USP1 inhibitor as well as preparation method and application thereof

Abstract

The invention relates to a compound as shown in a formula (I), or pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphic substances, eutectic substances, hydrates, solvates, metabolites, prodrugs and deuterated compounds thereof. The invention also relates to a pharmaceutical composition containing the compound as an active ingredient and application of the compound or the pharmaceutical composition to treatment and / or prevention of USP1 related diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to a USP1 inhibitor and a preparation method and use thereof. Background Art

[0002] Ubiquitination is a common post-translational modification that can be deubiquitinated by deubiquitinating enzymes (DUBs) acting on ubiquitinated substrates to catalyze the removal of ubiquitin moieties. Ubiquitin-specific proteases (USPs) contain more than 50 family members and are the largest family of deubiquitinating enzymes. USPs can regulate a variety of important cellular functions in the tumor environment, such as cell cycle, DNA damage repair mechanism, chromatin remodeling and other signaling pathways.

[0003] USP1 belongs to the USPs family and is one of the most well-studied DUBs. USP1 is highly expressed in a variety of tumors and is also associated with poor prognosis and metastasis of some tumors. USP1 can form a complex with USP1-Associated Factor 1 (UAF1), thereby regulating two DNA damage repair pathways, namely, translesion synthesis (TLS) and interstrand cross-linking damage repair pathway (ICL), and can also affect cell differentiation, thereby affecting cancer progression; in the TLS pathway, USP1 regulates the recruitment and conversion of high-fidelity and low-fidelity TLS polymerases by regulating the deubiquitination of proliferating cell nuclear antigen (PCNA); in the ICL repair pathway, USP1 regulates the deubiquitination of FANCD2, directs to nuclear DNA damage sites, co-localizes with BRCA1 and RAD51, and interacts with downstream FA proteins. In addition, USP1 can also affect the ubiquitination of ID proteins (family of DNA-binding protein inhibitors) to regulate cell proliferation and differentiation. USP1 inhibition leads to blockage of the FA repair pathway and increased error-prone repair in the TLS pathway, resulting in increased SSB repair errors, replication fork collapse or premature arrest, and SSB forms DSBs during S phase replication.

[0004] Homologous recombination (HR) is an error-free repair pathway involved in repairing double-strand DNA breaks (DSBs). When BRCA1 / 2 and other factor mutations cause damage to the HR repair pathway, the DSBs generated after inhibiting USP1 can only be repaired through error-prone pathways such as NHEJ and MMEJ, which can easily cause abnormal mutations such as gene deletion or structural changes, and cannot be repaired in time and correctly, leading to cell cycle arrest and apoptosis. Studies have confirmed that USP1 is more highly expressed in BRCA1-deficient tumors than in wild-type cells, and knocking out or inhibiting USP1 can lead to unstable replication forks and reduced viability of BRCA1-deficient cells, indicating that inhibiting USP1 and HR pathway defects can form a synergistic lethal effect.

[0005] In summary, USP1 small molecule inhibitors are a potential therapy for treating HR pathway-deficient tumors and can provide a new therapeutic strategy for tumor treatment. Summary of the invention

[0006] The present invention provides a compound of general formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof:

[0007]

[0008] Among them, X 1 Select from N or CR 2 ; R 2 Selected from H, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy;

[0009] R 1 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 3-6 Cycloalkyl, -C 1-6 Alkyl-C 1-6 Alkoxy, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0010] L is selected from C(R 3 )(R 4 );R 3 and R 4 are each independently selected from H, deuterium, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy; or R 3 and R 4 Combined with the carbon atoms to which they are attached, they form C 3-6 Cycloalkyl;

[0011] Ring A is selected from C 6-10 aryl or 5-10 membered heteroaryl, the 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, the C 6-10 The aryl group and the 5-10-membered heteroaryl group are each independently unsubstituted or substituted by one or more R b replace;

[0012] B is selected from C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group, C 3-10 Cycloalkyl or C 3-10 The 5-10 membered heteroaryl and 4-10 membered heterocyclic group each independently contain 1-3 heteroatoms selected from N, O and S, and the C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group, C 3-10 Cycloalkyl, C 3-10 The cycloalkenyl groups are each independently unsubstituted or substituted with one or more R c replace;

[0013] Each R b and R c are independently selected from the same or different halogen, cyano, hydroxyl, amino, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 4-7 membered heterocyclic group, -SeR k 、-C(O)NR i R j , The 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted with one or more R a replace;

[0014] R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from hydrogen, deuterium, amino, C 1-6 Alkyl, C 3-10Cycloalkyl or 4-7 membered heterocyclic group, the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, the amino, C 1-6 Alkyl, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted with one or more R a replace;

[0015] or R 5 and R 6 The P to which they are connected together forms a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O, S and P, and at least one heteroatom is P, and the 4-7 membered heterocyclic group is unsubstituted or substituted by one or more R a replace;

[0016] or R 11 and R 12 The atoms to which they are attached together form a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 2-3 heteroatoms selected from N, O and S, and at least two heteroatoms are N and S, and the 4-7 membered heterocyclic group is unsubstituted or substituted by one or more R a replace;

[0017] C is selected from -C(O)NR i R j , C 6-10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group, wherein the 5-10 membered heteroaryl and 4-10 membered heterocyclic group each independently contain 1-3 heteroatoms selected from N, O and S, and the C 6-10 The aryl group, the 5-10 membered heteroaryl group, and the 4-10 membered heterocyclic group are each independently unsubstituted or substituted with one or more R d replace;

[0018] Each R d Each independently selected from the same or different halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl or 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted with one or more R a replace;

[0019] Each R a are independently selected from the same or different halogen, cyano, =O, hydroxyl, amino, C 1-6 Alkyl, C 1-6Alkoxy, C 3-10 Cycloalkyl or 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted with one or more R e replace;

[0020] Each R e are independently selected from the same or different deuterium, halogen, cyano, =O, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted with one or more R f replace;

[0021] Each R f Each independently selected from the same or different halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S;

[0022] Each R i , R j , R k are independently selected from the same or different hydrogen or C 1-6 alkyl.

[0023] In some embodiments, the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, X 1 Select from N or CR 2 ; R 2 Selected from H, halogen, cyano, C 1-4 Alkyl or C 1-4 Alkoxy.

[0024] In some embodiments, X 1 Select from N or CR 2 ; R 2 is selected from H, F, Cl, Br, cyano, methyl, ethyl, methoxy or ethoxy.

[0025] In some embodiments, X 1 is selected from N or CH.

[0026] In some embodiments, the above-mentioned compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, R 1 Selected from H, C 1-4 Alkyl, C 5-6 Alkyl, C 1-4 Haloalkyl, C 5-6 Haloalkyl, C 1-4 Deuterated alkyl, C 5-6 Deuterated alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-C 4-6 Alkoxy, -C 4-6 Alkyl-C 1-3 Alkoxy, -C 4-6 Alkyl-C 4-6 Alkoxy, C 2-4 Alkenyl, C 5-6 Alkenyl, C 2-4 Alkynyl, C 5-6 Alkynyl.

[0027] In some embodiments, R 1 Selected from H, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Deuterated alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkyl-C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl.

[0028] In some embodiments, R 1 Selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoroisopropyl, fluoro-n-butyl, fluoro-sec-butyl, fluoroisobutyl, fluoro-tert-butyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, deuterated n-butyl, deuterated sec-butyl, deuterated isobutyl, deuterated tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, vinyl, propenyl, butenyl, ethynyl, propynyl, butynyl.

[0029] In some embodiments, R 1Selected from H, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, fluoroethyl, deuterated methyl, deuterated ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethyl, vinyl, propenyl, ethynyl, propynyl.

[0030] In some embodiments, R 1 Selected from H, methyl, ethyl, isopropyl, -CD 3 , -CF 3 , -CHF 2 、-CH 2 CH 2 F, cyclopropyl, methoxyethyl, vinyl, ethynyl.

[0031] In some embodiments, the above compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, L is selected from C(R 3 )(R 4 );R 3 and R 4 are each independently selected from H, deuterium, halogen, cyano, C 1-4 Alkyl or C 1-4 Alkoxy; or R 3 and R 4 Combined with the carbon atoms to which they are attached, they form C 3-6 Cycloalkyl.

[0032] In some embodiments, L is selected from C(R 3 )(R 4 );R 3 and R 4 are each independently selected from H, deuterium, F, Cl, Br, cyano, methyl, ethyl, methoxy, ethoxy; or R 3 and R 4 Combined with the carbon atoms to which they are attached they form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

[0033] In some embodiments, L is selected from methylene,

[0034] In some embodiments, L is selected from methylene.

[0035] In some specific embodiments, in the above compounds, or pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, cocrystals, hydrates, solvates, metabolites, prodrugs, deuterated compounds thereof, Ring A is selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heteroaryl and 5-membered heteroaryl, 5-membered heteroaryl and 6-membered heteroaryl, 6-membered heteroaryl and 6-membered heteroaryl, phenyl and 5-membered heteroaryl or phenyl and 6-membered heteroaryl, the 5-membered heteroaryl and 6-membered heteroaryl each independently contain 1-3 heteroatoms selected from N, O and S, and the phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heteroaryl and 5-membered heteroaryl, 5-membered heteroaryl and 6-membered heteroaryl, 6-membered heteroaryl and 6-membered heteroaryl, phenyl and 5-membered heteroaryl, phenyl and 6-membered heteroaryl each independently are unsubstituted or substituted with one or more R b replace.

[0036] In some specific embodiments, ring A is selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl or phenyl-5-membered heteroaryl, wherein the 5-membered heteroaryl and 6-membered heteroaryl each independently contain 1-3 heteroatoms selected from N, O and S, and the phenyl, 5-membered heteroaryl, 6-membered heteroaryl and phenyl-5-membered heteroaryl each independently are unsubstituted or substituted with 1 or more R b replace.

[0037] In some specific embodiments, ring A is selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl or phenyl-5-membered heteroaryl, wherein the 5-membered heteroaryl and 6-membered heteroaryl each independently contain 1-2 N heteroatoms, and the phenyl, 5-membered heteroaryl, 6-membered heteroaryl, phenyl-5-membered heteroaryl each independently are unsubstituted or substituted with 1 or more R b replace.

[0038] In some specific embodiments, ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, benzopyrazolyl or benzimidazolyl, and the phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, benzopyrazolyl, benzimidazolyl are each independently unsubstituted or substituted with one or more R b replace.

[0039] In some specific embodiments, ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl or benzopyrazolyl, wherein the phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, benzopyrazolyl are each independently unsubstituted or substituted with one or more R b replace.

[0040] In some embodiments, Ring A is selected from

[0041] In some embodiments, each R bare independently selected from the same or different halogen, amino, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 4-7 membered heterocyclic group, -SeR k 、-C(O)NR i R j , The 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the amino, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted with one or more R a Replacement; R i , R j , R k Each independently selected from H or C 1-4 Alkyl; R 5 , R 6 , R 7 , R 8 , R 11 and R 12 Each independently selected from H or C 1-4 alkyl.

[0042] In some embodiments, each R b are independently selected from the same or different halogen, amino, SH, C 1-4 Alkyl, C 5-6 Alkyl, C 1-4 Alkoxy, C 5-6 Alkoxy, C 3-8 Cycloalkyl, 4-7 membered heterocycloalkyl, -SeR k 、-C(O)NR i R j , The 4-7 membered heterocycloalkyl group contains 1-3 heteroatoms selected from N, O and S. 1-4 Alkyl, C 5-6 Alkyl, C 1-4 Alkoxy, C 5-6 Alkoxy, C 3-8 The cycloalkyl and 4-7 membered heterocycloalkyl groups are each independently unsubstituted or substituted with one or more R a Replacement; R i , R j , R k Each independently selected from H or C 1-4 Alkyl; R 5 , R 6 , R 7 , R 8 , R11 and R 12 Each independently selected from H or C 1-4 alkyl.

[0043] In some embodiments, each R b are independently selected from the same or different halogen, amino, SH, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, -SeR k 、-C(O)NR i R j , The 4-7 membered heterocycloalkyl group contains 1-2 heteroatoms selected from N, O and S. 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl and 4-7 membered heterocycloalkyl groups are each independently unsubstituted or substituted with one or more R a Replacement; R i , R j , R k Each independently selected from H or C 1-4 Alkyl; R 5 , R 6 , R 7 , R 8 , R 11 and R 12 Each independently selected from H or C 1-4 alkyl.

[0044] In some embodiments, each R b each independently selected from the same or different F, Cl, Br, amino, SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-7 membered heterocycloalkyl, -SeR k 、-C(O)NR i R j , The 4-7 membered heterocycloalkyl contains 1 N heteroatom, and the amino, SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-7 membered heterocycloalkyl are each independently unsubstituted or substituted by one or more R a Replacement; R i , R j , Rk are each independently selected from hydrogen, methyl, ethyl, n-propyl or isopropyl; R 5 , R 6 , R 7 , R 8 , R 11 and R 12 Each is independently selected from hydrogen, methyl, ethyl, n-propyl or isopropyl.

[0045] In some embodiments, each R b each independently selected from the same or different F, Cl, amino, SH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, azetidinyl, -SeR k 、-C(O)NR i R j , The amino, SH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, azetidinyl are each independently unsubstituted or substituted with one or more R a Replacement; R i , R j , R k are each independently selected from hydrogen, methyl or ethyl; R 5 , R 6 , R 7 , R 8 , R 11 and R 12 Each is independently selected from hydrogen, methyl or ethyl.

[0046] In some embodiments, each R b each independently selected from the same or different F, Cl, amino, SH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, azetidinyl, -SeCH 3 , The amino, SH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, azetidinyl are each independently unsubstituted or substituted with one or more R a replace.

[0047] In some embodiments, each R a Each independently selected from the same or different halogen, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy.

[0048] In some embodiments, each R a Each independently selected from the same or different halogen, hydroxyl, C 1-4 Alkyl or C 1-4 Alkoxy.

[0049] In some embodiments, each R a Each is independently selected from the same or different F, Cl, Br, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy.

[0050] In some embodiments, each R a Each is independently selected from the same or different F, Cl, Br, hydroxy, methyl, ethyl, methoxy or ethoxy.

[0051] In some embodiments, each R a Each is independently selected from the same or different F, hydroxy, methyl or methoxy.

[0052] In some embodiments, each R b Each is independently selected from the same or different F, Cl, amino, methyl-substituted amino, -SCH 3 , methyl, fluoromethyl, methoxy, fluoromethoxy, ethoxy, fluoroethoxy, hydroxy-substituted isopropyl, hydroxy-substituted cyclopropyl, methoxy-substituted ethoxy, isopropyl, isopropoxy, cyclopropyl, azetidinyl, -SeCH 3 ,

[0053] In some embodiments, each R b Each is independently selected from the same or different methyl, methoxy, cyclopropyl, isopropyl, ethoxy, isopropoxy, -SCH 3 , -SeCH 3 , Amino, F, Cl, -OCHF 2 、-OCF 3 , -CF 3 ,

[0054] In some embodiments, Ring A is selected from

[0056] In some embodiments, the above compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, B is selected from C 2-6 Alkynyl, C 6-10Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl or C 3-10 The 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl groups each independently contain 1-3 heteroatoms selected from N, O and S. 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl or C 3-10 Each cycloalkyl group is independently unsubstituted or substituted with 1 or more halogen groups which may be the same or different.

[0057] In some embodiments, B is selected from C 2-4 Alkynyl, phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4-7-membered heterocycloalkyl or C 3-8 The 5-membered heteroaryl, 6-membered heteroaryl, and 4-7-membered heterocycloalkyl groups each independently contain 1-3 heteroatoms selected from N, O, and S. 2-4 Alkynyl, phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4-7-membered heterocycloalkyl, C 3-8 Each cycloalkyl group is independently unsubstituted or substituted with 1 or more halogen groups which may be the same or different.

[0058] In some embodiments, B is selected from C 2-4 Alkynyl, phenyl, 6-membered heteroaryl, 4-7-membered heterocycloalkyl, C 7-8 Cycloalkyl or C 3-6 The 6-membered heteroaryl and 4-7-membered heterocycloalkyl groups each independently contain 1-2 heteroatoms selected from N. 2-4 Alkynyl, phenyl, 6-membered heteroaryl, 4-7-membered heterocycloalkyl, C 3-6 Cycloalkyl, C 7-8 Each cycloalkyl group is independently unsubstituted or substituted with 1 or more halogen groups which may be the same or different.

[0059] In some embodiments, B is selected from ethynyl, propynyl, butynyl, phenyl, pyridyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, The propynyl, butynyl, phenyl, pyridyl, pyrimidyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl and piperazinyl are each independently unsubstituted or substituted with one or more identical or different F, Cl or Br.

[0060] In some embodiments, B is selected from ethynyl, phenyl, pyridinyl, pyrimidinyl, cyclohexyl, piperidinyl, The phenyl, pyridyl, pyrimidyl, cyclohexyl or piperidyl groups are each independently unsubstituted or substituted with one or more identical or different F, Cl or Br groups.

[0061] In some embodiments, B is selected from phenyl, pyridyl, pyrimidinyl, cyclohexyl, piperidinyl, fluoropiperidinyl, ethynyl,

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

[0063] In one embodiment, B is selected from

[0064] In some embodiments, the above compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof, C is selected from C 6-10 aryl or 5-10 membered heteroaryl, the 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, the C 6-10 The aryl group and the 5-10-membered heteroaryl group are each independently unsubstituted or substituted by one or more R d replace.

[0065] In some specific embodiments, C is selected from phenyl, pyridyl, pyrimidyl, and 5-membered heteroaryl, wherein the 5-membered heteroaryl contains 1-3 heteroatoms selected from N, O, and S, and the phenyl, pyridyl, pyrimidyl, and 5-membered heteroaryl are each independently unsubstituted or substituted with one or more R d replace.

[0066] In some embodiments, C is selected from a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group contains 1-2 heteroatoms selected from N, O and S, and the 5-membered heteroaryl group is unsubstituted or substituted by one or more R d replace.

[0067] In some embodiments, C is selected from imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, and the imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl groups, each of which is independently unsubstituted or substituted with one or more R d replace.

[0068] In some embodiments, C is selected from imidazolyl, pyrazolyl, oxazolyl, thiazolyl, and the imidazolyl, pyrazolyl, oxazolyl, thiazolyl are each independently unsubstituted or substituted with one or more R d replace.

[0069] In some embodiments, C is selected from

[0070] In some embodiments, C is selected from

[0071] In some embodiments, each R d are independently selected from the same or different halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl or 4-7 membered heterocyclic group, the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted with one or more R a replace.

[0072] In some embodiments, each R d are independently selected from the same or different halogen, C 1-4 Alkyl, C 5-6 Alkyl, C 1-4 Alkoxy, C 5-6 Alkoxy, C 3-8 Cycloalkyl or 4-7 membered heterocycloalkyl, the 4-7 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O and S, the C 1-4 Alkyl, C 5-6 Alkyl, C 1-4 Alkoxy, C 5-6 Alkoxy, C 3-8 The cycloalkyl and 4-7 membered heterocycloalkyl groups are each independently unsubstituted or substituted with one or more R a replace.

[0073] In some embodiments, each R d are independently selected from the same or different halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl, the 4-7 membered heterocycloalkyl contains 1 N heteroatom, the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl and 4-7 membered heterocycloalkyl groups are each independently unsubstituted or substituted with one or more R a replace.

[0074] In some embodiments, each R dR is each independently selected from the same or different F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or azetidinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl are each independently unsubstituted or replaced by one or more R a replace.

[0075] In some embodiments, each R d Each is independently selected from the same or different F, Cl, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl or azetidinyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, azetidinyl is each independently unsubstituted or substituted by one or more R a replace.

[0076] In some embodiments, each R d Each is independently selected from the same or different Cl, methyl, ethyl, isopropyl, methoxy, cyclopropyl or azetidinyl, wherein the methyl, ethyl, methoxy, azetidinyl is each independently unsubstituted or substituted by one or more R a replace.

[0077] In some embodiments, each R a are independently selected from the same or different halogen, =O or C 1-6 alkyl.

[0078] In some embodiments, each R a are independently selected from the same or different halogen, =O or C 1-4 alkyl.

[0079] In some embodiments, each R a Each is independently selected from the same or different F, Cl, Br, =O, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0080] In some embodiments, each R a Each is independently selected from the same or different F, =0 or methyl.

[0081] In some embodiments, each R dEach is independently selected from the same or different Cl, methyl, fluoromethyl, ethyl, fluoroethyl, isopropyl, methoxy, fluoromethoxy, cyclopropyl,

[0082]

[0083] In some embodiments, each R d Each independently selected from the same or different methyl, isopropyl, -CF 3 , -CHF 2 , Cyclopropyl, methoxy, Cl, or -OCF 3 .

[0084] In some embodiments, C is selected from

[0085] The preferred technical solution of the present invention, the above compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, has the structure shown in Formula II:

[0086]

[0087] Among them, ring A, R 1 , L, B and C are defined as above.

[0088] The preferred technical solution of the present invention, the above-mentioned compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, has the structure shown in Formula II-1:

[0089]

[0090] Wherein, the definition of L is as shown above.

[0091] The preferred technical solution of the present invention, the above compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, has the structure shown in Formula II-2:

[0092]

[0093] Among them, R 1 The definition of is as shown above.

[0094] The preferred technical solution of the present invention, the above-mentioned compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, has the structure shown in Formula II-3:

[0095]

[0096] Among them, R b The definition of is as shown above.

[0097] The preferred technical solution of the present invention, the above-mentioned compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, has the structure shown in Formula II-4:

[0098]

[0099] Wherein, the definition of B is as shown above.

[0100] The preferred technical solution of the present invention, the above compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, has the structure shown in Formula II-5:

[0101]

[0102] Among them, R d The definition of is as shown above.

[0103] The preferred technical solution of the present invention, the above-mentioned compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, has the structure shown in Formula II-6:

[0104]

[0105] Among them, R d The definition of is as shown above.

[0106] The preferred technical solution of the present invention, the above compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, has the structure shown in Formula II-7:

[0107]

[0108] Among them, R b The definition of is as shown above.

[0109] The preferred technical solution of the present invention, the above compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, has the structure shown in Formula II-8:

[0110]

[0111] Among them, R b The definition of is as shown above.

[0112] The preferred technical solution of the present invention, the above compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, has the structure shown in Formula II-9:

[0113]

[0114] Among them, R b The definition of is as shown above.

[0115] The preferred technical solution of the present invention, the above-mentioned compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, has the structure shown in Formula II-10:

[0116]

[0117] Among them, R b The definition of is as shown above.

[0118] The preferred technical solution of the present invention, the above compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, has the structure shown in Formula III:

[0119]

[0120] Among them, ring A, R 1 , L, B and C are defined as above.

[0121] The preferred technical solution of the present invention, the above compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, has the structure shown in formula III-1:

[0122]

[0123] Wherein, the definition of L is as shown above.

[0124] The preferred technical solution of the present invention, the above compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, has the structure shown in formula III-2:

[0125]

[0126] Among them, R 1 The definition of is as shown above.

[0127] The preferred technical solution of the present invention, the above compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, has the structure shown in formula III-3:

[0128]

[0129] Among them, R b The definition of is as shown above.

[0130] The preferred technical solution of the present invention, the above compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, has the structure shown in formula III-4:

[0131]

[0132] Wherein, the definition of B is as shown above.

[0133] The preferred technical solution of the present invention, the above-mentioned compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, has the structure shown in formula III-5:

[0134]

[0135] Among them, R d The definition of is as shown above.

[0136] The preferred technical solution of the present invention, the above compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, has the structure shown in formula III-6:

[0137]

[0138] Among them, R d The definition of is as shown above.

[0139] The preferred technical solution of the present invention, the above compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, has the structure shown in formula III-7:

[0140]

[0141] Among them, R b The definition of is as shown above.

[0142] The preferred technical solution of the present invention, the above compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, has the structure shown in formula III-8:

[0143]

[0144] Among them, R b The definition of is as shown above.

[0145] The preferred technical solution of the present invention, the above-mentioned compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, has the structure shown in formula III-9:

[0146]

[0147] Among them, R b The definition of is as shown above.

[0148] The preferred technical solution of the present invention, the above-mentioned compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, has the structure shown in Formula III-10:

[0149]

[0150] Among them, R b The definition of is as shown above.

[0151] The preferred technical solution of the present invention is that the above-mentioned compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, is selected from the following compounds:

[0152]

[0153]

[0154]

[0155] Preparation method:

[0156] The present invention also provides a method for preparing the compound.

[0157]

[0158] Step 1: The compound represented by formula IA-1 reacts with a halogenating agent to obtain a compound represented by formula IA-2;

[0159] Step 2: The compound represented by formula IA-2 is protected by a protecting group to obtain a compound represented by formula IA-3;

[0160] Step 3: The compound represented by Formula IA-3 and the compound represented by Formula IA-4 or the compound represented by Formula IA-5 are subjected to Suzuki coupling to obtain the compound represented by Formula IA-6;

[0161] Step 4: The compound represented by Formula IA-6 and the compound represented by Formula IA-7 are subjected to coupling reaction to obtain the compound represented by Formula IA-8;

[0162] Step 5: removing the protecting group from the compound represented by Formula IA-8 to obtain the compound represented by Formula IA-9;

[0163] Step 6: The compound represented by Formula IA-9 undergoes a substitution reaction to obtain a compound represented by Formula I;

[0164] Among them, X 1 , R 1 , L, rings A, B, and C are defined as above.

[0165] Pharmaceutical composition

[0166] The present invention also provides a pharmaceutical composition, which comprises a compound of the aforementioned formula (I), (II), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (II-9), (II-10), (III), (III-1), (III-2), (III-3), (III-4), (III-5), (III-6), (III-7), (III-8), (III-9) or (III-10) or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, and optionally a pharmaceutically acceptable carrier and / or adjuvant and / or diluent.

[0167] Medical Uses

[0168] In another aspect, the present invention also provides a compound of the aforementioned formula (I), (II), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (II-9), (II-10), (III), (III-1), (III-2), (III-3), (III-4), (III-5), (III-6), (III-7), (III-8), (III-9) or (III-10) or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, or the pharmaceutical composition thereof in the preparation of a medicament for preventing and / or treating USP1-mediated diseases.

[0169] Preferably, the USP1-mediated disease is a tumor or cancer.

[0170] Preferably, the USP1-mediated disease refers to a USP1-mediated related disease with HR deficiency.

[0171] Preferably, the USP1-mediated disease refers to cancer or tumor with HR deficiency.

[0172] Beneficial effects of the present invention:

[0173] The compounds of the present invention have excellent USP1 inhibitory activity and can be used as drugs for preventing and / or improving and / or treating diseases associated with this activity. DETAILED DESCRIPTION

[0174] The content of the present invention is further described below in conjunction with specific examples, but the protection scope of the present invention is not limited to these examples.

[0175] Preparation of intermediate int-a

[0176]

[0177] Step 1: Synthesis of compound int-ac

[0178] At room temperature, int-ab (9.9 g, 37.0 mmol) and sodium acetate (3.0 g, 37.0 mmol) were added to water, and the resulting mixture was stirred and heated at 100 ° C for 1 h. The reaction solution was cooled to room temperature and slowly added dropwise to a methanol (100 mL) solution containing int-aa (5.0 g, 30.5 mmol), and then ammonia water (35 mL) was added to the reaction solution, and the reaction was stirred at room temperature for 16 h. After the resulting mixture was concentrated under reduced pressure to remove the solvent, the resulting residue was added to water (100 mL), extracted with ethyl acetate (3*100 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (PE:EA=5:1–1:1) gave 5.0 g of a white solid compound int-ac. MS m / z(ESI):271.06[M+H] + .

[0179] Step 2: Synthesis of compound int-ad

[0180] The compound int-ac (3.0 g, 11.0 mmol) was dissolved in N,N-dimethylformamide (30 mL), and sodium hydride (60%, 0.67 g, 17.0 mmol) was added in batches at 0°C. The reaction solution was stirred at 0°C for 0.5 h, and then iodomethane (3.2 g, 22.0 mmol) was added, and the temperature was raised to 80°C for 2 h. The reaction solution was added to ice water (30 mL), and extracted with ethyl acetate (3*20 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3.0 g of crude white solid compound int-ad. MS m / z (ESI): 285.08 [M+H] + .

[0181] Step 3: Synthesis of compound int-ae

[0182] Compound int-ad (3.0 g, 11.0 mmol) was added to tetrahydrofuran (60 mL), and lithium aluminum tetrahydride (1.3 g, 33.0 mmol) was added in batches at 0°C. The resulting mixture was stirred at 0°C for 1 h, and then slowly returned to room temperature for 1 h. Water (10 mL), 15% NaOH aqueous solution (10 mL), and water (30 mL) were added to the reaction solution at 0°C in sequence. The resulting mixture was stirred at room temperature for 1 hour and filtered through diatomaceous earth. The filter cake was rinsed with dichloromethane. The filtrates were combined and concentrated under reduced pressure to remove the solvent to obtain 3.0 g of crude oily compound int-ae. MS m / z (ESI): 257.08 [M+H] + .

[0183] Step 4: Synthesis of intermediate int-a

[0184] Dissolve int-ae (2.0 g, 7.8 mmol) and triphenylphosphine (3.1 g, 11.7 mmol) in acetonitrile (40 mL), add carbon tetrabromide (3.9 g, 11.7 mmol) at 0°C, and stir at room temperature for 3 hours. Concentrate the reaction solution under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography (PE:EA=10:1–3:1) to obtain 1.5 g of a white solid intermediate product int-a. MS m / z(ESI):319.00[M+H] + .

[0185] Preparation of intermediate int-b

[0186]

[0187] Step 1: Synthesis of compound int-bc

[0188] Dissolve the hydrochloride of int-ba (9.0 g, 44.4 mmol) and int-bb (6.8 g, 44.4 mmol) in hexafluoroisopropanol (70 mL), add triethylamine (8.9 g, 87.9 mmol) dropwise at 0°C, and stir at room temperature for 2 h. Concentrate under reduced pressure, and separate the residue by silica gel column chromatography (PE:EA=10:1) to obtain 9.2 g of white solid int-bc. MS m / z(ESI):285.08[M+H] + .

[0189] Step 2: Synthesis of compound int-bd

[0190] Dissolve int-bc (9.2 g, 32.4 mmol) in THF (90 mL), add DIBAL-H (1 M, 97.2 mL, 97.2 mmol) dropwise at 0°C, stir at 20°C for 2 h after addition. Slowly add water to quench the reaction, add saturated aqueous ammonium chloride solution (100 mL) and EA (150 mL) to extract and separate, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is separated by silica gel column chromatography (PE:EA=3:1) to obtain 8.2 g of white solid int-bd. MS m / z(ESI):257.08[M+H] + .

[0191] Step 3: Synthesis of compound int-b

[0192] Dissolve int-bd (8.0 g, 31.22 mmol) and triphenylphosphine (12.28 g, 46.83 mmol) in acetonitrile (200 mL), add carbon tetrabromide (15.53 g, 46.83 mmol) at 0°C, and stir at room temperature for 3 hours. Concentrate the reaction solution under reduced pressure to obtain a crude product, which is separated by silica gel column chromatography (PE:EA=20:1–3:1) to obtain 8.1 g of intermediate int-b as a white solid. MS m / z(ESI):319.00[M+H] + .

[0193] Preparation of intermediate int-c

[0194]

[0195] Step 1: Synthesis of compound int-cc

[0196] Under nitrogen protection, int-ca (3.0 g, 35.19 mmol) and int-cb (5.0 g, 35.19 mmol) were dissolved in 100 mL of tetrahydrofuran and 100 mL of methanol, and sodium methoxide (14.08 mL, 5 mol / L) was added. The mixture was stirred at 60°C overnight. After the reaction was completed, it was cooled in an ice-water bath, and 2N dilute hydrochloric acid was added to the mixture to quench the reaction. It was extracted with ethyl acetate (3*50 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a mixture, and separated and purified using a normal phase chromatography column (PE:EA=40:1) to obtain 4.0 g of colorless oily liquid int-cc. MS m / z(ESI):181.04[M+H] + .

[0197] Step 2: Synthesis of compound int-cd

[0198] Dissolve the hydrochloride of int-ba (3.7 g, 22.21 mmol) and int-cc (4 g, 22.21 mmol) in hexafluoroisopropanol (70 mL), add sodium acetate (1.8 g, 22.21 mmol) dropwise at 0°C, and stir at room temperature for 2 h. Concentrate under reduced pressure, and separate the residue by silica gel column chromatography (PE:EA=10:1) to obtain 4.0 g of white solid int-cd. MS m / z(ESI):311.08[M+H] + .

[0199] Step 3: Synthesis of compound Int-CE

[0200] Dissolve int-cd (4.0 g, 12.89 mmol) in THF (90 mL), add DIBAL-H (1 M, 19.3 mL, 19.33 mmol) dropwise at 0°C, stir at 20°C for 2 h after addition. Slowly add water to quench the reaction, add saturated aqueous ammonium chloride solution (100 mL) and EA (150 mL) to extract and separate, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is separated by silica gel column chromatography (PE:EA=3:1) to obtain 3.0 g of the product, a white solid, int-ce. MS m / z(ESI):283.10[M+H] + .

[0201] Step 4: Synthesis of compound int-c

[0202] Dissolve int-ce (3.0 g, 10.63 mmol) and triphenylphosphine (4.2 g, 15.94 mmol) in acetonitrile (200 mL), add carbon tetrabromide (5.3 g, 15.94 mmol) at 0°C, and stir at room temperature for 3 hours. Concentrate the reaction solution under reduced pressure to obtain a crude product, which is separated by silica gel column chromatography (PE:EA=20:1–3:1) to obtain 3.0 g of the intermediate int-c as a white solid. MS m / z(ESI):345.01[M+H] + .

[0203] Example 1 Preparation of Compound 1

[0204]

[0205] Step 1: Synthesis of compound 1-b

[0206] 1-a (3.0 g, 19.5 mmol) was added to a two-necked bottle, and DMF (30 mL) was added to dissolve it. N-bromosuccinimide (3.8 g, 21.3 mmol) was added thereto under an ice bath, and then stirred at room temperature for 2 h. After the reaction was completed, water was added to quench the reaction as monitored by LC-MS, and the reaction was extracted with ethyl acetate (3*50 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4.2 g of crude white solid compound 1-b. MS m / z (ESI): 231.98 [M+H] + .

[0207] Step 2: Synthesis of compound 1-c

[0208] 1-b (4.2 g, 18.2 mmol) was added to a two-necked bottle, tetrahydrofuran (20 mL) was added to dissolve, and then 3,4-dihydro-2H-pyran (3.05 g, 36.3 mmol) and 4-methylbenzenesulfonic acid pyridine (1.1 g, 4.5 mmol) were added in sequence, and then the temperature was raised to 60 ° C and stirred for 2 h. After the reaction was completed by LC-MS, water was added to quench, and the mixture was extracted with ethyl acetate (3*50 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue after concentration was purified by C18 column (ACN:H 2 O=70:30), collect and purify the product to obtain 5.4 g of yellow oily compound 1-c. MS m / z (ESI): 315.89 [M+H] + .

[0209] Step 3: Synthesis of compound 1-e

[0210] 1-c (2.7 g, 8.6 mmol), 1-d (1.7 g, 8.7 mmol), sodium carbonate (2.3 g, 21.7 mmol), Pd(dppf)Cl 2 (350.0 mg, 0.4 mmol) was dissolved in dioxane (63 mL) and water (7 mL), and the atmosphere was replaced with nitrogen. The reaction was stirred at 90 °C for 2 h. After LC-MS monitoring, the reaction of the raw material was complete. The product was cooled to room temperature, filtered and concentrated, and purified by C18 column (ACN:H 2 O=65:35), vacuum freeze-dried to obtain 960.0 mg of light yellow solid compound 1-e. MS m / z (ESI): 386.16 [M+H] + .

[0211] Step 4: Synthesis of compound 1-f

[0212] Under nitrogen protection, zinc powder (408.1 mg, 6.2 mmol), iodine (39.6 mg, 0.16 mmol) and DMF (2 mL) were added to a two-necked bottle, stirred at 30 ° C for 10 min, then TMSCl (17.4 mg, 0.16 mmol) was added, the reaction system was heated to 45 ° C for 45 min, then int-a (165.9 mg, 0.5 mmol) was added, the temperature was maintained for 1 h, and then Pd (PPh 3 ) 4 (184.9 mg, 0.16 mmol) and 1-e (200.0 mg, 0.5 mmol), heated to 60 °C for 2 h, LC-MS monitored the completion of the reaction of the raw materials, cooled to room temperature, filtered and concentrated, and purified by C18 column (ACN:H 2O=65:35), vacuum freeze-dried to obtain 20.0 mg of off-white solid compound 1-f. MS m / z (ESI): 590.20 [M+H] + .

[0213] Step 5: Synthesis of compound 1

[0214] 1-f (20.0 mg, 0.03 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added. The reaction was stirred at 40°C for 2 h. After the reaction was completed by LC-MS monitoring, the raw material was concentrated and purified by C18 column (ACN:H 2 O=65:35), vacuum freeze-dried to obtain 3.0 mg of white solid compound 1. MS m / z (ESI): 506.21 [M+H] + .

[0215] 1 H NMR (400 MHz, DMSO-d 6 )δ13.92(s,1H),9.06(d,J=1.4Hz,1H),8.72(s,1H),7.91(d,J=1.4Hz,1H),7.64(d,J=8.2Hz,2H),7.54-7.42(m,3H) ,4.26(s,2H),3.86(s,3H),3.77(s,3H),1.99(dt,J=8.2,3.8Hz,1H),1.17-1.05(m,2H),0.90(dq,J=7.2,3.6Hz,2H).

[0216] Example 2 Preparation of Compound 2

[0217]

[0218] Step 1: Synthesis of compound 2-b

[0219] 2-a (2.0 g, 13.9 mmol) was added to a two-necked bottle, and DCM (40 mL) was added to dissolve it. (Boc) was added under ice bath. 2 O (9.1 g, 41.8 mmol), triethylamine (4.2 g, 41.8 mmol) and DMAP (0.9 g, 7.0 mmol), and then stirred at room temperature to react overnight. After the reaction was completed, LC-MS monitored the reaction and quenched with water. The mixture was extracted with ethyl acetate (3*50 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by C18 column (ACN:H 2 O=65:35), and vacuum freeze-dried to obtain 2.5 g of white solid crude compound 2-b. MS m / z (ESI): 344.12 [M+H]+ .

[0220] Step 2: Synthesis of compound 2-c

[0221] Under nitrogen protection, zinc powder (5.7 g, 87.3 mmol), iodine (0.6 g, 2.2 mmol) and DMF (10 mL) were added to a two-necked bottle, stirred at 30 °C for 10 min, then TMSCl (0.2 g, 2.2 mmol) was added, the reaction system was heated to 45 °C for 45 min, then int-a (2.3 g, 7.3 mmol) was added, the temperature was maintained for 1 h, and then Pd (PPh 3 ) 4 (0.3 g, 0.22 mmol) and 2-b (2.5 g, 7.3 mmol), heated to 60 °C for 2 h, LC-MS monitored the completion of the reaction of the raw materials, cooled to room temperature, filtered and concentrated, and purified by C18 column (ACN:H 2 O=65:35), vacuum freeze-dried to obtain 2.5 g of off-white solid compound 2-c. MS m / z (ESI): 548.24 [M+H] + .

[0222] Step 3: Synthesis of compound 2-d

[0223] 2-c (2.5 g, 4.6 mmol) was added to a two-necked bottle, DCM (20 mL) was added to dissolve, trifluoroacetic acid (10 mL, 4.6 mmol) was added, and then stirred at room temperature for 2 h. After the reaction was completed, water was added to quench the mixture after monitoring by LC-MS. The mixture was extracted with ethyl acetate (3*50 mL), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by C18 column (ACN:H 2 O=55:45), vacuum freeze-dried to obtain 1.6 g of white solid compound 2-d. MS m / z (ESI): 348.15 [M+H] + .

[0224] Step 4: Synthesis of compound 2-e

[0225] 2-d (0.9 g, 2.6 mmol) was added to a two-necked bottle, and chloroform (15 mL) was added to dissolve it. Isoamyl nitrite (1.8 g, 15.7 mmol), potassium acetate (307.0 mg, 3.1 mmol) and acetic anhydride (1.1 g, 10.5 mmol) were added thereto, and then stirred at 80 ° C for 1 h. After the reaction was completed, water was added to quench the reaction after LC-MS monitoring, and the mixture was extracted with ethyl acetate (3*50 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. It was purified by C18 column (ACN:H 2 O=65:35), vacuum freeze-dried to obtain 0.9 g of white solid compound 2-e. MS m / z (ESI): 401.16 [M+H] + .

[0226] Step 5: Synthesis of compound 2-f

[0227] 2-e (0.9 g, 2.3 mmol) was added to a single-mouth bottle, methanol (10 mL) was added to dissolve, potassium carbonate (0.9 g, 6.7 mmol) was added thereto, and then stirred at room temperature for 2 h. After the reaction was completed as monitored by LC-MS, water was added to quench, and the mixture was extracted with ethyl acetate (3*50 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by C18 column (ACN:H 2 O=55:45), vacuum freeze-dried to obtain 545.0 mg of white solid compound 2-f. MSm / z(ESI):359.13[M+H] + .

[0228] Step 6: Synthesis of compound 2-g

[0229] 2-f (100.0 mg, 0.28 mmol) was added to a two-necked bottle, and DMF (5 mL) was added to dissolve it. N-bromosuccinimide (59.6 mg, 0.33 mmol) was added thereto under ice bath, and then stirred at room temperature for 2 h. After the reaction was completed, water was added to quench the reaction after LC-MS monitoring, and the reaction was extracted with ethyl acetate (3*50 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by C18 column (ACN:H 2 O=55:45), vacuum freeze-dried to obtain 69.0 mg of white solid crude compound 2-g. MS m / z (ESI): 437.02 [M+H] + .

[0230] Step 7: Synthesis of compound 2-h

[0231] 2-g (35.0 mg, 0.08 mmol) was added to a two-necked bottle, and DMF (1 mL) was added to dissolve it. Then sodium hydrogen (5.8 mg, 0.24 mmol) was added in an ice bath. After stirring for 10 min, SEM-Cl (40.0 mg, 0.24 mmol) was added, and then the reaction was stirred at room temperature for 1 h. After LC-MS detection, water was added to quench the reaction, and it was extracted with ethyl acetate (3*50 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue after concentration was purified by C18 column (ACN:H 2 O=70:30), the purified product was collected to obtain 29.0 mg of colorless oily compound 2-h. MS m / z (ESI): 567.10 [M+H] + .

[0232] Step 8: Synthesis of compound 2-i

[0233] 2-h (29.0 mg, 0.05 mmol), 1-d (49.6 mg, 0.26 mmol), sodium carbonate (13.5 mg, 0.13 mmol), Pd(dppf)Cl 2 (2.1 mg, 0.003 mmol) was dissolved in dioxane (2 mL) and water (0.2 mL), and the atmosphere was replaced with nitrogen. The reaction was stirred at 90 °C for 2 h. After the reaction was completed by LC-MS monitoring, the raw material was cooled to room temperature, filtered and concentrated, and purified by C18 column (ACN:H 2 O=65:35), vacuum freeze-dried to obtain 22.0 mg of off-white solid compound 2-i. MS m / z (ESI): 637.30 [M+H] + .

[0234] Step 9: Synthesis of Compound 2

[0235] 2-i (22.0 mg, 0.03 mmol) was added to a single-mouth bottle, DCM (5 mL) was added to dissolve, trifluoroacetic acid (2 mL) was added, and then stirred at room temperature for 2 h. After the reaction was completed, water was added to quench the reaction after LC-MS monitoring, and the mixture was extracted with ethyl acetate (3*20 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by C18 column (ACN:H 2 O=55:45), vacuum freeze-dried to obtain 7.0 mg of white solid compound 2. MS m / z (ESI): 507.16 [M+H] + .

[0236] 1 H NMR (400 MHz, DMSO-d 6)δ9.37(s,1H),8.75(s,1H),7.92(d,J=1.4Hz,1H),7.64(d,J=8.2Hz,2H),7.46(d,J=8.2Hz,2H), 4.39(s,2H),3.84(s,3H),3.77(s,3H),1.86-1.80(m,1H),1.12-1.07(m,2H),0.92-0.85(m,2H).

[0237] Example 3 Preparation of Compound 3

[0238]

[0239] Step 1: Synthesis of compound 3

[0240] Compound 2 (20.0 mg, 0.04 mmol) was added to a two-necked bottle, and DMF (2 mL) was added to dissolve it. Cesium carbonate (51.5 mg, 0.16 mmol) and iodomethane (11.2 mg, 0.08 mmol) were added thereto under an ice bath, and then stirred at room temperature for 1 h. After the reaction was completed as monitored by LC-MS, water was added to quench, and the mixture was extracted with ethyl acetate (3*50 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by C18 column (ACN:H 2 O=55:45), vacuum freeze-dried to obtain 5.0 mg of white solid compound 3. MS m / z (ESI): 521.17 [M+H] + .

[0241] 1 H NMR (400 MHz, DMSO-d 6 )δ9.49(s,1H),8.74(s,1H),7.92(d,J=1.6Hz,1H),7.64(d,J=8.2Hz,2H),7.45(d,J=8.0Hz,2H),4.40( s,2H),4.27(s,3H),3.84(s,3H),3.77(s,3H),1.86-1.81(m,1H),1.11-1.08(m,2H),0.91-0.86(m,2H).

[0242] Example 4 Preparation of Compound 4

[0243]

[0244] Step 1: Synthesis of compound 4-b

[0245] Compound 4-a (4.0 g, 25.87 mmol) was dissolved in N,N-dimethylformamide (40 mL), N-iodosuccinimide (7.0 g, 31.05 mmol) was added, nitrogen was replaced, and the reaction was heated to 60 ° C for 2 h. The reaction solution was added to water (200 mL), extracted with ethyl acetate (3*50 mL), the organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (PE:EA=5:1–1:1) gave 4.5 g of compound 4-b. MS m / z(ESI):280.9[M+H] + .

[0246] Step 2: Synthesis of compound 4-c

[0247] Compound 4-b (4.5 g, 16.04 mmol) was dissolved in N,N-dimethylformamide (50 mL), replaced with nitrogen and cooled to 0 ° C, sodium hydride (963.0 mg, 24.06 mmol, 60%) was added, and the reaction was carried out at low temperature for 10 min, 2-(trimethylsilyl)ethoxymethyl chloride (7.0 g, 31.05 mmol) was added, and the temperature was naturally raised to room temperature for 2 h. The reaction solution was added to water (200 mL) and extracted with ethyl acetate (3*50 mL). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel chromatography (PE:EA=1:0–5:1) gave 5.3 g of compound 4-c. MS m / z(ESI):410.9[M+H] + .

[0248] Step 3: Synthesis of compound 4-d

[0249] Under nitrogen protection, compound 4-c (2.0 g, 4.87 mmol), compound 1-d (1.89 g, 9.74 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.93 g, 1.95 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.77 g, 0.97 mmol), potassium phosphate (20.7 g, 9.74 mmol) were dissolved in a mixed solution of dioxane (20 mL) and water (4 mL), stirred at 80 ° C for 3 hours, the reaction solution was added to water (50 mL), extracted with ethyl acetate (3*20 mL), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (PE:EA=1:0-3:2) gave 1.2 g of compound 4-d. MS m / z(ESI):433.15[M+H] + .

[0250] Step 4: Synthesis of compound 4-e

[0251] Under nitrogen protection, zinc powder (543.7 mg, 8.31 mmol) and iodine (87.9 mg, 0.35 mmol) were dissolved in N, N-dimethylformamide (5 mL), reacted at room temperature for 10 min, then trimethylsilyl chloride (37.6 mg, 0.35 mmol) was added, heated to 45 ° C for 1 hour, then compound int-b (884.3 mg, 2.77 mmol) was added, reacted at 45 ° C for 1 hour, and finally compound 4-d (300.0 mg, 0.69 mmol) and tetrakis(triphenylphosphine)palladium (160.0 mg, 0.14 mmol) were added, heated to 60 ° C for 3 hours, the reaction solution was added to water (20 mL), and extracted with ethyl acetate (3*10 mL), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (PE:EA=5:1-1:1) gave 320.0 mg of compound 4-e. MS m / z (ESI): 637.26 [M+H] + .

[0252] Step 5: Synthesis of compound 4

[0253] Compound 4-e (320.0 mg, 0.47 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added, the mixture was reacted at room temperature for 2 hours, and the mixture was concentrated under reduced pressure. Tetrahydrofuran (5 mL) and ammonia water (10 mL) were added, and the mixture was reacted for 1 hour. The reaction solution was added to water (20 mL), and extracted with ethyl acetate (3*10 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was then purified by reverse phase medium pressure preparation (ACN:H 2 O=20:1–1:1) was freeze-dried to obtain 65.71 mg of compound 4. MS m / z (ESI): 507.18 [M+H] + .

[0254] 1 H NMR (400 MHz, DMSO-d 6 )δ9.36(s,1H),8.74(s,1H),7.53-7.47(m,4H),6.74(s,1H),4.41(s,2H),3.83 (s,3H),2.32(s,3H),1.88-1.80(m,1H),1.12-1.05(m,2H),0.90-0.84(m,2H).

[0255] Example 5 Preparation of Compound 5

[0256]

[0257] Step 1: Synthesis of compound 5-a

[0258] Under nitrogen protection, zinc powder (181.2 mg, 2.77 mmol) and iodine (29.3 mg, 0.12 mmol) were dissolved in N, N-dimethylformamide (3 mL), reacted at room temperature for 10 min, then trimethylsilyl chloride (12.5 mg, 0.12 mmol) was added, heated to 45 ° C for 1 hour, then compound int-c (318.9 mg, 0.92 mmol) was added, reacted at 45 ° C for 1 hour, and finally compound 4-d (100.0 mg, 0.23 mmol) and tetrakis(triphenylphosphine)palladium (53.4 mg, 0.05 mmol) were added, heated to 60 ° C for 3 hours, the reaction solution was added to water (20 mL), and extracted with ethyl acetate (3*10 mL), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (PE:EA=5:1-1:1) gave 70.0 mg of compound 5-a. MS m / z(ESI):663.28[M+H] + .

[0259] Step 2: Synthesis of compound 5

[0260] Compound 5-a (70.0 mg, 0.1 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (4 mL) was added, the mixture was reacted at room temperature for 2 hours, and the mixture was concentrated under reduced pressure. Tetrahydrofuran (2 mL) and ammonia water (4 mL) were added, and the mixture was reacted for another hour. The reaction mixture was added to water (10 mL), and extracted with ethyl acetate (3*10 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was then purified by reverse phase medium pressure preparation (ACN:H 2 O=20:1–1:1) was freeze-dried to obtain 11.39 mg of compound 5. MS m / z (ESI): 533.19 [M+H] + .

[0261] 1 H NMR (400 MHz, DMSO-d 6)δ9.34(s,1H),8.73(s,1H),7.59-7.54(m,2H),7.54-7.50(m,2H),6.61(s,1H),4.41(s,2H),3.83(s ,3H),1.88-1.77(m,2H),1.10-1.06(m,2H),0.97-0.93(m,2H),0.89-0.84(m,2H),0.84-0.80(m,2H).

[0262] Control Compound A Prepared according to CN113164485A.

[0263] Example 6

[0264] The FI method was used to evaluate the inhibitory effect of compounds on USP1 enzyme activity.

[0265] USP1 (R&D, U-555-050) enzyme solution (USP1 enzyme concentration is 0.03 nM) and Recombinant Human Ubiquitin Rhodamine 110 Protein (R&D, E-568-050) substrate solution (Recombinant Human Ubiquitin Rhodamine 110 Protein concentration is 450 nM) were prepared using reaction buffer (50 mM Tris-HCl, pH 7.8, 0.5 mM EDTA, 0.01% Tween-20, 0.01% BSA, 1 mM DTT). The 10 mM compound stock solution was diluted 11.11x with DMSO (Sigma, D5879), then 4x gradient dilution was performed, and then the compound was diluted 100x with reaction buffer (the final reaction system compound starting concentration was 3 μM, 4x dose dilution, a total of 8 concentration points). In a 384-well test plate (Coring, 3575), 5 μL of reaction buffer was added to each well of the blank group and the protein control group, and 5 μL of diluted compounds of each concentration were added to each well of the compound group. Then 5 μL of reaction buffer was added to each well of the blank group, and 5 μL of USP1 enzyme solution was added to each well of the protein control group and the compound group, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 10 minutes. Then 5 μL of Recombinant Human Ubiquitin Rhodamine 110 Protein substrate solution was added to each well of each group (at this time, the starting concentration of the compound gradient concentration in the compound group reaction system was 3 μM), centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 30 minutes. Finally, a high-throughput drug screening multifunctional microplate reader (TECAN Spark) was used to read the luminescent signal of the reaction system in the FlourescenIntensity mode to read the FI signal (ex485 / em535). IC was obtained using GraphPad Prism software. 50 Values ​​and nonlinear regression curve fitting.

[0266] The inhibition percentage (%) of each concentration of the compound is calculated based on the signals of the minimum fluorescence signal group (blank group) and the maximum fluorescence signal group (protein control group) contained in each test plate. The minimum fluorescence signal group has no added enzymes and compounds, and the others are consistent with the compound group. The fluorescence signal is the minimum and is set to 100% inhibition. The maximum fluorescence signal group has no added compounds, and the others are consistent with the compound group. The fluorescence signal is the maximum and is set to 0% inhibition. The inhibition rate of each compound concentration is calculated as follows: Inhibition rate % = {1-[(maximum luminescence signal group-luminescence signal of compound group) / (maximum luminescence signal group-minimum luminescence signal group)]}*100%. Finally, the four-parameter logistic dose-response equation is used to determine the compound concentration required for 50% inhibition, that is, IC 50 The results are shown in Table 1.

[0267] Table 1 USP1 inhibitory activity of compounds of the present invention

[0268] Compound <![CDATA[IC 50 (nM)]]> Compound <![CDATA[IC 50 (nM)]]> 1 ++++ 4 ++ 2 ++++ 5 +++ 3 ++++

[0269] USP1 IC 50 "+" indicates 150nM < IC 50 ≤200nM; "++" indicates 100nM<IC 50 ≤150nM;

[0270] “+++” indicates 50nM<IC 50 ≤100nM; “++++” indicates IC 50 ≤50nM.

[0271] As can be seen from Table 1, the compounds of the present invention have excellent USP1 inhibitory activity and can be used as drugs for preventing and / or improving and / or treating diseases related to this activity.

[0272] Example 7 Cell assay evaluation

[0273] BRCA1 was cultured in complete medium DMEM (Gibco, 11963092) / 10% FBS (Gibco, 10099141C) / 1% ITS (Gibco, 41400045) / 1% GSH (Sigma, G6013-5G). - / - MDA-MB-436 cell line (Nanjing Kebai Biotechnology Co., Ltd.) was cultured with complete medium DMEM (Gibco, 11963092) / 20% FBS (Gibco, 10099141C) to culture wild-type CAL-51 cell line (Nanjing Kebai Biotechnology Co., Ltd.) to evaluate the effects of compounds on BRCA1 - / -Selective inhibition of cell proliferation of MDA-MB-436 and CAL-51 cell lines. Day 0, on a 96-well cell culture plate (Corning, 3599), BRCA1 - / - 800 cells / 100 μL of MDA-MB-436 cells and 50 cells / 100 μL of wild-type CAL-51 cells were added to each well and placed at 37°C and 5% CO 2 Day 1: DMSO (Sigma, D5879) was used to dilute the 10 mM compound stock solution 2.5x, and then the compound was diluted 3x in a gradient, for a total of 10 concentration points. The starting concentration of wild-type CAL-51 cells was the first concentration point, and BRCA1 - / - The starting concentration of MDA-MB-436 cells was the third concentration point, and the compound was diluted 200x with the corresponding culture medium using a multichannel pipette (Rainin: Pipet-Lite XLS+) (the final starting concentration of wild-type CAL-51 cells in the culture medium was 20 μM, BRCA1 - / - The final starting concentration of MDA-MB-436 cells was 2.2 μM, all diluted 3x, and a total of 8 concentration points). Compounds of various concentrations were added to the cells as the compound group; the control group did not contain any compound, and the rest was the same as the compound group, with a final DMSO concentration of 0.5%. The compound group and the control group were incubated at 37°C and 5% CO 2 The cells were cultured in the incubator for 10 days. The blank group contained 100 μL of the corresponding culture medium. On Day 11, 20 μL of MTS (CellTiter A Queous One Solution Cell Proliferation Assay) (Promega, G3581), at 37°C, 5% CO 2 After culturing in the incubator for 2 hours, the cells were read using Tecan Spark (OD = 490 nM). The data were then analyzed using the data analysis software GraphPad Prism 8, using the equation "log (inhibitor) vs. normalized response--variable slope" (formula Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope))) to analyze the data and obtain the IC value of the compound 50 Where Y is the inhibition rate, X is the logarithmic value of the compound concentration, Top refers to the maximum response (inhibition rate when the compound concentration is the maximum), Bottom refers to the baseline response (inhibition rate when the compound concentration is 0), and Hill Slope refers to IC50 The slope of the curve, IC 50 The results are shown in Table 2.

[0274] Table 2 Inhibitory activity of the compounds of the present invention on MDA-MB-436 cells

[0275] Compound <![CDATA[IC 50 (nM)]]> Compound <![CDATA[IC 50 (nM)]]> 1 ++++ 4 +++ 2 ++++ 5 ++++ 3 ++++

[0276] IC 50 "+" indicates 150nM < IC 50 ≤200nM; "++" indicates 100nM<IC 50 ≤150nM; "+++"

[0277] Indicates 50nM<IC 50 ≤100nM; “++++” indicates IC 50 ≤50nM; “ / ” means not tested.

[0278] As shown in Table 2, the compounds of the present invention have an effect on BRCA1 - / - MDA-MB-436 cells have a good inhibitory effect.

[0279] Example 8 Evaluation of metabolic stability of liver microsomes

[0280] Experimental materials: Human liver microsomes (purchased from BIOIVT, catalog number: X008070) were used in the experiment;

[0281] Reagent preparation:

[0282] PBS: 0.1M KH 2 PO 4 and K 2 HPO 4 Buffer, pH 7.4.

[0283] MgCl 2 :Weigh a certain amount of MgCl 2 , 16 mM MgCl was prepared in PBS 2 Solution.

[0284] NADPH (Chinese name: reduced nicotinamide adenine dinucleotide phosphate, purchased from Sigma, catalog number: 481973-500mg): weigh a certain amount of NADPH and use 16mM MgCl 2 The solution was prepared to 4 mM NADPH, and the final incubation concentration was 1 mM.

[0285] Compounds: The test compounds were prepared to 4 μM in PBS, and the final incubation concentration was 1 μM.

[0286] Liver microsomes: Dilute liver microsomes to 1 mg / mL with PBS, and the final incubation concentration is 0.5 mg / mL.

[0287] Experimental steps:

[0288] Add the prepared test compound to the test tube, then add the prepared NADPH and mix well. Pre-incubate in a 37°C, 220rpm constant temperature incubator. After pre-incubation for 5 minutes, add the prepared liver microsomes to start the reaction, and perform duplicate operations. At 0min, 15min, 30min, 45min, and 60min, add a certain volume of ice acetonitrile solution containing internal standard to the corresponding tube to precipitate protein, vortex for 5min, then centrifuge at 4000rpm for 10min, and take the supernatant in a 96-well plate. Put it into LC-MS / MS for analysis. The concentration (peak area ratio) of the example compound is determined by LC-MS / MS, and the rate constant is obtained by plotting "Ln (compound residual amount %)" against "incubation time" in Excel, thereby calculating the half-life and intrinsic clearance of the drug, providing a basis for the prediction of the in vivo clearance rate.

[0289] Data Analysis:

[0290] CL int =(0.693 / t 1 / 2 , microsomes) × [incubation fluid volume (mL) / microsomal protein mass (mg)] × [microsomal protein mass (mg) / liver mass (g)] × [liver mass (g) / body weight (kg)] [1]

[0291] CL H =CL int ×f u ×Q h / (CL int ×f u +Q h )

[0292] In the formula, CL int --Intrinsic clearance (mL / min / kg); CL H --Hepatic clearance (mL / min / kg); f u --The unbound fraction of plasma proteins is 1; Q h -- Liver blood flow. See Table 3 for the results.

[0293] Table 3 Stability of human liver microsomes of the compounds of the present invention

[0294] Compound <![CDATA[t in HLM 1 / 2 min]]> Compound <![CDATA[t in HLM 1 / 2 min]]> 2 153 4 >240 3 112 5 238 Compound A 99.7

[0295] [1]Davies B, Morris T.Physiological parameters in laboratory animals and humans.Pharm Res.1993;10:1093-5.

[0296] As shown in Table 3, the stability of the compound of the present invention in human liver microsomes is better than that of the control compound A.

[0297] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof: in, X1 is selected from N or CR2; R2 is selected from H, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy; R1 is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 3-6 Cycloalkyl, -C 1-6 Alkyl-C 1-6 Alkoxy, C 2-6 Alkenyl or C 2-6 Alkynyl; L is selected from C(R3)(R4); R3 and R4 are each independently selected from H, deuterium, halogen, cyano, C 1-6 Alkyl or C 1-6 Alkoxy; or R3 and R4 are combined with the carbon atom to which they are attached to form C 3-6 Cycloalkyl; Ring A is selected from C 6-10 aryl or 5-10 membered heteroaryl, the 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, the C 6-10 The aryl group and the 5-10-membered heteroaryl group are each independently unsubstituted or substituted by one or more R b replace; B is selected from C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group, C 3-10 Cycloalkyl or C 3-10 The 5-10 membered heteroaryl and 4-10 membered heterocyclic group each independently contain 1-3 heteroatoms selected from N, O and S, and the C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group, C 3-10 Cycloalkyl, C 3-10 The cycloalkenyl groups are each independently unsubstituted or substituted with one or more R c replace; Each R b and R c are independently selected from the same or different halogen, cyano, hydroxyl, amino, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 4-7 membered heterocyclic group, -SeR k 、-C(O)NR i R j , The 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted with one or more R a replace; R5, R6, R7, R8, R9, R 10 , R 11 and R 12 are each independently selected from hydrogen, deuterium, amino, C 1-6 Alkyl, C 3-10 Cycloalkyl or 4-7 membered heterocyclic group, the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, the amino, C 1-6 Alkyl, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted with one or more R a replace; or R5 and R6 together with the P to which they are connected form a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O, S and P, and at least one heteroatom is P, and the 4-7 membered heterocyclic group is unsubstituted or substituted by one or more R a replace; or R 11 and R 12 The atoms to which they are attached together form a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 2-3 heteroatoms selected from N, O and S, and at least two heteroatoms are N and S, and the 4-7 membered heterocyclic group is unsubstituted or substituted by one or more R a replace; C is selected from -C(O)NR i R j , C 6-10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group, wherein the 5-10 membered heteroaryl and 4-10 membered heterocyclic group each independently contain 1-3 heteroatoms selected from N, O and S, and the C 6-10 The aryl group, the 5-10 membered heteroaryl group, and the 4-10 membered heterocyclic group are each independently unsubstituted or substituted with one or more R d replace; Each R d Each independently selected from the same or different halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl or 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted with one or more R a replace; Each R a are independently selected from the same or different halogen, cyano, =O, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl or 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted with one or more R e replace; Each R e are independently selected from the same or different deuterium, halogen, cyano, =O, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted with one or more R f replace; Each R f Each independently selected from the same or different halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S; Each R i , R j , R k are independently selected from the same or different hydrogen or C 1-6 alkyl.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof, characterized in that: R1 is selected from H, C 1-4 Alkyl, C 5-6 Alkyl, C 1-4 Haloalkyl, C 5-6 Haloalkyl, C 1-4 Deuterated alkyl, C 5-6 Deuterated alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-C 4-6 Alkoxy, -C 4-6 Alkyl-C 1-3 Alkoxy, -C 4-6 Alkyl-C 4-6 Alkoxy, C 2-4 Alkenyl, C 5-6 Alkenyl, C 2-4 Alkynyl, C 5-6 Alkynyl; Preferably, R1 is selected from H, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Deuterated alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkyl-C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl; Preferably, R1 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoroisopropyl, fluoro-n-butyl, fluoro-sec-butyl, fluoroisobutyl, fluoro-tert-butyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, deuterated n-butyl, deuterated sec-butyl, deuterated isobutyl, deuterated tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, vinyl, propenyl, butenyl, ethynyl, propynyl, butynyl; Preferably, R1 is selected from H, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, fluoroethyl, deuterated methyl, deuterated ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethyl, vinyl, propenyl, ethynyl, propynyl; Preferably, R1 is selected from H, methyl, ethyl, isopropyl, -CD3, -CF3, -CHF2, -CH2CH2F, cyclopropyl, methoxyethyl, vinyl, ethynyl.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof, characterized in that: Ring A is selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heteroaryl and 5-membered heteroaryl, 5-membered heteroaryl and 6-membered heteroaryl, 6-membered heteroaryl and 6-membered heteroaryl, phenyl and 5-membered heteroaryl or phenyl and 6-membered heteroaryl, the 5-membered heteroaryl and 6-membered heteroaryl each independently contain 1-3 heteroatoms selected from N, O and S, and the phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heteroaryl and 5-membered heteroaryl, 5-membered heteroaryl and 6-membered heteroaryl, 6-membered heteroaryl and 6-membered heteroaryl, phenyl and 5-membered heteroaryl, phenyl and 6-membered heteroaryl are each independently unsubstituted or substituted with one or more R b replace; Preferably, ring A is selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl or phenyl-5-membered heteroaryl, wherein the 5-membered heteroaryl and 6-membered heteroaryl each independently contain 1-3 heteroatoms selected from N, O and S, and the phenyl, 5-membered heteroaryl, 6-membered heteroaryl and phenyl-5-membered heteroaryl each independently are unsubstituted or substituted with one or more R b replace; Preferably, ring A is selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl or phenyl-5-membered heteroaryl, wherein the 5-membered heteroaryl and 6-membered heteroaryl each independently contain 1-2 N heteroatoms, and the phenyl, 5-membered heteroaryl, 6-membered heteroaryl and phenyl-5-membered heteroaryl each independently are unsubstituted or substituted with one or more R b replace; Preferably, ring A is selected from phenyl, pyridyl, pyrimidyl, pyrazolyl, imidazolyl, benzopyrazolyl or benzimidazolyl, wherein the phenyl, pyridyl, pyrimidyl, pyrazolyl, imidazolyl, benzopyrazolyl, benzimidazolyl are each independently unsubstituted or substituted with one or more R b replace; Preferably, ring A is selected from phenyl, pyridyl, pyrimidyl, pyrazolyl, imidazolyl or benzopyrazolyl, wherein the phenyl, pyridyl, pyrimidyl, pyrazolyl, imidazolyl and benzopyrazolyl are each independently unsubstituted or substituted with one or more R b replace; Preferably, ring A is selected from Each R b are independently selected from the same or different halogen, amino, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 4-7 membered heterocyclic group, -SeR k 、-C(O)NR i R j , The 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the amino, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted with one or more R a Replacement; R i , R j , R k Each independently selected from H or C 1-4 Alkyl; R5, R6, R7, R8, R 11 and R 12 Each independently selected from H or C 1-4 alkyl; Preferably, each R b are independently selected from the same or different halogen, amino, SH, C 1-4 Alkyl, C 5-6 Alkyl, C 1-4 Alkoxy, C 5-6 Alkoxy, C 3-8 Cycloalkyl, 4-7 membered heterocycloalkyl, -SeR k 、-C(O)NR i R j , The 4-7 membered heterocycloalkyl group contains 1-3 heteroatoms selected from N, O and S. 1-4 Alkyl, C 5-6 Alkyl, C 1-4 Alkoxy, C 5-6 Alkoxy, C 3-8 The cycloalkyl and 4-7 membered heterocycloalkyl groups are each independently unsubstituted or substituted with one or more R a Replacement; R i , R j , R k Each independently selected from H or C 1-4 Alkyl; R5, R6, R7, R8, R 11 and R 12 Each independently selected from H or C 1-4 alkyl; Preferably, each R b are independently selected from the same or different halogen, amino, SH, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, -SeR k 、-C(O)NR i R j , The 4-7 membered heterocycloalkyl group contains 1-2 heteroatoms selected from N, O and S. 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl and 4-7 membered heterocycloalkyl groups are each independently unsubstituted or substituted with one or more R a Replacement; R i , R j , R k Each independently selected from H or C 1-4 Alkyl; R5, R6, R7, R8, R 11 and R 12 Each independently selected from H or C 1-4 alkyl; Preferably, each R b each independently selected from the same or different F, Cl, Br, amino, SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-7 membered heterocycloalkyl, -SeR k 、-C(O)NR i R j , The 4-7 membered heterocycloalkyl contains 1 N heteroatom, and the amino, SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-7 membered heterocycloalkyl are each independently unsubstituted or substituted by one or more R a Replacement; R i , R j , R k are each independently selected from hydrogen, methyl, ethyl, n-propyl or isopropyl; R5, R6, R7, R8, R 11 and R 12 are each independently selected from hydrogen, methyl, ethyl, n-propyl or isopropyl; Preferably, each R b each independently selected from the same or different F, Cl, amino, SH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, azetidinyl, -SeR k 、-C(O)NR i R j , The amino, SH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, azetidinyl are each independently unsubstituted or substituted with one or more R a Replacement; R i , R j , R k are each independently selected from hydrogen, methyl or ethyl; R5, R6, R7, R8, R 11 and R 12 are each independently selected from hydrogen, methyl or ethyl; Preferably, each R b Each is independently selected from the same or different F, Cl, amino, SH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, azetidinyl, -SeCH3, The amino, SH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, azetidinyl are each independently unsubstituted or substituted with one or more R a replace; Each R a Each independently selected from the same or different halogen, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy; Preferably, each R a Each independently selected from the same or different halogen, hydroxyl, C 1-4 Alkyl or C 1-4 Alkoxy; Preferably, each R a each independently selected from the same or different F, Cl, Br, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy; Preferably, each R a Each independently selected from the same or different F, Cl, Br, hydroxy, methyl, ethyl, methoxy or ethoxy; Preferably, each R a Each independently selected from the same or different F, hydroxy, methyl or methoxy; Preferably, each R b Each is independently selected from the same or different F, Cl, amino, methyl-substituted amino, -SCH3, methyl, fluoromethyl, methoxy, fluoromethoxy, ethoxy, fluoroethoxy, hydroxy-substituted isopropyl, hydroxy-substituted cyclopropyl, methoxy-substituted ethoxy, isopropyl, isopropoxy, cyclopropyl, azetidinyl, -SeCH3, Preferably, each R b Each is independently selected from the same or different methyl, methoxy, cyclopropyl, isopropyl, ethoxy, isopropoxy, -SCH3, -SeCH3, Amino, F, Cl, -OCHF2, -OCF3, -CF3, Preferably, ring A is selected from 4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof, characterized in that: B is selected from C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl or C 3-10 The 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl groups each independently contain 1-3 heteroatoms selected from N, O and S. 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl or C 3-10 The cycloalkyl groups are each independently unsubstituted or substituted with one or more halogen groups which may be the same or different; Preferably, B is selected from C 2-4 Alkynyl, phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4-7-membered heterocycloalkyl or C 3-8 The 5-membered heteroaryl, 6-membered heteroaryl, and 4-7-membered heterocycloalkyl groups each independently contain 1-3 heteroatoms selected from N, O, and S. 2-4 Alkynyl, phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4-7-membered heterocycloalkyl, C 3-8 The cycloalkyl groups are each independently unsubstituted or substituted with one or more halogen groups which may be the same or different; Preferably, B is selected from C 2-4 Alkynyl, phenyl, 6-membered heteroaryl, 4-7-membered heterocycloalkyl, C 7-8 Cycloalkyl or C 3-6 The 6-membered heteroaryl and 4-7-membered heterocycloalkyl groups each independently contain 1-2 heteroatoms selected from N. 2-4 Alkynyl, phenyl, 6-membered heteroaryl, 4-7-membered heterocycloalkyl, C 3-6 Cycloalkyl, C 7-8 The cycloalkyl groups are each independently unsubstituted or substituted with one or more halogen groups which may be the same or different; Preferably, B is selected from ethynyl, propynyl, butynyl, phenyl, pyridyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, The propynyl, butynyl, phenyl, pyridyl, pyrimidyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl are each independently unsubstituted or substituted with one or more identical or different F, Cl or Br; Preferably, B is selected from ethynyl, phenyl, pyridyl, pyrimidinyl, cyclohexyl, piperidinyl, The phenyl, pyridyl, pyrimidyl, cyclohexyl, piperidyl are each independently unsubstituted or substituted by one or more identical or different F, Cl or Br; Preferably, B is selected from phenyl, pyridyl, pyrimidinyl, cyclohexyl, piperidinyl, fluoropiperidinyl, ethynyl, Preferably, B is selected from Ethylene, 5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof, characterized in that: C is selected from C 6-10 aryl or 5-10 membered heteroaryl, the 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, the C 6-10 The aryl group and the 5-10-membered heteroaryl group are each independently unsubstituted or substituted by one or more R d replace; Preferably, C is selected from phenyl, pyridyl, pyrimidyl, 5-membered heteroaryl, wherein the 5-membered heteroaryl contains 1-3 heteroatoms selected from N, O and S, and the phenyl, pyridyl, pyrimidyl, 5-membered heteroaryl are each independently unsubstituted or substituted by one or more R d replace; Preferably, C is selected from a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group contains 1-2 heteroatoms selected from N, O and S, and the 5-membered heteroaryl group is unsubstituted or substituted by one or more R d replace; Preferably, C is selected from imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, and the imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl groups, each of which is independently unsubstituted or substituted with one or more R d replace; Preferably, C is selected from imidazolyl, pyrazolyl, oxazolyl, thiazolyl, and the imidazolyl, pyrazolyl, oxazolyl, thiazolyl are each independently unsubstituted or substituted with one or more R d replace; Preferably, C is selected from Each R d are independently selected from the same or different halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl or 4-7 membered heterocyclic group, the 4-7 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 The cycloalkyl group and the 4-7 membered heterocyclic group are each independently unsubstituted or substituted with one or more R a replace; Preferably, each R d are independently selected from the same or different halogen, C 1-4 Alkyl, C 5-6 Alkyl, C 1-4 Alkoxy, C 5-6 Alkoxy, C 3-8 Cycloalkyl or 4-7 membered heterocycloalkyl, the 4-7 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O and S, the C 1-4 Alkyl, C 5-6 Alkyl, C 1-4 Alkoxy, C 5-6 Alkoxy, C 3-8 The cycloalkyl and 4-7 membered heterocycloalkyl groups are each independently unsubstituted or substituted with one or more R a replace; Preferably, each R d are independently selected from the same or different halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl, the 4-7 membered heterocycloalkyl contains 1 N heteroatom, the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl and 4-7 membered heterocycloalkyl groups are each independently unsubstituted or substituted with one or more R a replace; Preferably, each R d R is each independently selected from the same or different F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or azetidinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl are each independently unsubstituted or replaced by one or more R a replace; Preferably, each R d Each is independently selected from the same or different F, Cl, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl or azetidinyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, azetidinyl is each independently unsubstituted or substituted by one or more R a replace; Preferably, each R d Each is independently selected from the same or different Cl, methyl, ethyl, isopropyl, methoxy, cyclopropyl or azetidinyl, wherein the methyl, ethyl, methoxy, azetidinyl is each independently unsubstituted or substituted by one or more R a replace; Each R a are independently selected from the same or different halogen, =O or C 1-6 alkyl; Preferably, each R a are independently selected from the same or different halogen, =O or C 1-4 alkyl; Preferably, each R a Each is independently selected from the same or different F, Cl, Br, =O, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; Preferably, each R a Each is independently selected from the same or different F, =O or methyl; Preferably, each R d Each is independently selected from the same or different Cl, methyl, fluoromethyl, ethyl, fluoroethyl, isopropyl, methoxy, fluoromethoxy, cyclopropyl, Preferably, each R d Each independently selected from the same or different methyl, isopropyl, -CF3, -CHF2, Cyclopropyl, methoxy, Cl, or -OCF3; Preferably, each R d Each independently selected from the same or different methyl, isopropyl, -CF3, -CHF2, Cyclopropyl, methoxy, Cl or Most preferably, C is selected from 6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof, selected from the following structures: in, The definitions of ring A, R1, L, B and C are as shown in claims 1-5; Further, Formula II is selected from the following structures: Among them, R1, L, R b , R d and B are as defined in claims 1-5.

7. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, or deuterated compound thereof, selected from the following structures: in, The definitions of ring A, R1, L, B and C are as shown in claims 1-5; Further, Formula III is selected from the following structures: Among them, R1, L, R b , R d and B are as defined in claims 1-5.

8. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, wherein the compound is selected from the following structures:

9. A pharmaceutical composition, characterized in that: Comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound thereof, and optionally a pharmaceutically acceptable carrier and / or adjuvant and / or diluent.

10. Use of the compound according to any one of claims 1 to 8 or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, cocrystal, hydrate, solvate, metabolite, prodrug, deuterated compound, or the pharmaceutical composition according to claim 9 in the preparation of a medicament for preventing and / or treating USP1-mediated diseases; Preferably, the USP1-mediated disease is a tumor or cancer; Preferably, the USP1-mediated disease refers to a USP1-mediated related disease with HR deficiency; Preferably, the USP1-mediated disease refers to cancer or tumor with HR deficiency.

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