : 525.25 [M+H] ⁺ .

b) Preparation of 4-bromo-2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) oxazolo [5, 4-c] pyridine: To a solution of N- (2-bromo-3-hydroxypyridin-4-yl) -4-cyclopropyl-6-methoxypyrimidine-5-carboxamide (8.3 g, 22.8 mmol) in DCM (80 mL) was added hexachloroethane (14.5 g, 57.0 mmol) , triphenylphosphine (19.3 g, 68.4 mmol) and TEA (18.4 g, 182.4 mmol) at room temperature, the mixture was stirred at room temperature for 48 hours. After the reaction was completed, the solvent was removed under reduced pressure, the residue was purified by column over silica gel (PE/EA=10/1) to afford the title compound (5.5 g, white solid, yield: 70 %) . MS (ESI) : 349.00 [M+H] ⁺.

c) Preparation of 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- (3-fluoro-4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine: To a solution of Zn (79 mg, 1.21 mmol) , I₂ (5 mg, 0.02mmol) in DMF (2 mL) , The system was evacuated and backfilled with N₂ three times and stirred at 30 ℃ for 10 min. TMSCl (3 mg, 0.02 mmol) was added, the mixture was stirred at 30 ℃ for 45 min. 2- (4- (bromomethyl) -2-fluorophenyl) -1-methyl-4- (trifluoromethyl) -1H-imidazole (40 mg, 0.121 mmol) dissolve in DMF (1 mL) was added. The mixture was stirred at 45 ℃ for 1 hours. The result mixture was added to a system of Pd (PPh₃) ₄ (12 mg, 0.01 mmol) and 4-bromo-2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) oxazolo [5, 4-c] pyridine (35 mg, 0.101 mmol) . The mixture was stirred at 60 ℃ for 2 hours. After the reaction was completed, the mixture was cooled down to room temperature, to the mixture was diluted with water (30 mL) and the mixture was extracted with EA (40 mL × 3) . The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product. The residue was purified by Prep-HPLC to afford the target compound (13 mg, white solid, yield: 24.6%) .

The following compounds of Examples 12-18 were prepared using a synthesis method similar to that described in Example 11.

Example 19

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1-methyl-7- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -1H-benzo [d] imidazole

a) Procedure for N-methyl-2- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6-nitroaniline: To a stirred solution of 2- (4- (2-fluoro-3-nitrobenzyl) phenyl) -1-methyl-4- (trifluoromethyl) -1H-imidazole (500 mg, 1.32 mmol) in THF (5 mL) was added dropwise methylamine (5 ml, 2 mmol, 1.0 M in THF) at room temperature. The mixture was stirred at 60 ℃for 2 hourrs. After the reaction was completed, the reaction mixture was evaporated to dryness under reduced pressure to afford the title compound (crude, 419 mg, yellow solid) . MS (ESI) : 391.10 [M+H] ⁺.

b) Procedure for N¹-methyl-6- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) benzene-1, 2-diamine: To a stirred solution of N-methyl-2- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -6-nitroaniline (350 mg, 0.89 mmol) in MeOH (20 mL) was added Pd/C (70 mg, 0.72 mmol, 20%) at room temperature. The mixture was stirred at room temperature for 3 hours under H₂ atmosphere. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column over silica gel (PE/EA=10/1～1/1) to give the title compound (50 mg, white solid, yield: 15%) . MS (ESI) : 361.10 [M+H] ⁺.

c) Preparation of 2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1-methyl-7- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -1H-benzo [d] imidazole: To a solution of N¹-methyl-6- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) benzene-1, 2-diamine (35 mg, 0.10 mmol) in AcOH (5 mL) was added 4-cyclopropyl-6-methoxypyrimidine-5-carbaldehyde (18 mg, 0.10 mmol) and Cu (OAc) ₂ (60 mg, 0.30 mmol) at room temperature, the mixture was stirred at 70℃ for 3hourrs. After the reaction was completed, the reaction was cooled to room temperature. The resulting reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (20 mL) and extracted with EA (20 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 Pre-HPLC to afford the target compound (15 mg, white solid, yield: 29 %) . MS (ESI) : 519.20 [M+H] ⁺. ¹H NMR (400MHz, CDCl₃) : δ 8.67 (s, 1H) , 7.78 (d, J = 8.0 Hz, 1H) , 7.56-7.54 (m, 2H) , 7.29 (s, 1H) , 7.27-7.22 (m, 3H) , 7.07 (d, J = 8.0 Hz, 1H) , 4.56 (s, 2H) , 3.90 (s, 3H) , 3.74 (s, 3H) , 3.59 (s, 3H) , 1.59-1.57 (m, 1H) , 1.31 –1.29 (m, 1H) , 1.14 –1.13 (m, 1H) , 1.02 –0.98 (m, 1H) , 0.88-0.86 (m, 1H) .

The following compounds of Examples 20-29 were prepared using a synthesis method similar to that described in Example 1 or Example 11.

Example 30

4- (4- (1- (azetidin-3-yl) -4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) oxazolo [5, 4-c] pyridine

a) Preparation of tert-butyl 3- (2- (4- ( (2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) oxazolo [5, 4-c] pyridin-4-yl) methyl) phenyl) -4- (trifluoromethyl) -1H-imidazol-1-yl) azetidine-1-carboxylate: To a stirred solution of (2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- (4- (4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine (100 mg, 0.2 mmol) in dry-toluene (2 mL) was added tert-butyl 3-hydroxyazetidine-1-carboxylate (105 mg, 0.6 mmol) and cyanomethylene tri-n-butylphosphine (96 mg, 0.4 mmol) . The mixture was stirred at 120 ℃ for 16 hours. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with EA (20 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 Pre-TLC (PE/EA=3/1) to afford the title compound (20 mg, yellow solid, yield: 15 %) . MS (ESI) : 648.10 [M+H] ⁺.

b) Preparation of 4- (4- (1- (azetidin-3-yl) -4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) oxazolo [5, 4-c] pyridine: To a stirred solution of tert-butyl 3- (2- (4- ( (2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) oxazolo [5, 4-c] pyridin-4-yl) methyl) phenyl) -4- (trifluoromethyl) -1H-imidazol-1-yl) azetidine-1-carboxylate (20 mg, 0.03 mmol) in DCM (2 mL) was added TFA (2 mL) . The mixture was stirred at 50 ℃ for 2 hours. After the reaction was completed, the mixture was diluted with saturation NaHCO₃ solution (10 mL) and extracted with EA (10 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 Pre-HPLC to afford the title compound (3 mg, white solid, yield: 18 %) . MS (ESI) : 548.05 [M+H] ⁺. ¹H NMR (400MHz, CDCl₃) : δ 8.69 (s, 1H) , 8.52 (s, 1H) , 7.98 (s, 1H) , 7.65 (s, 1H) , 7.50 (s, 2H) , 7.36 (s, 2H) , 5.25 (s, 1H) , 4.51 (s, 2H) , 4.39-4.10 (m, 4H) , 4.01 (s, 3H) , 2.26-2.25 (m, 1H) , 1.33 –1.28 (m, 2H) , 1.08-1.02 (m, 2H) .

Example 31

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- (4- (1- (oxetan-3-yl) -4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine

The compound was prepared using a synthesis method similar to that described in Example 30. MS (ESI) : 549.20 [M+H] ⁺. ¹H NMR (400 MHz, CD₃Cl) : δ 8.71 (s, 1H) , 8.56 (d, J = 5.4 Hz, 1H) , 7.86 (s, 1H) , 7.68 (d, J = 5.4 Hz, 1H) , 7.53 (d, J = 7.9 Hz, 2H) , 7.35 (d, J = 7.9 Hz, 2H) , 5.42 (p, J = 6.6 Hz, 1H) , 5.02 (t, J = 7.4 Hz, 2H) , 4.81 (t, J = 6.6 Hz, 2H) , 4.03 (s, 3H) , 2.27 (tt, J = 8.4, 4.7 Hz, 1H) , 1.32 (dt, J = 6.8, 3.3 Hz, 2H) , 1.07 (dq, J = 7.2, 3.9 Hz, 2H) .

Example 32

2- (4-chloro-1-isopropyl-1H-pyrazol-5-yl) -4- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine

a) Preparation of 3-methoxy-2- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) pyridin-4-amine: To a solution of Zn (3.8 g, 59.4 mmol) , I₂ (380 mg, 1.0 mmol) in DMF (6 mL) , The system was evacuated and backfilled with N₂ three times and stirred at 30 ℃ for 10 min. TMSCl (53 mg, 0.5 mmol) was added, the mixture was stirred at 30 ℃ for 45 min. 2- (4- (bromomethyl) phenyl) -1-methyl-4- (trifluoromethyl) -1H-imidazole (2.7 g, 7.4 mmol) dissolve in DMF (5 mL) was added. The mixture was stirred at 45 ℃ for 1 hours. The result mixture was added to a system of Pd (PPh₃) ₄ (856.0 mg, 0.74 mmol) and 2-bromo-3-methoxypyridin-4-amine (1.0 g, 4.95 mmol, 1.0 eq) in DMF (6 mL) . the mixture was stirred at 60 ℃ for 2 hours. After the reaction was completed, the mixture was cooled down to room temperature, to the mixture was added water (40 mL) and the mixture was extracted with EA (40 mL × 3) . The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product. The residue was purified by column over silica gel (PE/EA=1/1) to afford the title compound (330 mg, yellow solid, yield: 18 %) . MS (ESI) : 363.15 [M+H] ⁺.

b) Preparation of 4-amino-2- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) pyridin-3-ol: To a solution of 3-methoxy-2- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) pyridin-4-amine (120.0 mg, 0.4 mmol) in DCM (5.0 mL) was added dropwise BBr₃ (2.0 ml, 2.0 mmol, 1 M in DCM) at 0 ℃. The mixture was warmed slowly to room temperature and stirred for 2 hrs. After the reaction was completed, the reaction mixture was quenched with MeOH (3.0 mL) and concentrated in vacuum. The residue was purified by column over silica gel (DCM/MeOH=100/1-15/1) to give the title compound (88 mg, yellow solid, yield: 63%) . MS (ESI) : 348.10 [M+H] ⁺.

c) Preparation of 4-chloro-N- (3-hydroxy-2- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) pyridin-4-yl) -1-isopropyl-1H-pyrazole-5-carboxamide: To a solution of 4-amino-2- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) pyridin-3-ol (90.0 mg, 0.26 mmol) in DMF (2 mL) was added 4-chloro-1-isopropyl-1H-pyrazole-5-carboxylic acid (53.0 mg, 0.28 mmol) , HATU (118.0 mg, 0.31 mmol) and DIEA (100.0 mg, 0.78 mmol) at room temperature, the mixture was stirred at room temperature for overnight. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with EA (10 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 Prep-TLC (DCM/MeOH=10/1) to afford the title compound (60.0 mg, yellow solid, yield: 44 %) . MS (ESI) : 519.15 [M+H] ⁺.

d) Preparation of 2- (4-chloro-1-isopropyl-1H-pyrazol-5-yl) -4- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine: To a solution of 4-chloro-N- (3-hydroxy-2- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) pyridin-4-yl) -1-isopropyl-1H-pyrazole-5-carboxamide (60.0 mg, 0.12 mmol) in DCM (5 mL) was added hexachloroethane (68.0 mg, 0.29 mmol) , triphenylphosphine (90.0 mg, 0.35 mmol) and TEA (92.0 mg, 0.92 mmol) at room temperature, the mixture was stirred at room temperature for 48 hours. After the reaction was completed, the solvent was removed under reduced pressure, the residue was purified by Pre-HPLC to afford the target compound (4.5 mg, white solid, yield: 1.3 %) . MS (ESI) : 501.10 [M+H] ⁺. ¹H NMR (400MHz, CD₃OD) : δ 8.51 (d, J = 5.6 Hz, 1H) , 7.77 (d, J = 5.4 Hz, 1H) , 7.72 (s, 1H) , 7.65 (s, 1H) , 7.58 (d, J = 1.3 Hz, 4H) , 5.85 –5.70 (m, 1H) , 4.57 (s, 2H) , 3.73 (s, 3H) , 1.52 (d, J = 6.6 Hz, 6H) .

Example 33 and Example 34

2- (1-isopropyl-4-methyl-1H-pyrazol-5-yl) -4- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine (Example 33) and 2- (1-isopropyl-1H-pyrazol-5-yl) -4- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine (Example 34)

To a solution of 2- (4-chloro-1-isopropyl-1H-pyrazol-5-yl) -4- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine (60.0 mg, 0.12 mmol) in dioxane/H₂O (1.0 mL, v/v = 5/1) was added 2, 4, 6-trimethyl-1, 3, 5, 2, 4, 6-trioxatriborinane (0.34 ml, 1.2 mmol) , K₃PO₄ (72.0 mg, 0.36 mmol) and Pd (dppf) Cl₂ (9.6 mg, 0.01 mmol) at room temperature. The mixture was stirred at 105 ℃ overnight under N₂ atmosphere. After the reaction was completed, the mixture was cooled to room temperature, the resulting reaction mixture was extracted with EA (10.0 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 Prep-TLC (PE/EA=1/1) to give the compound of Example 33 (3.1 mg, white solid, yield: 5%) and Example 34 (1.0 mg, white solid, yield: 2%) .

Example 33: MS (ESI) : 481.20 [M+H] ⁺. ¹H NMR (400MHz, CD₃OD) : δ 8.49 (d, J = 5.4 Hz, 1H) , 7.74 (d, J = 5.5 Hz, 1H) , 7.65 (s, 1H) , 7.60 (d, J = 8.0 Hz, 2H) , 7.55 –7.50 (m, 3H) , 5.82 –5.71 (m, 1H) , 4.57 (s, 2H) , 3.73 (s, 3H) , 2.41 (s, 3H) , 1.50 (d, J = 6.4 Hz, 6H) .

Example 34: MS (ESI) : 467.25 [M+H] ⁺. ¹H NMR (400MHz, CD₃OD) : δ 8.48 (d, J = 5.5 Hz, 1H) , 7.73 (d, J = 5.6 Hz, 1H) , 7.68 (d, J = 2.1 Hz, 1H) , 7.65 (s, 1H) , 7.58 (q, J = 8.1 Hz, 4H) , 7.17 (d, J = 2.1 Hz, 1H) , 5.94 –5.83 (m, 1H) , 4.57 (s, 2H) , 3.73 (s, 3H) , 1.55 (d, J = 6.6 Hz, 6H) .

The following compounds of Examples 35-54 were prepared using a synthesis method similar to that described in Example 1, Example 11 or Example 32.

Example 55

USP1/UAF1 activity

USP1/UAF1 activity was determined by using ubiquitin-rhodamine110-glycine (Ub-Rho; Boston Biochem) assay. Enzymatic reactions were conducted in an 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) that contained 0.1 nM USP1/UAF1. Each individual compound was tested at ten concentrations in the range of 0.0005 to 10 μM. The plates were incubated for 15 min to attain equilibrium, and then the enzymatic reaction was initiated by dispensing 10 μL of Ub-Rho solution (100 nM final concentration) . After treating 120 minutes with Ub-Rho solution, the rhodamine fluorescence was acquired using a 480 nm excitation/540 nm emission filter set by using Envision instrument. The inhibition rate of the compound to USP1/UAF1 enzyme activity was calculated according to the following formula.

IC₅₀ value is obtained by fitting the s-shaped dose response curve equation by using XL Fit software. The curve equation is Y=100 / (1+10^ (logC-logIC₅₀) ) , C is the compound concentration.

Table 1 summarizes the inhibitory effects of compounds on USP1/UAF1 activity (IC₅₀) .

Table 1

Therefore, as determined by the Ubiquitin-rhodamine110-glycine assay, the compounds of this disclosure herein have a good inhibitory effect on USP1/UAF1 enzyme activity.

Example 56

Growth inhibition assays against BRCA mutant human breast cancer MDA-MB-436 cell line

The cells were cultured in complete medium (DMEM medium +10%FBS+ Insulin +glutathione) . When the confluence reached about 80%, cells were digested and gently dispensed from the bottom of the dish with a 1 mL pipette. Cell suspension was collected and centrifuged at 500rpm for 3min. The supernatant was discarded, and the cell pellet were re-suspended in complete medium. The cells were seeded into a culture dish at an appropriate proportion, and then cultured in a 5%CO₂ incubator at 37℃. The assay was carried out when the cells were in optimum condition and the confluence was reached 80%. Cells in the logarithmic growth phase were taken to centrifugate, and the culture supernatant was removed. The cells were resuspended in refresh complete medium and counted. The resuspended cells were seeded at 3000/well in a 96-well plate and incubated at 37℃, 5%CO₂ incubator overnight. The compound was prepared as below: 1000×dilution tested compound solution to 40× test compound solution by adding 5μL 1000× compound solution to 120 μL Medium (25-fold dilution) . The solution was mixed by oscillation. 0.1%DMSO was used as the control.

The next day, the 96-well plate inoculated with cells was taken out from the incubator, and the culture supernatant was removed. Then fresh medium of 195 uL/well and 5μL/well of 40× test compound solution as mentioned above were added into the 96 well plate, respectively. Finally, the plate was incubated for 7 days in a 37℃ 5%CO₂ incubator. The medium containing compound was changed on the fourth day. After 7 days, 20μL of CCK-8 was added to each well and shaken gently, then was cultured for 4 hours. The plate was shaken for 5min after incubation. the absorbance values of 450nm or 650nm wavelengths were recorded respectively (OD = absorbance value of 450nm -absorbance value of 650nm) by using the multifunction readout instrument.

Data were analyzed by software GraphPad Prism 6.0. The inhibitory activity of compounds on cell proliferation was plotted using cell survival rate against the compound concentration as coordinates. Cell survival rate %= (OD_compound -OD_background) / (OD_DMSO-OD_background) ×100. The IC₅₀ value was fitted by the s-shaped dose response curve equation: Y=100 / (1+10^ (logC-logIC₅₀) ) , and C was the compound concentration.

Table 2 summarizes the inhibitory effect data (IC₅₀) of the compounds on the proliferation of human breast cancer cells MDA-MB-436.

Table 2

Therefore, the compounds herein have a good inhibitory effect on the proliferation of human breast cancer cells MDA-MB-436 determined by CCK-8 method.

Having now fully described this disclosure, it will be understood by those of ordinary skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations and other parameters without affecting the scope of the disclosure or any embodiment thereof. All patents, patent applications and publications cited herein are fully incorporated by reference herein in their entirety.

Claims

A compound of Formula I:

or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-substituted derivatives, or pharmaceutically acceptable salts thereof, or mixtures thereof, wherein:

A₁ and A₂ are each independently selected from a group consisting of N, NR₁, O and S;

B₁, B₂ and B₃ are each independently selected from a group consisting of N and CR₂;

ring Z is selected from a group consisting of an optionally substituted carbocyclic group, an optionally substituted heterocyclic group, an optionally substituted aryl and an optionally substituted heteroaryl;

L is selected from a group consisting of NR₆, O, S, SO, SO₂, C=O and an alkylene optionally substituted with R₄ and/or R₅;

Cy₁ is selected from a group consisting of an optionally substituted carbocyclic group, an optionally substituted heterocyclic group, an optionally substituted aryl and an optionally substituted heteroaryl;

Cy₂ is selected from a group consisting of an optionally substituted carbocyclic group, an optionally substituted heterocyclic group, an optionally substituted aryl and an optionally substituted heteroaryl; or ring Z and Cy₂ together form an optionally substituted 11-14 membered heterocyclic group;

R₁ is selected from a group consisting of hydrogen and an optionally substituted alkyl;

R₂ is selected from a group consisting of hydrogen, halogen, cyano, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted carbocyclic group, an optionally substituted alkenyl, an optionally substituted alkynyl, and an optionally substituted amino;

R₄ and R₅ are each independently selected from a group consisting of halogen, cyano, hydroxyl, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted carbocyclic group, an optionally substituted alkenyl and an optionally substituted alkynyl; or R₄ and R₅ together with the attached C atom form a ring;

R₆ is selected from a group consisting of hydrogen and an optionally substituted alkyl.
The compound of Formula I as claimed in claim 1, or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-substituted derivatives, or pharmaceutically acceptable salts thereof, or mixtures thereof, wherein:

A₂ is N, A₁ is O, S or NR₁, wherein R₁ is hydrogen or C_1-4 alkyl, preferably methyl; or A₂ is N, A₁ is O or S; or A₂ is N, A₁ is O; or A₁ is N, A₂ is O or S, preferably O; and/or

B₁, B₂ and B₃ are each independently selected from a group consisting of N and CR₂, wherein R₂ is H, halogen, C_1-4 alkyl or C_1-4 alkoxy; preferably, B₁, B₂ and B₃ are each independently N or CH, and at most one of B₁, B₂ and B₃ is N; preferably, both of B₁ and B₂ are CH, B₃ is N; or all of B₁, B₂ and B₃ are CH;

preferably, the fused heteroaromatic bicyclic ring containing A₁, A₂, B₁, B₂ and B₃ is selected from the following groups:

preferably:

more preferably:

wherein, *1 and *2 refer to the position of attachment of the group to Cy₁ and L of the compound, respectively.
The compound of Formula I as claimed in claim 1 or claim 2, or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-substituted derivatives, or pharmaceutically acceptable salts thereof, or mixtures thereof, wherein:

ring Z is an optionally substituted C_3-8 cycloalkyl group, 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, when ring Z is substituted, the substituent (s) is 1 or 2 groups selected from a group consisting of halogen, cyano, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group and an optionally substituted amino group; preferably, the said optionally substituted alkyl group and optionally substituted alkoxy group are an optionally substituted C_1-4 alkyl and an optionally substituted C_1-3 alkoxy, respectively, the said optionally substituted cycloalkyl is an optionally substituted C_3-8 cycloalkyl, the said optionally substituted alkenyl and optionally substituted alkynyl group are an optionally substituted C_2-4 alkenyl group and an optionally substituted C_2-4 alkynyl group, respectively, and the said optionally substituted amino group is -NR_aR_b, wherein R_a and R_b are each independently H or C_1-4 alkyl; preferably, the substituent (s) on the Z ring is 1 or 2 substituents selected from halogen and C_1-3 alkoxy; or

the ring Z and the Cy₂ together form an optionally substituted 11-14 membered heterocyclic, the said heterocyclic is 11-14 membered heterotricyclic group containing 2, 3 or 4 heteroatoms selected from nitrogen and oxygen, such as benzimidazoloxazinyl, dihydrobenzimidazoloxazepine, dihydrobenzimidazodiazepine and benziimidazooxazepine; preferably, when the 11-14 membered heterocyclic group is substituted, the substituent (s) is 1 or 2 groups selected from a group consisting of halogen, an optionally substituted alkyl and an optionally substituted alkoxy; preferably, the said optionally substituted alkyl and the optionally substituted alkoxy group are an optionally substituted C_1-4 alkyl group and an optionally substituted C_1-3 alkoxy group; preferably, the alkyl group and the alkoxy group are optionally substituted by 1-5 groups selected from halogen, hydroxyl and -NR_aR_b, wherein R_a and R_b are each independently H or C_1-4 alkyl.
The compound of Formula I as claimed in any one of claims 1-3, or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-substituted derivatives, or pharmaceutically acceptable salts thereof, or mixtures thereof, wherein:

Cy₁ 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, the said 4-10 membered heterocyclic group is a heterocyclic group containing nitrogen and/or oxygen, the said 5-10 membered heteroaryl group is a nitrogen-containing monocyclic heteroaryl group and the said aryl group is phenyl;

preferably, Cy₁ is an optionally substituted phenyl, an optionally substituted pyrazolyl, an optionally substituted pyridyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted pyridazinyl, an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted tetrahydrofuranyl, an optionally substituted pyrrolidinyl or an optionally substituted pyrazolyl; more preferably, Cy₁ is optionally substituted pyrimidinyl or optionally substituted pyrazolyl;

preferably, when Cy₁ is substituted, the substituent (s) is 1, 2 or 3 groups selected from a group consisting of halogen, cyano, an optionally substituted C_1-4 alkyl, an optionally substituted C_1-4 alkoxy, an optionally substituted C_3-6 cycloalkyl and an optionally substituted amino; preferably, the C_1-4 alkyl and C_1-4 alkoxy are each optionally substituted by 1-5 groups selected from a group consisting of deuterium, halogen, hydroxyl and -NR_aR_b, the said C_3-6 cycloalkyl is optionally substituted by 1-5 groups selected from a group consisting of halogen, hydroxyl, -NR_aR_b, C_1-4 alkyl, halogenated C_1-4 alkyl, C_1-4 alkyl substituted with hydroxyl, C_1-4 alkoxy and halogenated C_1-4 alkoxy, and the amino group is optionally substituted by 1 or 2 groups selected from C_1-4 alkyl and halogenated C_1-4, wherein R_a and R_b are each independently H or C_1-4 alkyl;

preferably, when Cy₁ is substituted, the substituent is selected from a group consisting of halogen, C_1-4 alkyl, C_1-4 alkoxy, deuterated C_1-4 alkoxy and C_3-6 cycloalkyl; further preferably, the substituent is selected from a group consisting of C_1-4 alkoxy, deuterated C_1-4 alkoxy and C_3- ₆ cycloalkyl;

preferably, the substituents on Cy₁ are located ortho to the position where the ring containing A₁ and A₂ is connected to Cy₁.
The compound of Formula I as claimed in any one of claims 1-4, or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-substituted derivatives, or pharmaceutically acceptable salts thereof, or mixtures thereof, wherein:

Cy₂ 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, the said 6-14 membered aryl group is phenyl, the said 4-10 membered heterocyclic group is a heterocyclic group containing 1-3 heteroatoms selected from nitrogen and oxygen, including a partially saturated 8-10 membered nitrogen-and/or oxygen-containing heterocyclic group, such as azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroimidazopyrazinyl and dihydroimidazoxazinyl, and the said 5-10 membered heteroaryl group is a heteroaryl group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, such as imidazolyl, pyrazolyl, triazolyl, pyridyl and pyrazinyl;

preferably, Cy₂ is an optionally substituted nitrogen-containing 5-10 membered heteroaryl group or an optionally substituted nitrogen-and/or oxygen-containing 8-10-membered heterocyclic group, more preferably a nitrogen-containing five-membered heteroaryl group; more preferably, Cy₂ is an optionally substituted imidazolyl or an optionally substituted pyrazolyl;

preferably, when Cy₂ is substituted, the substituent (s) is 1, 2, 3, 4 or 5 substituents selected from a group consisting of halogen, cyano, an optionally substituted C_1-4 alkyl, an optional substituted C_2-4 alkenyl, an optionally substituted C_2-4 alkynyl, an optionally substituted C_3-6 cycloalkyl, an optionally substituted 4-10 membered heterocyclic groups, and an optionally substituted C_1-4 alkoxy; wherein the said C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl and C_1-4 alkoxy groups are each optionally substituted by 1-5 groups selected from a group consisting of deuterium, halogen, hydroxyl and -NR_aR_b; the said C_3-6 cycloalkyl and 4-10 membered heterocyclic groups are each optionally substituted by 1-5 groups selected from a group consisting of halogen, hydroxyl, -NR_aR_b, C_1-4 alkyl, halogenated C_1-4 alkyl, C_1-4 alkyl substituted with hydroxyl, C_1-4 alkoxy group and halogenated C_1-4 alkoxy group, wherein R_a and R_b are each independently H or C_1-4 alkyl group;

preferably, when Cy₂ is substituted, the substituent (s) is 1 or 2 groups selected from a group consisting of halogen, cyano, C_1-4 alkyl, C_2-4 alkynyl, halogenated C_1-4 alkyl, deuterated C_1-4 alkyl, 4-10 membered heterocyclic groups, C_3-6 cycloalkyl and C_1-4 alkoxy;

preferably, Cy₂ is imidazolyl or pyrazolyl, optionally substituted by 1 or 2 substituents selected from a group consisting of halogen, cyano, C_1-4 alkyl, C_2-4 alkynyl, halogenated C_1-4 alkyl, deuterated C_1-4 alkyl, 4-10 membered heterocyclic groups, C_3-6 cycloalkyl and C_1-4 alkoxy;

preferably, Cy₂ is substituted with 1-2 substituents selected from a group consisting of halogen, cyano, C_1-4 alkyl, C₃-C₆ cycloalkyl and halogenated C_1-4 alkyl.
The compound of Formula I as claimed in any one of claims 1-5, or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-substituted derivatives, or pharmaceutically acceptable salts thereof, or mixtures thereof, wherein:

L is an alkylene group, NH, N-C_1-3 alkyl or O, preferably L is a C_1-3 alkylene group, more preferably a methylene group;

R₄ and R₅ are each independently selected from a group consisting of C_1-4 alkyl and hydroxyl; or R₄ and R₅ together with the C atom they attach form a 3-5 membered cycloalkyl or 3-5 membered heterocyclic group; and/or

R₆ is H or C_1-3 alkyl.
The compound as claimed in claim 1, or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-substituted derivatives, or pharmaceutically acceptable salts thereof, or mixtures thereof, wherein the compound of Formula I is a compound represented by Formula II, IIIa, IIIb, IVa, IVb or V:

wherein,

A₁, A₂, B₁, B₂, B₃, L, Cy₁ and Cy₂ are as defined in any one of claims 1 to 6;

D₁, D₂, D₃ and D₄ are each independently selected from a group consisting of N and CR₃;

R₃ is selected from a group consisting of hydrogen, halogen, cyano, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted carbocyclic group, an optionally substituted alkenyl, an optionally substituted alkynyl, and an optionally substituted amino;

R₇ and R₉ are each independently selected from a group consisting of hydrogen, halogen, cyano, an optionally substituted C_1-4 alkyl, an optionally substituted C_1-4 alkoxy, an optionally substituted C_3-6 cycloalkyl and an optionally substituted amino;

R₈ is selected from a group consisting of hydrogen, halogen and an optionally substituted C_1-4 alkyl;

R₁₀ and R₁₁ are each independently selected from a group consisting of hydrogen, halogen, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted cycloalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, and an optionally substituted amino;

R₁₂ is selected from a group consisting of hydrogen, an optionally substituted C_1-4 alkyl, an optionally substituted C_3-6 cycloalkyl and an optionally substituted C_4-6 heterocyclic group; alternatively, R₁₁ and R₁₂ are connected to form an optionally substituted 6-7 membered heterocyclic group;

R₁₃ is selected from a group consisting of hydrogen, halogen, an optionally substituted C_1-4 alkyl and an optionally substituted C_1-4 alkoxy; alternatively, R₁₂ and R₁₃ are connected to form an optionally substituted 5-7 membered heterocyclic group;

R₁₄ is selected from a group consisting of hydrogen, cyano, halogen and an optionally substituted C_1-4 alkyl.
The compound of Formula I as claimed in claim 7, or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-substituted derivatives, or pharmaceutically acceptable salts thereof, or mixtures thereof, wherein:

R₃ is selected from a group consisting of hydrogen, halogen, cyano, an optionally substituted C_1-4 alkyl, an optionally substituted C_1-3 alkoxy, an optionally substituted C_3-8 cycloalkyl, an optionally substituted C_2-4 alkenyl, an optionally substituted C_2-4 alkynyl and -NR_aR_b, wherein R_a and R_b are each independently H or C_1-4 alkyl; preferably, R₃ is each independently selected from a group consisting of halogen, an optionally substituted C_1-4 alkyl and an optionally substituted C_1-3 alkoxy; preferably, the said alkyl, alkoxy, alkenyl, alkynyl and cycloalkyl groups is optionally substituted by 1-5 groups selected from a group consisting of halogen, hydroxyl and -NR_aR_b, the R_a and R_b are each independently H or C_1-4 alkyl; more preferably, R₃ is selected from a group consisting of H, halogen, and C_1-3 alkoxy; and/or

for R₇ and R₉, the said C_1-4 alkyl and C_1-4 alkoxy groups are each optionally substituted by 1-5 groups selected from a group consisting of halogen, hydroxyl and -NR_aR_b, and the C_3-6 cycloalkyl group is optionally substituted by 1-5 groups selected from a group consisting of halogen, hydroxyl, -NR_aR_b, C_1-4 alkyl, halogenated C_1-4 alkyl, C_1-4 alkyl substituted with hydroxy, C_1-4 alkoxy and halogenated C_1-4 alkoxy, the amino group is optionally substituted by 1 or 2 substituents selected from a group consisting of C_1-4 alkyl and halogenated C_1-4 alkyl, wherein R_a and R_b are each independently H or C_1-4 alkyl; preferably, R₇ and R₉ are each independently hydrogen, cyano, C_1-4 alkyl, C_1-4 alkoxy, deuterated C_1-4 alkoxy or C_3-6 cycloalkyl, and R₇ and R₉ are not hydrogen at the same time; more preferably, R₇ and R₉ are each independently C_1-4 alkoxy, deuterated C_1-4 alkoxy or C_3-6 cycloalkyl; and/or

R₈ is hydrogen, halogen or C_1-4 alkyl optionally substituted by 1-5 groups selected from a group consisting of halogen, hydroxyl and -NR_aR_b, wherein R_a and R_b are each independently H or C_1-4 alkyl; preferably, R₈ is hydrogen; and/or

R₁₀ and R₁₁ are each independently hydrogen, halogen, an optionally substituted C_1-4 alkyl or an optionally substituted C_1-4 alkoxy; preferably, the said C_1-4 alkyl and C_1-4 alkoxy are optionally substituted by 1-5 groups selected from a group consisting of halogen, hydroxyl and -NR_aR_b, wherein R_a and R_b are each independently H or C_1-4 alkyl; preferably, one of R₁₀ and R₁₁ is H, and the other is halogen, an optionally substituted C_1-4 alkyl, or an optionally substituted C_1- ₄ alkoxy; and/or

R₁₂ is selected from a group consisting of hydrogen, an optionally substituted C_1-4 alkyl, an optionally substituted C_1-4 alkoxy, an optionally substituted C_2-4 alkenyl, an optionally substituted C_2-4 alkynyl, an optionally substituted C_3-6 cycloalkyl and an optionally substituted C_4-6 heterocyclic group; preferably, the optionally substituted C_4-6 heterocyclic group is a nitrogen-or oxygen-containing heterocyclic group, such as oxetanyl, nitrogen heterocyclobutanyl, pyrrolidinyl, piperidinyl and piperazinyl; preferably, the substituent (s) of R₁₂ is 1-3 substituents selected from a group consisting of halogen, hydroxyl and -NR_aR_b, wherein R_a and R_b are each independently H or C_1-4 alkyl; more preferably, R₁₂ is C_1-4 alkyl, deuterated C_1-4 alkyl, C_1-4 alkoxy, C_2-4 alkynyl or C_3-6 cycloalkyl; and/or

R₁₃ is selected from a group consisting of hydrogen, halogen, an optionally substituted C_1-4 alkyl and an optionally substituted C_1-4 alkoxy; preferably, R₁₃ is hydrogen;

R₁₄ is selected from a group consisting of hydrogen, cyano, halogen, an optionally substituted C_1-4 alkyl; preferably, the alkyl group is optionally substituted with 1 to 5 substituents selected from a group consisting of hydroxyl and halogen; more preferably, R₁₄ is halogen or halogenated C_1-4 alkyl, such as trifluoromethyl;

or R₁₁ and R₁₂ are connected to form an optionally substituted 6-7 membered heterocyclic group, the said heterocyclic group together with the phenyl and imidazolyl groups form a 11-14 membered heterotricyclic group containing 2, 3 or 4 selected from a group consisting of nitrogen and oxygen as described herein, such as benzimidazoloxazinyl, dihydrobenzimidazoloxazepine, dihydrobenzimidazodiazepine and benzimidazoloxazepine; or R₁₂ and R₁₃ are connected to form an optionally substituted 5-7-membered nitrogen-and/or oxygen-containing heterocyclic group, the said heterocyclic group together with the imidazolyl group forms a 7-10 membered nitrogen-and/or oxygen-containing bicyclic heterocyclic group, such as tetrahydroimidazopyrazineyl and dihydroimidazooxazineyl.
The compound of claim 1, wherein the compound is selected from a group consisting of:

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) benzo [d] oxazole;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) benzo [d] oxazole;

7- (4- (1-cyclopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) benzo [d] oxazole;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl) benzyl) benzo [d] oxazole;

2- (4-cyclobutyl-6-methoxypyrimidin-5-yl) -7- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) benzo [d] oxazole;

2- (4, 6-dimethoxypyrimidin-5-yl) -7- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) benzo [d] oxazole;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (3-fluoro-4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) benzo [d] oxazole;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-ethyl-4- (trifluoromethyl) -1H-imidazol-2-yl) -3, 5-difluorobenzyl) benzo [d] oxazole;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) benzo [d] thiazole;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- (3-fluoro-4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine;

4- (4- (1-cyclopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) oxazolo [5, 4-c] pyridine;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- (4- (1-ethyl-4- (trifluoromethyl) -1H-imidazol-2-yl) -3, 5-difluorobenzyl) oxazolo [5, 4-c] pyridine;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- (4- (1-ethyl-4- (trifluoromethyl) -1H-imidazol-2-yl) -3-fluoro-5-methoxybenzyl) oxazolo [5, 4-c] pyridine;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [4, 5-c] pyridine;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [4, 5-b] pyridine;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) thiazolo [5, 4-c] pyridine;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [4, 5-c] pyridine;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1-methyl-7- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -1H-benzo [d] imidazole;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -7- (4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) benzo [d] oxazole;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- (4- (1- (methyl-d3) -4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- (2-fluoro-4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- (3-methoxy-4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- (4- (5-methoxy-3- (trifluoromethyl) -1H-pyrazol-1-yl) benzyl) oxazolo [5, 4-c] pyridine;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- (4- (1, 4-dimethyl-1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine;

4- (4- (4-chloro-1-methyl-1H-imidazol-2-yl) benzyl) -2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) oxazolo [5, 4-c] pyridine;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- (4- (1- (trifluoromethyl) -5, 6, 7, 8-tetrahydroimidazo [1, 5-a] pyrazin-3-yl) benzyl) oxazolo [5, 4-c] pyridine;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- (4- (1- (trifluoromethyl) -5, 6-dihydro-8H-imidazo [5, 1-c] [1, 4] oxazin-3-yl) benzyl) oxazolo [5, 4-c] pyridine;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- (4- (4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine;

4- (4- (1- (azetidin-3-yl) -4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) -2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) oxazolo [5, 4-c] pyridine;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- (4- (1- (oxetan-3-yl) -4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine;

2- (4-chloro-1-isopropyl-1H-pyrazol-5-yl) -4- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine;

2- (1-isopropyl-4-methyl-1H-pyrazol-5-yl) -4- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine;

2- (1-isopropyl-1H-pyrazol-5-yl) -4- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine;

2- (4-cyclopropyl-6- (methoxy-d3) pyrimidin-5-yl) -4- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine;

2- (4, 6-dimethoxypyrimidin-5-yl) -4- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine;

2- (4-isopropylpyrimidin-5-yl) -4- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine;

2- (4-methoxy-6-methylpyrimidin-5-yl) -4- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine;

9- ( (2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) oxazolo [5, 4-c] pyridin-4-yl) methyl) -2- (trifluoromethyl) -5, 6-dihydrobenzo [f] imidazo [1, 2-d] [1, 4] oxazepane;

8- ( (2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) oxazolo [5, 4-c] pyridin-4-yl) methyl) -2- (trifluoromethyl) -5H-benzo [e] imidazo [1, 2-c] [1, 3] oxazine;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- ( (2- (trifluoromethyl) -6, 7-dihydro-5H-benzo [f] imidazo [1, 2-d] [1, 4] diazepin-9-yl) methyl) oxazolo [5, 4-c] pyridine;

9- ( (2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) oxazolo [5, 4-c] pyridin-4-yl) methyl) -2- (trifluoromethyl) -5H, 7H-benzo [e] imidazo [1, 2-c] [1, 3] oxazepane;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- ( (2- (trifluoromethyl) -6, 7-dihydro-5H-benzo [e] imidazo [1, 2-c] [1, 3] diazepin-9-yl) methyl) oxazolo [5, 4-c] pyridine;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- ( (6- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) pyridin-3-yl) methyl) oxazolo [5, 4-c] pyridine;

1- (4- ( (2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) oxazolo [5, 4-c] pyridin-4-yl) methyl) phenyl) -5-methyl-1H-pyrazole-3-carbonitrile;

6-cyclopropyl-5- (4- (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridin-2-yl) pyrimidine-4-carbonitrile;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- (4- (1- (prop-2-yn-1-yl) -4- (trifluoromethyl) -1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- ( (4- (1-methyl-4- (trifluoromethyl) -1H-imidazol-2-yl) bicyclo [2.2.2] octan-1-yl) methyl) oxazolo [5, 4-c] pyridine;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- (4- (7-methyl-1- (trifluoromethyl) -5, 6, 7, 8-tetrahydroimidazo [1, 5-a] pyrazin-3-yl) benzyl) oxazolo [5, 4-c] pyridine;

4- (4- (1-chloro-5, 6, 7, 8-tetrahydroimidazo [1, 5-a] pyrazin-3-yl) benzyl) -2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) oxazolo [5, 4-c] pyridine;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- (4- (1-fluoro-5, 6, 7, 8-tetrahydroimidazo [1, 5-a] pyrazin-3-yl) benzyl) oxazolo [5, 4-c] pyridine;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- (4- (5, 6, 7, 8-tetrahydroimidazo [1, 5-a] pyrazin-3-yl) benzyl) oxazolo [5, 4-c] pyridine;

2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -4- (4- (4-fluoro-1-methyl-1H-imidazol-2-yl) benzyl) oxazolo [5, 4-c] pyridine;

2- (4- ( (2- (4-cyclopropyl-6-methoxypyrimidin-5-yl) oxazolo [5, 4-c] pyridin-4-yl) methyl) phenyl) -1-methyl-1H-imidazole-4-carbonitrile.

or stereoisomers, tautomers, N-oxides, hydrates, isotope-substituted derivatives, solvates or pharmaceutically acceptable salts thereof, or mixtures thereof.
Use of the compound of any one of claims 1-9, or stereoisomers, tautomers, N-oxides, hydrates, isotope-substituted derivatives, solvates or pharmaceutically acceptable salts thereof, or mixtures thereof in the manufacture of a medicament for treatment or prevention of an USP1 regulation related disease; preferably, the disease is cancer;

preferably, the cancer is liver cancer, melanoma, Hodgkin’s disease, non-Hodgkin’s lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, Wilms tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, non-small lung cancer, small cell lung cancer, gastric cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi’s sarcoma, urogenital tumors, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocythemia, adrenocortical carcinoma, skin cancer, and prostate cancer;

preferably, the medicament further comprises at least one known anticancer drug or a pharmaceutically acceptable salt thereof; preferably, the anticancer drug is selected from a group consisting of: busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cis-platin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, methylhydroxy ellipticine, etoposide, 5-azacytidine, gemcitabine, 5-fluorouracil, capecitabine, methotrexate, 5-fluoro-2'-deoxy-uridine, fludarabine, nelarabine, ara-C, pralatrexate, pemetrexed, hydroxyurea, 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, torisel, 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, and sipueucel-T;

preferably, the medicament is used in combination with radiotherapy.
A pharmaceutical composition comprising the compound any one of claims 1-9, or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-substituted derivatives, or pharmaceutically acceptable salts thereof, or mixtures thereof, and a pharmaceutically acceptable carriers; preferably, the pharmaceutical composition further comprises at least one known anticancer drug or pharmaceutically acceptable salts thereof; preferably, the anticancer drug is selected from a group consisting of: busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cis-platin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, methylhydroxy ellipticine, etoposide, 5-azacytidine, gemcitabine, 5-fluorouracil, capecitabine, methotrexate, 5-fluoro-2'-deoxy-uridine, fludarabine, nelarabine, ara-C, pralatrexate, pemetrexed, hydroxyurea, 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, torisel, 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, sipueucel-T, palbociclib, olaparib, niraparib, rucaparib, talazoparib and senaparib.