Compounds as USP1 inhibitors

Abstract

The invention provides a compound. Specifically, the invention provides a compound with a structure as shown in a formula (I), or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate and a solvate of the compound. The compound can effectively inhibit USP1, and is used for treating or preventing diseases or symptoms related to the activity or expression quantity of USP1. # imgabs0 #

Description

Compounds as USP1 inhibitors Technical Field

[0001] The present invention relates to the field of medicinal chemistry; specifically, the present invention relates to a novel compound, a synthesis method thereof, and its use as a USP1 inhibitor in the preparation of drugs for treating various diseases such as tumors. Background Art

[0002] Ubiquitination, the covalent attachment of ubiquitin molecules to target proteins, is one of the most common post-translational modifications of proteins. Ubiquitin is a small 76-amino acid protein that is ubiquitinated in all eukaryotic cells and has a highly conserved sequence. There are multiple types of ubiquitination, including monoubiquitination, polyubiquitination, and polyubiquitination. Ubiquitination chains vary in type, such as those linked through Lys6, Lys11, Lys27, Lys33, Lys48, and Lys63. Different ubiquitination types regulate distinct functions. For example, proteins with polyubiquitin chains linked to Lys48 are typically degraded by the proteasome, while monoubiquitination or polyubiquitination linked to other lysine residues is often involved in cell cycle regulation, DNA damage repair, transcription, immune response, and endocytosis.

[0003] Ubiquitination is a reversible post-translational modification of proteins. Deubiquitinating enzymes can reverse ubiquitination by hydrolyzing peptide or isopeptide bonds between ubiquitin molecules or between ubiquitin and substrate proteins. USP1 (Ubiquitin-specific protease 1) is a deubiquitinating enzyme that is primarily involved in regulating DNA damage repair processes, including translesion synthesis (TLS) and the Fanconi anemia (FA) pathway. PCNA plays a key role in translesion DNA replication. PCNA is monoubiquitinated by RAD6 and RAD18 in response to replication fork stalling. Monoubiquitinated PCNA allows the recruitment of TLS polymerases, allowing replication to bypass DNA damage. Fanconi anemia is a rare autosomal recessive disorder. Defects in key genes in the Fanconi anemia signaling pathway lead to defects in the cell's DNA interstrand cross-link repair function. Fifteen FA genes have been identified, eight of which (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, and FANCM) encode proteins that form the FA core complex, which monoubiquitinates FANCD2 and FANCI, recruiting the intrachain cross-link repair complex. USP1 interacts with UAF1 to form a complex that deubiquitinates. The USP1 / UAF1 complex regulates DNA damage repair by deubiquitinating PCNA, FANCD2, and FANCI. Inhibiting USP1 enzymatic activity can significantly suppress the growth of tumor cells harboring BRCA mutations or other homologous recombination repair defects. Therefore, USP1 inhibitors hold broad anti-tumor potential.

[0004] Summary of the Invention

[0005] The purpose of the present invention is to provide a new type of USP1 inhibitors.

[0006] The first aspect of the present invention provides a compound having a structure shown in the following formula (I), or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, or solvate thereof:

[0007] In formula (I):

[0008] B is selected from Formula (Ia) or Formula (Ib):

[0009] represents the site where A in the compound of formula (Ia) or formula (Ib) is connected to the compound of formula (I); represents the site of attachment of the compound of formula (Ia) or (Ib) to the benzene ring in the compound of formula (I);

[0010] Each R 1 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, CN; m is selected from 0, 1, or 2;

[0011] Each R 2 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2- 4-alkynyl, CN; n is selected from 0, 1, 2, 3, or 4;

[0012] R 3 and R 4 are each independently selected from hydrogen, halogen, C 1-4 Alkyl; or R 3 and R 4 Together with the carbon atom to which it is attached, they form a 3- to 6-membered ring structure, which optionally contains 0 or 1 heteroatom selected from N, O, and S;

[0013] Each R 5 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2- 4-alkynyl, CN; p is selected from 0, 1, or 2;

[0014] Each R 6 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl-C 2-4 Alkynyl, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyl-C 2-4 Alkynyl, CN, OR f SR f NR d R d 、C(O)R g 、C(O)OR f , or S(O)2R g q is selected from 0, 1, 2, or 3;

[0015] A is selected from Formula (Ic), Formula (Id), Formula (Ie), Formula (If), or Formula (Ig):

[0016] represents the site at which B is linked to the compound of formula (Ic), formula (Id), formula (Ie), formula (If), or formula (Ig);

[0017] Indicates a single bond or a double bond;

[0018] Each R a are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 2-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, CN, C(O)R g 、C(O)OR f 、C(O)NR d R d , or S(O)2NR d R d ; R a The alkyl, cycloalkyl, 3- to 8-membered heterocyclic, aryl and heteroaryl groups are optionally substituted by one or more groups selected from the group consisting of halogen, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, CN, OR f SR f NR d R d 、C(O)R g 、C(O)OR f 、OC(O)R g 、C(O)NR d R d NR d C(O)R g NR d C(O)NR d R d 、OC(O)NR d R d NR d C(O)OR f 、OC(O)OR f 、S(O)2NR d R d NR d S(O)2R g , or NR d S(O)2NRd R d ; or R a The cycloalkyl and 3- to 8-membered heterocyclyl groups are optionally substituted by =T, wherein T is selected from O or CR m R n ; R m and R n are each independently selected from hydrogen, halogen, or C 1-4 alkyl;

[0019] Each R b are each independently selected from hydrogen, halogen, C 1-4 Alkyl; or two R b The carbon atoms connected to it together form C 3-6 Cycloalkyl; each k is independently selected from 0, 1, 2, or 3;

[0020] R c Selected from hydrogen, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 2-4 Alkynyl, CN, C(O)R g 、C(O)OR f 、C(O)NR d R d The alkyl, alkenyl or alkynyl group is optionally substituted by one or more groups selected from the group consisting of halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, CN, OR f SR f NR d R d 、C(O)R g 、C(O)OR f 、OC(O)R g 、C(O)NR d R d NR d C(O)R g 、S(O)2NR d R d , or NR d S(O)2R g ;

[0021] Each R d are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 alkyl halide;

[0022] Each R d’are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, hydroxy, C 1-4 alkoxy, or CN; each t is independently selected from 0, 1, 2, 3, or 4;

[0023] k 1 、k 2 、k 3 , and k 4 Each independently selected from 0, 1, 2, 3, 4 or 5;

[0024] D is selected from chemical bond, O, NR e , or CR b R b ; Among them, R e Selected from hydrogen or C 1-4 Alkyl; R b The definition of is as above;

[0025] M is selected from O or CR h R i ; Among them, R h and R i are each independently selected from hydrogen, halogen, or C 1-4 Alkyl; said alkyl is optionally substituted by one or more groups selected from the group consisting of halogen, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl, CN, OR f SR f NR d R d 、C(O)R g 、C(O)OR f 、OC(O)R g 、C(O)NR d R d NR d C(O)R g NR d C(O)NR d R d 、OC(O)NR d R d NR d C(O)OR f 、OC(O)OR f 、S(O)2NR d R d NR d S(O)2R g , or NR d S(O)2NR d Rd ; or R h and R i Together with the carbon atom to which it is attached, it forms a 3- to 8-membered ring structure, which optionally contains 0, 1, or 2 heteroatoms selected from N, O, and S;

[0026] X 1 、X 2 、X 3 、X 4 , and X 5 Each independently selected from N or CR k ; The prerequisite is that X 1 、X 2 、X 3 、X 4 , and X 5 At most two are selected from N; each R k are each independently selected from hydrogen, halogen, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, CN, OR f SR f NR d R d 、C(O)R g , or C(O)OR f ;

[0027] The above R d are each independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 cycloalkyl, or 3- to 6-membered heterocyclic group; each R f are each independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, or heteroaryl; each R g are each independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, aryl, or heteroaryl;

[0028] wherein each of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, cyclic structure, aryl and heteroaryl groups is optionally and independently substituted with 1-3 substituents each independently selected from the group consisting of halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C2-4 Alkynyl, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, CN, NO2, OR f SR f NR d R d 、C(O)R g 、C(O)OR f 、C(O)NR d R d NR d C(O)R g 、S(O)2R g , or NR d S(O)2R g , the prerequisite is that the chemical structure formed is stable and meaningful; among them, R d 、R f , and R g The definition of is as above;

[0029] Unless otherwise specified, the above-mentioned aryl group is an aromatic group containing 6 to 12 carbon atoms; the heteroaryl group is a 5- to 15-membered heteroaromatic group; and the cyclic structure is a saturated or unsaturated cyclic group containing or not containing heteroatoms.

[0030] In another preferred embodiment, the formula (I) is formula (IIa) or formula (IIb):

[0031] The definitions of the groups in formula (IIa) or (IIb) are as described above.

[0032] In another preferred embodiment, the formula (I) is formula (IIc) or formula (IId):

[0033] Each R a are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 2-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, CN, C(O)R g 、C(O)OR f , or C(O)NR d R d ; R a The alkyl, cycloalkyl, 3- to 8-membered heterocyclic, aryl and heteroaryl groups are optionally substituted by one or more groups selected from the group consisting of halogen, C 2-4 Alkenyl, C 2-4Halogenated alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, CN, OR f SR f NR d R d 、C(O)R g 、C(O)OR f 、OC(O)R g 、C(O)NR d R d NR d C(O)R g , or NR d S(O)2R g ; or R a The cycloalkyl and 3- to 8-membered heterocyclyl groups are optionally substituted by =T, wherein T is selected from CR m R n ; R m and R n are each independently selected from hydrogen, halogen, or C 1-4 alkyl;

[0034] R d 、R f , and R g The definition of is as described above.

[0035] In another preferred embodiment, the formula (I) is formula (IIe) or formula (IIf):

[0036] Each R a are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 2-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 2- 4-Alkynyl, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, CN, C(O)R g 、C(O)OR f , or C(O)NR d R d ; R a The alkyl, cycloalkyl, 3- to 8-membered heterocyclic, aryl and heteroaryl groups are optionally substituted by one or more groups selected from the group consisting of halogen, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, CN, OR f NR d R d ; or R aThe cycloalkyl and 3- to 8-membered heterocyclyl groups are optionally substituted by =T, wherein T is selected from CR m R n ; R m and R n are each independently selected from hydrogen, halogen, or C 1-4 alkyl;

[0037] R d 、R f , and R g The definition of is as described above.

[0038] In another preferred embodiment, each R in the formula (IIe) or formula (IIf) a are each independently a group selected from the following group:

[0039] In another preferred embodiment, the formula (I) is formula (IIIa) or formula (IIIb):

[0040] Each R a are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 2-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, CN, C(O)R g 、C(O)OR f , or C(O)NR d R d ; R a The alkyl, cycloalkyl, 3- to 8-membered heterocyclic, aryl and heteroaryl groups are optionally substituted by one or more groups selected from the group consisting of halogen, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, CN, OR f SR f NR d R d 、C(O)R g 、C(O)OR f 、OC(O)R g 、C(O)NR d R d NR d C(O)R g , or NR d S(O)2R g; or R a The cycloalkyl and 3- to 8-membered heterocyclyl groups are optionally substituted by =T, wherein T is selected from CR m R n ; R m and R n are each independently selected from hydrogen, halogen, or C 1-4 alkyl;

[0041] R d 、R f , and R g The definition of is as described above.

[0042] In another preferred embodiment, each R in the formula (IIIa) or formula (IIIb) a are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 2-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, CN, C(O)R g 、C(O)OR f , or C(O)NR d R d ; R a The alkyl, cycloalkyl, 3- to 8-membered heterocyclic, aryl and heteroaryl groups are optionally substituted by one or more groups selected from the group consisting of halogen, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, CN, OR f NR d R d ; or R a The cycloalkyl and 3- to 8-membered heterocyclyl groups are optionally substituted by =T, wherein T is selected from CR m R n ; R m and R n are each independently selected from hydrogen, halogen, or C 1-4 alkyl;

[0043] R d 、R f , and R g The definition of is as described above.

[0044] In another preferred embodiment, each R in the formula (IIIa) or formula (IIIb) a Each independently selected from the group consisting of:

[0045] In another preferred embodiment, the formula (I) is formula (IVa) or formula (IVb):

[0046] The definitions of the various groups in formula (IVa) or formula (IVb) are as described above.

[0047] In another preferred embodiment, the formula (I) is formula (V):

[0048] R c Selected from halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, CN, C(O)R g 、C(O)OR f 、C(O)NR d R d The alkyl, alkenyl or alkynyl group is optionally substituted by one or more groups selected from the group consisting of halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, CN, OR f SR f NR d R d 、C(O)R g 、C(O)OR f 、OC(O)R g 、C(O)NR d R d NR d C(O)R g , or NR d S(O)2R g ;

[0049] k 1 Selected from 1, 2, 3, or 4;

[0050] R d’ , t are defined as above;

[0051] R d 、R f , and R g The definition of is as described above.

[0052] In another preferred embodiment, the formula (I) is formula (VIa) or formula (VIb):

[0053] The definitions of the various groups in formula (VIa) or formula (VIb) are as described above.

[0054] In another preferred embodiment, the formula (I) is formula (VIIa) or formula (VIIb):

[0055] The definitions of the respective groups in formula (VIIa) or formula (VIIb) are as described above.

[0056] In another preferred embodiment, the formula (I) is formula (VIIIa) or formula (VIIIb):

[0057] X 1 、X 2 、X 3 、X 4 , and X 5 Each independently selected from N or CR k ; The prerequisite is that X 1 、X 2 、X 3 、X 4 , and X 5 At most two are selected from N; each R k are each independently selected from hydrogen, halogen, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, CN, OR f SR f NR d R d 、C(O)R g , or C(O)OR f ;

[0058] R d 、R f , and R g The definition of is as described above.

[0059] In another preferred embodiment, the compound is selected from the following group:

[0060] “*” indicates a chiral center.

[0061] The second aspect of the present invention provides a pharmaceutical composition comprising the compound described in the first aspect of the present invention, or its optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, solvates, and pharmaceutically acceptable carriers.

[0062] In a second aspect, the present invention provides a use of the compound described in the first aspect of the present invention, or its optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, or solvates, for preparing a pharmaceutical composition for treating diseases, disorders, or conditions associated with USP1 activity or expression.

[0063] In another preferred embodiment, the disease, disorder or condition is selected from the following group: breast cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, colon cancer, colorectal cancer, thyroid cancer, embryonal rhabdomyosarcoma, cutaneous granular cell tumor, melanoma, liver cancer, rectal cancer, bladder cancer, pharyngeal cancer, pancreatic cancer, prostate cancer, glioma, ovarian cancer, endometrial cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, skin cancer, gastric cancer, mesothelioma, osteosarcoma, acute myeloid leukemia, myelofibrosis, B cell lymphoma, T cell lymphoma, monocytic leukemia, hypereosinophilic syndrome, multiple myeloma and other solid tumors and blood tumors. DETAILED DESCRIPTION

[0064] After extensive and in-depth research, the present inventors unexpectedly discovered a class of novel USP1 inhibitors, as well as their preparation methods and uses. These compounds can be used to treat various diseases associated with the activity of USP1. Based on these findings, the present invention was completed.

[0065] the term

[0066] Unless otherwise specified, "or" mentioned in this document has the same meaning as "and / or" (referring to "or" and "and").

[0067] Unless otherwise specified, in all compounds of the present invention, each chiral carbon atom (chiral center) may be optionally in the R configuration or the S configuration, or a mixture of the R and S configurations.

[0068] As used herein, the term "alkyl" refers to a straight-chain (i.e., unbranched) or branched saturated hydrocarbon group containing only carbon atoms, or a combination of straight-chain and branched hydrocarbon groups. 1-10 ), it means that the alkyl group contains 1 to 10 carbon atoms. For example, C 1-8 The alkyl group refers to an alkyl group containing 1 to 8 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.

[0069] As used herein, the term "alkenyl" when used alone or as part of another substituent refers to a straight or branched carbon chain group having at least one carbon-carbon double bond. Alkenyl groups can be substituted or unsubstituted. When the number of carbon atoms in the alkenyl group is limited (e.g., C2-8 ), it means that the alkenyl group contains 2 to 8 carbon atoms. For example, C 2-8 Alkenyl refers to an alkenyl group containing 2 to 8 carbon atoms, including ethenyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or similar groups.

[0070] As used herein, the term "alkynyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond, either alone or as part of another substituent. The alkynyl group may be straight-chain or branched, or a combination thereof. 2-8 When the term "alkynyl" is used, it means that the alkynyl contains 2 to 8 carbon atoms. 2-8 The term "alkynyl" refers to a straight or branched chain alkynyl group having 2 to 8 carbon atoms, including ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, tert-butynyl, or similar groups.

[0071] As used herein, the term "cycloalkyl" refers to a saturated or partially saturated ring, bicyclic or polycyclic (fused, bridged or spiro) ring system group when used alone or as part of another substituent. 3-10 ) refers to a cycloalkyl group containing 3 to 10 carbon atoms. In some preferred embodiments, the term "C 3-8 "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or bicyclic alkyl group having 3-8 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or similar groups. "Spirocycloalkyl" refers to a bicyclic or polycyclic group in which the monocyclic rings share a carbon atom (called a spiro atom), which may contain one or more double bonds, but no ring has a completely conjugated π electron system. "Fused cycloalkyl" refers to a full-carbon bicyclic or polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. "Bridged cycloalkyl" refers to a full-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. The atoms contained in the cycloalkyl group are all carbon atoms. The following are some examples of cycloalkyl groups, and the present invention is not limited to the following cycloalkyl groups.

[0072] Unless otherwise stated, the following terms used in the specification and claims have the following meanings. "Aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group with a conjugated π electron system, such as phenyl and naphthyl. The aryl ring can be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent must be on a carbon atom on the ring with a conjugated π electron system. Aryl groups can be substituted or unsubstituted. The following are some examples of aryl groups, and the present invention is not limited to the aryl groups described below.

[0073] "Heteroaryl" refers to a monocyclic or polycyclic group having aromaticity containing one or more heteroatoms (selectively selected from nitrogen, oxygen, and sulfur), or a polycyclic group formed by condensing a heterocyclic group (containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur) with an aryl group, wherein the attachment point is located on the aryl group. The heteroaryl group may be optionally substituted or unsubstituted. The following are some examples of heteroaryl groups, and the present invention is not limited to the following heteroaryl groups.

[0074] "Heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl. Polycyclic heterocyclyls refer to heterocyclyls including spirocyclic, fused, and bridged rings. "Spirocyclic heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares an atom (called a spiro atom) with the other rings in the system, in which one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. "Fused-ring heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with the other rings in the system, in which one or more rings may contain one or more double bonds, but in which no ring has a completely conjugated pi-electron system, and in which one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. "Bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. These may contain one or more double bonds, but no ring has a completely conjugated pi-electron system, and one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon. If a heterocyclic group contains both saturated and aromatic rings (for example, a saturated ring and an aromatic ring are fused together), the point of attachment to the parent group must be on the saturated ring. Note: When the point of attachment to the parent group is on the aromatic ring, it is called a heteroaryl group, not a heterocyclic group. The following are some examples of heterocyclic groups, and the present invention is not limited to the following heterocyclic groups.

[0075] As used herein, the term "halogen," by itself or as part of another substituent, refers to F, Cl, Br, and I.

[0076] As used herein, the term "substituted" (with or without the "arbitrarily" modifier) ​​refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent. The specific substituent is the substituent described accordingly in the preceding text, or the substituent appearing in the examples. Unless otherwise specified, an arbitrarily substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position. A cyclic substituent, such as a heterocyclic group, may be connected to another ring, such as a cycloalkyl group, to form a spirobicyclic system, i.e., the two rings have a common carbon atom. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible. The substituents are, for example (but not limited to): C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3- 8-cycloalkyl, 3- to 12-membered heterocyclic group, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C 1-8 Aldehyde, C 2-10 Acyl, C 2-10 Ester group, amino group.

[0077] For the sake of convenience and in accordance with common understanding, the term "arbitrary substitution" or "optionally substituted" only applies to sites that can be substituted by substituents, and does not include those substitutions that are chemically unfeasible.

[0078] As used herein, unless otherwise specified, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for contact with the tissues of a subject (e.g., a human) without producing undue side effects. In some embodiments, a pharmaceutically acceptable salt of a compound of the present invention includes a salt of the compound of the present invention having an acidic group (e.g., potassium salt, sodium salt, magnesium salt, calcium salt) or a salt of the compound of the present invention having a basic group (e.g., sulfate, hydrochloride, phosphate, nitrate, carbonate).

[0079] use:

[0080] The present invention provides a class of compounds of formula (I), or their deuterated derivatives, their salts, isomers (enantiomers or diastereomers, if any), hydrates, pharmaceutically acceptable carriers or excipients for use in inhibiting USP1.

[0081] The compound of the present invention is useful as a USP1 inhibitor.

[0082] The present invention is a single inhibitor of USP1, which modulates the activity of USP1 to prevent, alleviate, or cure diseases, including but not limited to breast cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, colon cancer, colorectal cancer, thyroid cancer, embryonal rhabdomyosarcoma, cutaneous granular cell tumor, melanoma, liver cancer, rectal cancer, bladder cancer, pharyngeal cancer, pancreatic cancer, prostate cancer, glioma, ovarian cancer, endometrial cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, skin cancer, gastric cancer, mesothelioma, osteosarcoma, acute myeloid leukemia, myelofibrosis, B-cell lymphoma, T-cell lymphoma, monocytic leukemia, hypereosinophilic syndrome, multiple myeloma, and other solid tumors and hematological tumors.

[0083] The compounds of the present invention and their deuterated derivatives, as well as pharmaceutically acceptable salts or isomers thereof (if present), or hydrates thereof, and / or compositions thereof, can be formulated with pharmaceutically acceptable excipients or carriers. The resulting compositions can be administered to mammals, such as men, women, and animals, in vivo for the treatment of conditions, symptoms, and diseases. The compositions can be in the form of tablets, pills, suspensions, solutions, emulsions, capsules, aerosols, sterile injectable solutions, sterile powders, and the like. In some embodiments, pharmaceutically acceptable excipients include microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, mannitol, hydroxypropyl-β-cyclodextrin, β-cyclodextrin (increased), glycine, disintegrants (such as starch, cross-linked sodium carboxymethyl cellulose, complex silicates, and high molecular weight polyethylene glycols), granulation binders (such as polyvinyl pyrrolidone, sucrose, gelatin, and gum arabic), and lubricants (such as magnesium stearate, glycerol, and talc). In a preferred embodiment, the pharmaceutical composition is a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, and powders. The amount of the compound of the present invention or the pharmaceutical composition administered to the patient is not fixed and is usually administered in a pharmaceutically effective amount. At the same time, the amount of the compound actually administered can be determined by the physician based on actual conditions, including the condition being treated, the selected route of administration, the actual compound administered, the individual condition of the patient, etc. The dosage of the compound of the present invention depends on the specific use of the treatment, the mode of administration, the patient's condition, and the physician's judgment. The ratio or concentration of the compound of the present invention in the pharmaceutical composition depends on various factors, including dosage, physicochemical properties, route of administration, etc.

[0084] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form new or preferred technical solutions.

[0085] Pharmaceutical compositions and methods of administration

[0086] Since the compounds of the present invention have excellent inhibitory activity against USP1, the compounds of the present invention and their various crystalline forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent, and alleviate diseases related to USP1 activity or expression.

[0087] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 5-200 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0088] "Pharmaceutically acceptable carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0089] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0090] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0091] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0092] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0093] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0094] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0095] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0096] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0097] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0098] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 5 to 500 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0099] The main advantages of the present invention include:

[0100] 1. Provided is a compound as shown in formula I.

[0101] 2. Provided is a novel USP1 inhibitor, and its preparation and use. The inhibitor can inhibit the activity of USP1 at extremely low concentrations.

[0102] 3. Provides a USP1 inhibitor with good oral absorption.

[0103] 4. Provided is a pharmaceutical composition for treating diseases associated with USP1 activity.

[0104] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0105] Some representative compounds of the present invention can be prepared by the following synthetic methods. In the following reaction formulas, the reagents and conditions of each step can be selected from conventional reagents or conditions for such preparation methods in the art. After the structure of the compound of the present invention is disclosed, the above selection can be made by those skilled in the art based on the knowledge in the art.

[0106] abbreviation

[0107] Boc = tert-butyloxycarbonyl

[0108] CN = cyano

[0109] m-CPBA=3-chloroperoxybenzoic acid

[0110] DCM = dichloromethane

[0111] DIPEA or DIEA=N,N-diisopropylethylamine

[0112] DIBAL-H = Diisobutylaluminum hydride

[0113] DMF=N,N-dimethylformamide

[0114] DMSO = dimethyl sulfoxide

[0115] DDQ = 2,3-dichloro-5,6-dicyanobenzoquinone

[0116] EtOAc or EA=ethyl acetate

[0117] Et = Ethyl

[0118] HATU = N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate)

[0119] LiHMDS = Lithium Bis(trimethylsilyl)amide

[0120] Me = methyl

[0121] MeOH = methanol

[0122] NMP = N-methylpyrrolidone

[0123] Ph = phenyl

[0124] PMB = p-methoxybenzyl

[0125] Pd(PPh3)2Cl2=Bistriphenylphosphine palladium dichloride

[0126] PhNTf2=phenylbis(trifluoromethanesulfonyl)imide

[0127] SOCl2=thionyl chloride

[0128] TIPS = triisopropylsilyl

[0129] TMS = trimethylsilyl

[0130] TBAF = Tetra-n-butylammonium fluoride

[0131] TEA = triethylamine

[0132] TFA = trifluoroacetic acid

[0133] THF = Tetrahydrofuran

[0134] TsCl = p-Toluenesulfonyl chloride

[0135] TBDPSCl = tert-butyldiphenylsilyl chloride

[0136] Example 1: Preparation of Compound 1

[0137] Compound 1-a (25 mg, 0.05 mmol) (the synthesis of common intermediate 1-a can be prepared by referring to the method in patent WO2020 / 132269Al) and compound 1-b (27 mg, 0.10 mmol) were dissolved in DMF (1 mL) solution, and then cesium carbonate (49 mg, 0.15 mmol) was added. The reaction mixture was heated and stirred at 90 ° C overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by preparative thin layer plate separation (ethyl acetate: petroleum ether = 1: 1) to give white solid compound 1 (3 mg, yield 10%). 1 H NMR (500MHz, DMSO-d6) δ9.51(s,1H),8.71(s,1H),8.53(s,1H),8.38(d,J=1.0Hz,1H),7.53(d,J=8.3Hz,2H),7.42(d,J=8.3Hz, 2H),5.79(s,2H),4.95-4.87(m,1H),3.85(s,3H),3.20-3.15(m,4H),1.68-1.63(m,1H),1.08-1.04(m,2H),0.87-0.84(m,2H). MS m / z 595.2[M+H] + .

[0138] Example 2: Preparation of Compound 2

[0139] 3,3-Difluorocyclobutanol (200 mg, 1.85 mmol) and p-toluenesulfonyl chloride (371 mg, 1.94 mmol) were dissolved in dichloromethane (10 mL). Sodium hydroxide (148 mg, 3.70 mmol, 60%) was added under ice-cooling. The reaction mixture was stirred for 0.5 hours. The reaction mixture was quenched with saturated ammonium chloride, and the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:20) to obtain compound 2-b (399 mg, 82% yield) as a colorless oil.

[0140] Compound 1-a (24 mg, 0.05 mmol) and compound 2-b (26 mg, 0.10 mmol) were dissolved in DMF (1 mL), and cesium carbonate (49 mg, 0.15 mmol) was added. The reaction mixture was heated and stirred at 90°C overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by preparative thin-layer plate separation (ethyl acetate:petroleum ether = 1:1) to obtain compound 2 as a white solid (11 mg, 41% yield). 1 H NMR(500MHz,DMSO-d6)δ9.51(s,1H),8.71(s,1H),8.53(s,1H),8.50(s,1H), 7.60(d,J=8.2Hz,2H),7.45(d,J=8.2Hz,2H),7.06(d,J=14.1Hz,1H),6.98-6. 88(m,1H),5.80(s,2H),4.94(dd,J=17.0,3.2Hz,1H),4.79(dd,J=50.6,3.2H z,1H),3.85(s,3H),1.68-1.62(m,1H),1.08-1.03(m,2H),0.89-0.81(m,2H). MS m / z 563.2[M+H] + .

[0141] Example 3: Preparation of Compound 3

[0142] Compound 2 (5 mg, 0.008 mmol) was dissolved in a solution of hydrogen fluoride in pyridine (0.5 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution, and the mixture was extracted with methyl tert-butyl ether (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer plate separation (ethyl acetate: petroleum ether = 1:1) to give compound 3 (3 mg, 58% yield) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ9.51(s,1H),8.71(s,1H),8.55-8.51(m,2H),7.62-7.58(m,2H),7.49-7.43(m,2H),7.21-7.17(m,1H), 6.67-6.60(m,1H),5.80(s,2H),3.85(s,3H),1.78(t,J=18.7Hz,3H),1.70-1.63(m,1H),1.07-1.03(m,2H),0.87-0.83(m,2H). MS m / z 583.2[M+H] + .

[0143] Example 4: Preparation of Compound 4

[0144] Compound 1-a (50 mg, 0.10 mmol), methyl 2,4-dibromobutyrate (28 mg, 0.11 mmol), and cesium carbonate (99 mg, 0.30 mmol) were dissolved in DMF (2 mL). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by preparative thin-layer plate (ethyl acetate: petroleum ether = 1:1) to give compound 4-a (31 mg, yield 50%) as a white solid. MS m / z 591.2 [M+H] + .

[0145] Compound 4-a (31 mg, 0.05 mmol) was dissolved in tetrahydrofuran (3 mL), and lithium aluminum hydride (4 mg, 0.10 mmol) was slowly added under ice bath. The reaction solution was stirred at room temperature for 0.5 hours. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate (3×10 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by preparative thin layer plate (ethyl acetate: petroleum ether = 1:1) to give a white solid compound 4-b (29 mg, yield 98%). MS m / z 565.2 [M+H] + .

[0146] Compound 4-b (29 mg, 0.05 mmol) was dissolved in dichloromethane (3 mL), and 2,3-dichloro-5,6-dicyanobenzoquinone (23 mg, 0.10 mmol) was added. The reaction was stirred at 50°C for 1 hour. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The product was purified by preparative thin-layer plate separation to obtain compound 4-c (11 mg, 38% yield) as a white solid. MS m / z 563.2 [M+H] + .

[0147] Compound 4-c (8 mg, 0.01 mmol) and p-toluenesulfonyl chloride (3 mg, 0.01 mmol) were dissolved in dichloromethane (2 mL). Sodium hydroxide (1.1 mg, 0.03 mmol, 60%) was added under ice-cooling. The reaction mixture was stirred for 0.5 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Compound 4-d (9 mg, 88% yield) was obtained by separation and purification using preparative thin-layer plate. MS m / z 717.2 [M+H] + .

[0148] Compound 4-d (9 mg, 0.01 mmol) was dissolved in tetrahydrofuran (2 mL), and a solution of tetrabutylammonium fluoride in tetrahydrofuran (0.2 mL, 1 M) was added dropwise. The reaction system was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and purified by preparative thin-layer plate to afford compound 4 (4 mg, 56% yield) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ9.52(s,1H),8.71(s,1H),8.53(s,1H),8.02(d,J=0.8Hz,1H),7.75-7.72(m,2H),7.39-7.36(m,2H),5.79(s,2H) ,4.68(s,1H),4.58(s,1H),3.85(s,3H),1.68-1.63(m,1H),1.20-1.17(m,2H),1.16-1.13(m,2H),1.08-1.04(m,2H),0.87-0.84(m,2H). MS m / z 565.1[M+H] + .

[0149] Example 5: Preparation of Compounds 6 and 7

[0150] 3-(Benzyloxy)-1-cyclobutanone (3.0 g, 17.02 mmol) and triphenylphosphine (22.3 g, 85.12 mmol) were dissolved in acetonitrile (50 mL). Carbon tetrabromide (14.1 g, 42.56 mmol) was added under ice-cooling. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the reaction system was filtered, and the filtrate was concentrated under reduced pressure. The product was then purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:10) to afford compound 6-b (5.4 g, 96% yield) as a colorless oil.

[0151] Compound 6-b (2.1 g, 6.32 mmol) was dissolved in dichloromethane (30 mL), cooled to -78°C, and a dichloromethane solution of boron tribromide (3.8 mL, 2.5 M) was slowly added dropwise. The reaction was stirred at this temperature for 0.5 hours. After completion of the reaction, the mixture was quenched with saturated sodium bicarbonate aqueous solution, and the mixture was extracted with dichloromethane (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered to obtain a dichloromethane solution containing compound 6-c, which was directly used in the next reaction.

[0152] To a dichloromethane solution of compound 6-c was added tert-butyldiphenylsilyl chloride (1.7 g, 6.32 mmol), and imidazole (861 mg, 12.65 mmol) was added under ice bath. The reaction solution was stirred at room temperature for 1 hour. The mixture was quenched with saturated aqueous ammonium chloride solution, and the mixture was extracted with dichloromethane (3 × 20 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:10) to give compound 6-d (2.8 g, yield 92%) as a colorless oil.

[0153] Cuprous iodide (7.9 g, 41.60 mmol) was added to tetrahydrofuran (20 mL), and a solution of methyl lithium in ether (52 mL, 1.6 M) was added dropwise under an ice bath. The reaction mixture was stirred at this temperature for 5 minutes. A solution of compound 6-d (2.0 g, 4.16 mmol) in tetrahydrofuran (20 mL) was added dropwise. After the addition, the reaction mixture was stirred at room temperature overnight. Methyl iodide (2.9 g, 20.80 mmol) was then added dropwise to the reaction system under an ice bath, and the mixture was stirred for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:10) to give compound 6-e (940 mg, 64% yield) as a colorless oil.

[0154] Compound 6-e (610 mg, 1.74 mmol) was dissolved in tetrahydrofuran (10 mL), and TBAF tetrahydrofuran solution (0.9 mL, 4 M) was slowly added dropwise. The reaction solution was stirred at room temperature overnight. p-Toluenesulfonyl chloride (499 mg, 2.61 mmol) and sodium hydride (209 mg, 5.22 mmol, 60%) were added to the reaction solution under an ice bath. The reaction mixture was stirred at this temperature for 0.5 hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The mixture was separated and purified by silica gel column chromatography to obtain a colorless oily compound 6-f (130 mg, 28% yield).

[0155] Intermediate 1-a (40 mg, 0.08 mmol) and compound 6-f (43 mg, 0.16 mmol) were dissolved in acetonitrile (1 mL), and cesium carbonate (79 mg, 0.24 mmol) was added. The reaction mixture was heated and stirred at 90°C overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The mixture was separated and purified by preparative thin-layer plate (ethyl acetate:petroleum ether = 1:1) to obtain white solid compounds 6 and 7 (4 mg, 8% yield). 1H NMR(500MHz,DMSO-d6)δ9.51(s,1H),8.71(s,1H),8.53(s,1H),8.24(s,1H),7.57-7.51(m,2H),7.43-7.39(m,2H),5.79(s,2H),4.77- 4.69(m,1H),3.85(s,3H),3.11-3.04(m,2H),2.98-2.92(m,2H),1.67-1.62(m,1H),1.50(s,6H),1.07-1.04(m,2H),0.88-0.83(m,2H). MS m / z 587.3[M+H] + .

[0156] White solid compound 7 (4 mg, yield 8%). 1 H NMR(500MHz,DMSO-d6)δ9.51(s,1H),8.71(s,1H),8.52(s,1H),7.63(s,1H),7.55-7.49(m,2H),7.41-7.38(m,2H),5.80(s,2H),4.95- 4.86(m,1H),3.85(s,3H),2.95-2.87(m,2H),2.80-2.72(m,2H),1.68-1.62(m,1H),1.35(s,6H),1.08-1.04(m,2H),0.87-0.83(m,2H). MS m / z 587.4[M+H] + .

[0157] Example 6: Preparation of Compounds 28 and 9

[0158] Compound 4c (25 mg, 0.04 mmol) was dissolved in dichloromethane (2 mL) and DMP oxidant (85 mg, 0.20 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by preparative thin-layer plate separation (ethyl acetate:petroleum ether = 1:1) to obtain compound 28 as a white solid (18 mg, yield 72%). MS m / z 561.2 [M+H] + .

[0159] Compound 28 (7 mg, 0.01 mmol), sodium difluorochloroacetate (5 mg, 0.03 mmol), and triphenylphosphine (8 mg, 0.03 mmol) were dissolved in DMF (1 mL). The reaction mixture was heated at 90°C overnight under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by preparative thin-layer plate separation (ethyl acetate:petroleum ether = 1:1) to afford compound 9 (0.5 mg, 7% yield) as a white solid. MS m / z 595.2 [M+H] + .

[0160] Example 7: Preparation of Compounds 10A, 10B and 11

[0161] Compound 28 (6 mg, 0.01 mmol) was dissolved in methanol, and dimethyl (1-diazo-2-oxopropyl)phosphonate (4 mg, 0.02 mmol) and potassium carbonate (3 mg, 0.02 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by preparative thin-layer plate separation (ethyl acetate:petroleum ether = 1:1) to afford compound 11 (4 mg, 67% yield) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ9.52(s,1H),8.71(s,1H),8.53(s,1H),8.18(d,J=1.2Hz,1H),7.93-7.88(m,2H),7.47-7.43(m,2H),5.80 (s,2H),3.86(s,3H),3.63(s,1H),1.70-1.64(m,1H),1.46-1.44(m,2H),1.41-1.39(m,2H),1.08-1.05(m,2H),0.87-0.85(m,2H). MS m / z 557.2[M+H] + .

[0162] Compound 11 (9 mg, 0.016 mmol) was dissolved in a hydrofluoric acid solution of pyridine (0.5 mL). The reaction solution was stirred at room temperature overnight. The reaction solution was quenched with a saturated aqueous sodium bicarbonate solution, and the mixed solution was extracted with ethyl acetate (3 × 5 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by preparative thin-layer plate (ethyl acetate: petroleum ether = 1:1) to give white solid compound 10A (0.3 mg, yield 3%) and white solid compound 10B (1.0 mg, yield 11%).

[0163] Compound 10A: 1H NMR (500MHz, DMSO-d6) δ9.51 (s, 1H), 8.71 (s, 1H), 8.53 (s, 1H), 8.16 (d, J = 1. 2Hz,1H),7.75-7.71(m,2H),7.41-7.39(m,2H),5.78(s,2H),4.88(dd,J=17. 4,4.2Hz,1H),4.24(dd,J=49.8,4.2Hz,1H),3.85(s,3H),1.67-1.63(m,1H), 1.52-1.49(m,2H),1.38-1.35(m,2H),1.07-1.04(m,2H),0.87-0.85(m,2H). MS m / z 577.1[M+H] + .

[0164] Compound 10B: 1 H NMR (500MHz, DMSO-d6) δ9.51 (s, 1H), 8.71 (s, 1H), 8.53 (s, 1H), 8.05 (d, J = 1.3Hz, 1H), 7.66-7.63 (m, 2H), 7.44-7.41 (m, 2H), 5.80 (s, 2H), 5. 70(br.s,1H),5.38(br.s,1H),3.85(s,3H),2.43-2.38(m,2H),2.32-2.26(m,2H),1.67-1.63(m,1H),1.07-1.04(m,2H),0.87-0.84(m,2H). MS m / z 577.2[M+H] + .

[0165] Example 8: Preparation of Compound 12

[0166] Compound 1-a (17 mg, 0.035 mmol), compound 12-a (8 mg, 0.069 mmol), and cesium carbonate (34 mg, 0.104 mmol) were dissolved in N,N-dimethylformamide (2 mL), and the reaction mixture was stirred at 90°C overnight. After completion of the reaction, the mixture was diluted with water and quenched, and then extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to afford compound 12 (10.66 mg, 53% yield) as a pale yellow solid. 1H NMR(500MHz,DMSO-d6)δ9.50(s,1H),8.71(s,1H),8.51(s,1H),8.39(d,J=1.3Hz,1H),8.32(d,J=5.4Hz,1H),7.41(s,1H),7 .38–7.35(m,2H),7.33–7.27(m,3H),5.73(s,2H),3.82(s,3H),1.67–1.58(m,1H),1.07–1.02(m,2H),0.85–0.78(m,2H)ppm. MS m / z 588.2[M+H] + .

[0167] Example 9: Preparation of Compound 13

[0168] Lithium aluminum hydride (1.64 g, 43.24 mmol) was dissolved in diethyl ether (35 mL) at -5°C, and aluminum chloride (1.92 g, 14.41 mmol) was slowly added. The reaction mixture was stirred at -5°C for 30 minutes, and then compound 13-a (1.5 g, 14.41 mmol) was slowly added dropwise. The mixture was stirred at -5°C for 1 hour. After completion of the reaction, the mixture was quenched with saturated sodium sulfate solution, filtered, and washed with diethyl ether. The filtrate was concentrated under reduced pressure to obtain a diethyl ether solution of compound 13-b, which was used directly in the next reaction.

[0169] A diethyl ether solution of compound 13-b (theoretical yield: 1.1 g, 14.41 mmol) was dissolved in dichloromethane (10 mL), and the mixture was cooled to -20°C. Triethylamine (2.19 g, 21.69 mmol) and p-toluenesulfonyl chloride (3.31 g, 17.35 mmol) were added sequentially. The reaction solution was stirred for 1 hour and slowly warmed to room temperature. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to obtain compound 13-c (1.6 g, 48% yield) as a colorless oil. MS m / z 253.1 [M+Na] + .

[0170] Compound 1-a (22 mg, 0.045 mmol), compound 13-c (31 mg, 0.134 mmol), and cesium carbonate (44 mg, 0.134 mmol) were dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature for 2 hours. After the reaction was completed, the mixture was diluted with water and extracted with ethyl acetate (3 x 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to obtain compound 13 (19.59 mg, 80% yield) as a white solid.1 H NMR (500MHz, DMSO-d6) δ9.51(s,1H),8.71(s,1H),8.52(s,1H),7.97(s,1H),7.61(d,J=8.3Hz,2H),7.43(d,J=8.3Hz,2H),5.79(s,2H),4.92(d,J= 12.8Hz,2H),4.83(dd,J=17.0,3.7Hz,1H),4.54(dd,J=50.1,3.7Hz,1H), 3.85(s,3H),1.69–1.63(m,1H),1.08–1.04(m,2H),0.88–0.83(m,2H)ppm. MS m / z 551.2[M+H] + .

[0171] Example 10: Preparation of Compound 15

[0172] Compound 2 (20 mg, 0.036 mmol), 1 drop of acetic acid, and palladium on carbon (10%, 10 mg) were added to methanol (3 mL) at room temperature. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 15 minutes. After the reaction was complete, the mixture was filtered and washed with celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to obtain the crude product 15-a (15 mg, 75% yield) as a colorless oil. MS m / z 567.2 [M+H] + .

[0173] Crude product 15-a (15 mg, 0.026 mmol) was dissolved in toluene (1.5 mL), and 2,3-dichloro-5,6-dicyanobenzoquinone (5 mg) was added. The mixture was stirred at 60°C for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 25:1) to afford compound 15 (1.79 mg, 12% yield) as a white solid. 1 H NMR (500MHz, DMSO-d6) δ9.51(s,1H),8.71(s,1H),8.52(s,1H),7.91(s,1H),7.59(d,J=8.2Hz,2H),7.41(d,J=8.2Hz,2H),5.79(s,2H),5. 07–4.94(m,1H),4.68(d,J=7.0Hz,2H),3.85(s,3H),1.85(d,J=17.5Hz,3H),1.70–1.60(m,1H),1.09–1.03(m,2H),0.90–0.82(m,2H)ppm. MS m / z 565.2[M+H] + .

[0174] Example 11: Preparation of Compound 16

[0175] Iodine (310 mg, 1.22 mmol) was dissolved in acetonitrile (4 mL) at room temperature, and triphenylphosphine (321 mg, 1.22 mmol) was added, followed by stirring for 2 hours. Triethylamine (124 mg, 1.22 mmol) and compound 16-a (100 mg, 1.02 mmol) were added to the reaction, and the mixture was refluxed and stirred for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain a light yellow solid product 16-b (109 mg, 51% yield). MS m / z 209.0 [M+H] + .

[0176] Compound 1-a (95 mg, 0.193 mmol), compound 16-b (96 mg, 0.463 mmol), methanesulfonic acid (2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl) palladium(II) (17 mg, 0.019 mmol), 2-dicyclohexylphosphino-2',6'-diisopropyloxy-1,1'-biphenyl (18 mg, 0.039 mmol), and cesium carbonate (189 mg, 0.579 mmol) were dissolved in 1,4-dioxane (3 mL), and the atmosphere was purged with nitrogen. The reaction mixture was stirred at 100°C overnight. After completion of the reaction, the mixture was diluted with water. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=25:1) to give a white solid product 16 (20 mg, yield 18%). 1 H NMR (500MHz, DMSO-d6) δ9.51(s,1H),8.71(s,1H),8.53(s,1H),8.49(d,J=1.3Hz,1H),7.57(d,J=8.3Hz,2H),7.39(d,J=8.3Hz,2H),5.80(s, 2H),5.60(t,J=1.5Hz,1H),3.84(s,3H),3.04–2.97(m,2H),2.46–2.43(m,2H),1.67–1.61(m,1H),1.08–1.02(m,2H),0.88–0.82(m,2H)ppm. MS m / z 573.1[M+H] + .

[0177] Example 12: Preparation of Compounds 29 and 22

[0178] Triethyl 2-phosphonopropyl ester (2.0 g, 8.51 mmol) was dissolved in tetrahydrofuran (20 mL) and sodium hydride (295 mg, 7.38 mmol, 60%) was slowly added under an ice bath nitrogen atmosphere. The reaction solution was stirred at this temperature for 1 hour, and then 3-(benzyloxy)-1-cyclobutanone (1.0 g, 5.67 mmol) was added. The reaction solution was stirred at room temperature overnight. After the reaction was completed, saturated ammonium chloride aqueous solution was quenched and the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:10) to give compound 29-a (1.1 g, yield 76%) as a colorless oil.

[0179] Compound 29-a (580 g, 2.23 mmol) was dissolved in dichloromethane (10 mL), cooled to -70°C, and boron tribromide (559 mg, 3.34 mmol) was slowly added dropwise. The reaction solution was stirred for 0.5 hours. The reaction solution was quenched with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with dichloromethane (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate containing compound 29-b was used directly in the next reaction.

[0180] To a dichloromethane solution containing compound 29-b (379 mg, 2.23 mmol) was added p-toluenesulfonyl chloride (468 mg, 2.45 mmol), and sodium hydride (178 mg, 4.46 mmol, 60%) was slowly added under ice bath, and the reaction solution was stirred for 0.5 hours. After the reaction was completed, the mixture was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted with dichloromethane (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:10) to obtain compound 29-c (534 mg, 74% yield) as a colorless oil.

[0181] Compounds 1-a (26 mg, 0.05 mmol) and 29-c (26 mg, 0.08 mmol) were dissolved in DMF (1 mL), and cesium carbonate (49 mg, 0.15 mmol) was added. The reaction mixture was heated and stirred at 90°C overnight. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The product was purified by preparative thin-layer plate separation (ethyl acetate:petroleum ether = 1:1) to obtain compound 29 (20 mg, yield 59%). MS m / z 645.3 [M+H] + .

[0182] Compound 29 (20 mg, 0.03 mmol) was dissolved in tetrahydrofuran (2 mL) and lithium aluminum hydride (3 mg, 0.06 mmol) was slowly added under ice-cooling. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was diluted with tetrahydrofuran (10 mL) and quenched with sodium sulfate decahydrate. The mixture was stirred at room temperature for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude compound 22-a (10 mg, 53% yield) was used directly in the next reaction. MS m / z 605.4 [M+H] + .

[0183] Compound 22-a (10 mg, 0.02 mmol) was dissolved in toluene (2 mL), and 2,3-dichloro-5,6-dicyanobenzoquinone (7 mg, 0.03 mmol) was added. The reaction mixture was heated and stirred at 40°C for 0.5 h. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The mixture was then purified by preparative thin-layer chromatography (ethyl acetate:petroleum ether = 1:1) to afford compound 22 (3 mg, 30% yield). 1 H NMR(500MHz,DMSO-d6)δ9.51(s,1H),8.71(s,1H),8.52(s,1H),8.24(d,J=0.8Hz,1H),7 .58-7.52(m,2H),7.44-7.39(m,2H),5.79(s,2H),4.79-4.72(m,1H),4.53(t,J=5.5Hz, 1H),3.85(d,J=1.9Hz,3H),3.80-3.71(m,2H),3.21-3.16(m,1H),3.13-3.08(m,1H),3. 03-2.96(m,2H),1.68-1.62(m,1H),1.51(s,3H),1.08-1.04(m,2H),0.88-0.83(m,2H). MS m / z 603.2[M+H] + .

[0184] Example 13: Preparation of Compound 23

[0185] Compound 22 (17 mg, 0.03 mmol) was dissolved in dichloromethane (2 mL), and thionyl chloride (18 mg, 0.15 mmol) was added dropwise. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude compound 23-a (17 mg, yield 97%), which was used directly in the next reaction.

[0186] Compound 23-a (17 mg, 0.03 mmol) was dissolved in acetonitrile (2 mL), and a solution of dimethylamine in tetrahydrofuran (0.2 mL, 2 M) was added dropwise. The reaction mixture was stirred at 50°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by preparative thin-layer plate separation (ethyl acetate:petroleum ether = 1:1) to afford compound 23 (3 mg, 17% yield) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ9.52(s,1H),8.71(s,1H),8.53(s,1H),8.32(s,1H),7.58-7.53(m,2H),7.45-7.40(m,2H),5.79(s,2H),4.86-4.80(m,1 H),3.85(s,3H),3.54-3.46(m,2H),3.26-3.21(m,2H),3.16-3.10(m,2H ),2.66(s,6H),1.72-1.62(m,4H),1.08-1.04(m,2H),0.89-0.85(m,2H). MS m / z 630.3[M+H] + .

[0187] Example 14: Preparation of Compound 24

[0188] Sodium iodide (1.39 g, 9.25 mmol) was dissolved in acetic acid (6 mL), and compound 24-a (600 mg, 8.81 mmol) was added. The reaction mixture was stirred at 70°C overnight. After the reaction mixture cooled to room temperature, diethyl ether (10 mL) and water (10 mL) were added sequentially. After the organic phase and the aqueous phase were separated, the aqueous phase was extracted with diethyl ether (2 x 15 mL). The combined organic phases were washed with 2M sodium hydroxide solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to obtain compound 24-b (860 mg, 50% yield) as a yellow solid. 1 H NMR (500MHz, CDCl3) δ7.83 (d, J = 15.1Hz, 1H), 7.15 (d, J = 15.1Hz, 1H), 2.25 (s, 3H) ppm.

[0189] Compound 1-a (35 mg, 0.071 mmol), compound 24-b (56 mg, 0.284 mmol), and cesium carbonate (69 mg, 0.213 mmol) were dissolved in N,N-dimethylformamide (2 mL) and stirred at 90°C overnight. After completion, the reaction was cooled to room temperature, diluted with water, and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 35:1) to afford compound 24 (2.9 mg, 7% yield) as a white solid. 1 H NMR (500MHz, DMSO-d6) δ9.52(s,1H),8.71(s,1H),8.67(d,J=1.1Hz,1H),8.53(s,1H),7.68(d,J=14.4Hz,1H),7.64(d,J=8.3Hz,2H),7.48(d ,J=8.3Hz,2H),6.89(d,J=14.4Hz,1H),5.82(s,2H),3.85(s,3H),2.25(s,3H),1.69–1.62(m,1H),1.09–1.02(m,2H),0.89–0.83(m,2H)ppm. MS m / z 561.2[M+H] + .

[0190] Example 15: Preparation of Compounds 25A and 25B

[0191] Sodium iodide (3.0 g, 20.0 mmol) was dissolved in acetic acid (10 mL), and compound 25-a (2.0 mL, 19.7 mmol) was added. The reaction mixture was stirred at 70°C overnight. After the reaction was cooled to room temperature, diethyl ether (20 mL) and water (20 mL) were added sequentially. After the organic phase and the aqueous phase were separated, the aqueous phase was extracted with diethyl ether (2 x 15 mL). The combined organic phases were washed with 2M sodium hydroxide solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether: diethyl ether = 15:1) to obtain compound 25-b (4.45 g, yield 100%) as a colorless oil.

[0192] Compound 1-a (30 mg, 0.061 mmol), compound 25-b (55 mg, 0.244 mmol) and cesium carbonate (60 mg, 0.183 mmol) were dissolved in N,N-dimethylformamide (2 mL) and stirred at 90 ° C overnight. After the reaction was cooled to room temperature, diluted with water, the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated and purified by preparative thin layer chromatography (petroleum ether: ether = 1:3) to give white solid compound 25A (23 mg, yield 64%) and white solid compound 25B (3 mg, yield 8%). 25A: 1 H NMR (500MHz, DMSO-d6) δ9.51(s,1H),8.72–8.70(m,2H),8.53(s,1H),7.67(d,J=14.2Hz,1H),7.61(d,J=8.3Hz,2H),7.48(d,J=8.3Hz,2H),6.69(d, J=14.1Hz,1H),5.82(s,2H),4.15(q,J=7.1Hz,2H),3.85(s,3H),1.69–1.6 3(m,1H),1.20(t,J=7.1Hz,3H),1.08–1.03(m,2H),0.88–0.82(m,2H)ppm. MS m / z 591.2[M+H] + .

[0193] 25B: 1 H NMR (500MHz, DMSO-d6) δ9.51(s,1H),8.71(s,1H),8.52(s,1H),8.24(d,J=1.2Hz,1H),7.62(d,J=8.3Hz,2H),7.43(d,J=8.4Hz,2H),7.27(d,J=9 .3Hz,1H),6.03(d,J=9.3Hz,1H),5.77(s,2H),4.01(q,J=7.1Hz,2H),3. 85(s,3H),1.70–1.61(m,1H),1.09–1.04(m,5H),0.88–0.83(m,2H)ppm. MS m / z 591.2[M+H] + .

[0194] Example 16: Preparation of Compound 30

[0195] Compound 30-a (125 mg, 0.991 mmol) (Compound 30-a synthesis reference: Angew Chem. Int. Ed. doi: 10.1002 / anie.202014308.) was dissolved in methanol (4 mL), and sodium borohydride (75 mg, 1.980 mmol) was added in batches. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was completed, water was added to quench the mixture, and the mixture was concentrated under reduced pressure. The crude product was extracted with diethyl ether (3 x 10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. A crude product of 30-b containing compound was obtained and used directly in the next reaction.

[0196] Crude compound 30-b was dissolved in dichloromethane (6 mL). Triethylamine (200 mg, 1.980 mmol) and p-toluenesulfonyl chloride (283 mg, 1.49 mmol) were added sequentially at 0°C. The mixture was stirred at room temperature for 3 hours. Upon completion of the reaction, the reaction solution was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to afford compound 30-c (15 mg, 5% yield) as a yellow oil.

[0197] Compound 1-a (2 mg, 0.004 mmol), compound 30-c (12 mg, 0.040 mmol) and cesium carbonate (4 mg, 0.012 mmol) were dissolved in N,N-dimethylformamide (1.5 mL) and stirred at 90°C for 2 hours. After the reaction was cooled to room temperature, diluted with water, and the mixture was extracted with ethyl acetate (3 x 5 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 30:1) to give compound 30 (0.50 mg, yield 20%) as a white solid. MS m / z 605.2 [M+H] + .

[0198] Example 17: Preparation of Compound 31

[0199] Compound 32 (13 mg, 0.024 mmol), sodium difluorochloroacetate (15 mg, 0.095 mmol), and triphenylphosphine (8 mg, 0.029 mmol) were dissolved in N,N-dimethylformamide (2 mL) and stirred at 100°C for 4 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (petroleum ether:methyl tert-butyl ether = 1:5) to afford compound 31 (5 mg, 36% yield) as a white solid. 1H NMR (500MHz, DMSO-d6) δ9.51(s,1H),8.72(s,1H),8.56(d,J=1.0Hz,1H),8.53(s,1H),7.58(d,J=8.3Hz,2H),7.46(d,J=8.4Hz,2H),7.09(d,J=13. 9Hz,1H),6.76(dd,J=13.7,11.1Hz,1H),5.79(s,2H),5.70–5.61(m,1H), 3.86(s,3H),1.69–1.63(m,1H),1.09–1.04(m,2H),0.89–0.85(m,2H)ppm. MS m / z 581.2[M+H] + .

[0200] Example 18: Preparation of Compound 32

[0201] Compound 25A (64 mg, 0.108 mmol) was dissolved in dichloromethane (4 mL) and a solution of diisobutylaluminum hydride in n-hexane (DIBAL-H, 1.0 M, 0.8 mL) was slowly added dropwise at -78°C. The reaction mixture was stirred at -78°C for 5 minutes. After the reaction was completed, a saturated sodium tartrate solution was added to quench the reaction. After warming to room temperature, the mixture was diluted with dichloromethane and stirred for 1 hour, then extracted with dichloromethane (3 x 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product containing compound 32-a was used directly in the next reaction. MS m / z 551.2 [M+H] + .

[0202] The crude product containing compound 32-a (theoretical yield: 60 mg, 0.108 mmol) was dissolved in dichloromethane (3 mL) and Dess-Martin periodinane (DMP, 55 mg, 0.130 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction mixture was filtered through celite and washed. The filtrate was concentrated under reduced pressure and purified by preparative thin-layer chromatography (petroleum ether: methyl tert-butyl ether = 1:4) to obtain compound 32 (20 mg, two-step yield 34%) as a white solid. 1H NMR (500MHz, DMSO-d6) δ9.61(d,J=7.6Hz,1H),9.52(s,1H),8.73(d,J=1.1Hz,1H),8.72(s,1H),8.54(s,1H),8.01(d,J=14.1Hz,1H),7.67(d,J=8.3 Hz,2H),7.50(d,J=8.3Hz,2H),6.81(dd,J=14.1,7.6Hz,1H),5.82(s,2H), 3.86(s,3H),1.70–1.63(m,1H),1.10–1.04(m,2H),0.90–0.84(m,2H)ppm. MS m / z 547.2[M+H] + .

[0203] Example 19: Preparation of Compound 34

[0204] Compound 34-a (110 mg, 0.22 mmol) (the synthesis of intermediate 34-a can be prepared by referring to the method in patent WO2020 / 132269Al) was dissolved in N, N-dimethylformamide (5 mL), and potassium carbonate (89 mg, 0.65 mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (386 mg, 1.08 mmol) were added sequentially. After addition, the mixture was stirred at room temperature for one hour. After completion of the reaction by TLC monitoring, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane: ethyl acetate = 10: 1) to give compound 34-b (100 mg, yield 72%) as a white solid.

[0205] Compound 34-b (50 mg, 0.08 mmol), tert-butyl 3-ethynyl-1-azetidinecarboxylate (21 mg, 0.12 mmol), cuprous iodide (2 mg, 0.01 mmol), bistriphenylphosphine palladium dichloride (6 mg, 0.008 mmol), pyridine (12 mg, 0.16 mmol) were dissolved in N, N-dimethylformamide (0.5 mL), and the reaction mixture was placed in a sealed tube and heated to 65 ° C under a nitrogen atmosphere and stirred for 3 hours. TLC monitored the completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane: methanol = 20: 1, 2% ammonia water) to give a yellow solid compound 34-c (40 mg, yield 76%).

[0206] Compound 34-c (40 mg, 0.06 mmol) was dissolved in methanol (1 mL), and a dioxane hydrochloride solution (4.0 M, 0.5 mL) was added. The reaction mixture was stirred at 30°C for 2 hours. After completion of the reaction, the reaction system was cooled to room temperature and concentrated under reduced pressure. The resulting mixture was dissolved in a small amount of methanol, neutralized with ammonia water, and then concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia water) to give compound 34 (20 mg, 59% yield) as a white solid. 1 H NMR (500MHz, DMSO-d6) δ9.51(s,1H),8.71(s,1H),8.53(s,1H),7.74-7.69(m,2H),7.48(d,J=8.6Hz,2H),7.28(s,1H),5.80(s,2 H),3.85(s,3H),3.65-3.60(m,1H),3.60-3.55(m,2H),3.46(br.,3H),1.68-1.60(m,1H),1.08-1.02(m,2H),0.87-0.83(m,2H). MS m / z 572.3[M+H] + .

[0207] Example 20: Preparation of Compound 35

[0208] Compound 34 (10 mg, 0.02 mmol) and paraformaldehyde (3 mg, 0.10 mmol) were dissolved in methanol (0.5 mL), and acetic acid (1 drop) was added dropwise. The reaction was stirred at room temperature for half an hour, and sodium cyanoborohydride (11 mg, 0.05 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. After TLC monitoring, the reaction mixture was filtered and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain compound 35 (2.60 mg, 25% yield) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ9.51(s,1H),8.71(s,1H),8.52(s,1H),7.73-7.69(m,2H),7.51-7.47(m,2H),7.27(s,1H),5.81(s,2H),3.85(s,3 H), 3.41 (t, J = 7.2Hz, 2H), 2.86 (t, J = 6.7Hz, 2H), 2.08 (s, 3H), 2.02-1.95 (m, 1H), 1.68-1.61 (m, 1H), 1.08-1.03 (m, 2H), 0.87-0.83 (m, 2H). MS m / z 586.3[M+H] + .

[0209] Example 21: Preparation of Compound 36

[0210] Compound 24 (25 mg, 0.045 mmol) was dissolved in tetrahydrofuran (3 mL), and a solution of methyl lithium in diethyl ether (1.6 M, 0.03 mL) was slowly added dropwise at -78°C. The reaction system was stirred at -78°C for 1 hour. After completion of the reaction, saturated ammonium chloride solution was added dropwise to quench the reaction. The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 30:1) to afford compound 36 (3.82 mg, 15% yield) as a white solid. 1 H NMR (500MHz, DMSO-d6) δ9.51(s,1H),8.71(s,1H),8.52(s,1H),8.31(d,J=1.1Hz,1H),7.60(d,J=8.3Hz,2H),7.44(d,J=8.4Hz,2H),6.86(d,J=14. 0Hz,1H),6.37(d,J=14.0Hz,1H),5.79(s,2H),4.85(s,1H),3.85(s,3H), 1.69–1.62(m,1H),1.22(s,6H),1.08–1.02(m,2H),0.91–0.83(m,2H)ppm. MS m / z 577.2[M+H] + .

[0211] Example 22: Preparation of Compound 37

[0212] Compound 1-a (50 mg, 0.101 mmol), iodobenzene (41 mg, 0.203 mmol), cuprous iodide (2 mg, 0.010 mmol), 8-hydroxyquinoline (2 mg, 0.010 mmol), and potassium carbonate (42 mg, 0.305 mmol) were dissolved in dimethyl sulfoxide (2.5 mL). Under a nitrogen atmosphere, the reaction mixture was stirred at 100°C overnight. After cooling to room temperature, the mixture was diluted with water. The mixture was extracted with ethyl acetate (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (petroleum ether:diethyl ether = 1:4) to obtain product 37 (2.4 mg, 4% yield) as a white solid. 1H NMR(500MHz,DMSO-d6)δ9.48(s,1H),8.71(s,1H),8.48(s,1H),8.20(s,1H),7.50–7.46(m,3H),7.40–7.36(m,2H),7.28(d, J=8.3Hz,2H),7.22(d,J=8.2Hz,2H),5.68(s,2H),3.80(s,3H),1.67–1.58(m,1H),1.07–1.02(m,2H),0.83–0.78(m,2H)ppm. MS m / z 569.3[M+H] + .

[0213] Example 23: Preparation of Compound 38

[0214] Compound 1-a (50 mg, 0.101 mmol), potassium hydroxide (40 mg, 0.711 mmol), potassium carbonate (35 mg, 0.254 mmol), and tetrabutylammonium bromide (3 mg, 0.010 mmol) were dissolved in 1,2-dichloroethane (3 mL). The reaction mixture was stirred at 50°C overnight. After the reaction was complete, the mixture was diluted with water. The mixture was extracted with dichloromethane (3 × 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to obtain crude yellow oil 38-a. MS m / z 555.0 [M+H] + .

[0215] Crude product 38-a (theoretical yield: 56 mg, 0.101 mmol) and potassium hydroxide (40 mg, 0.711 mmol) were dissolved in methanol (3 mL). The reaction mixture was stirred at reflux for 1.5 hours. After completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to afford product 38 (48 mg, 91% yield over two steps) as a white solid. 1H NMR (500MHz, DMSO-d6) δ9.51 (s, 1H), 8.71 (s, 1H), 8.52 (s, 1H), 8.44 (d, J = 1. 0Hz,1H),7.58(d,J=8.3Hz,2H),7.45(d,J=8.3Hz,2H),7.00(dd,J=15.5,8.7 Hz,1H),5.79(s,2H),5.74(dd,J=15.4,1.4Hz,1H),5.12(dd,J=8.7,1.4Hz,1 H),3.85(s,3H),1.69–1.61(m,1H),1.08–1.02(m,2H),0.88–0.83(m,2H)ppm. MS m / z 519.2[M+H] + .

[0216] Example 24: Preparation of Compound 39

[0217] Compound 34-b (35 mg, 0.05 mmol), a tetrahydrofuran solution of propyne (0.2 mL, 1 M), cuprous iodide (2 mg, 0.10 mmol), bistriphenylphosphine palladium dichloride (4 mg, 0.005 mmol), and pyridine (12 mg, 0.15 mmol) were dissolved in N,N-dimethylformamide (0.5 mL). The reaction mixture was placed in a sealed tube and heated to 65°C under a nitrogen atmosphere and stirred for 3 hours. The reaction was monitored by TLC. After the reaction mixture was cooled to room temperature, it was filtered and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia water) to obtain compound 39 (4.13 mg, 14% yield) as a yellow solid. 1 H NMR (500MHz, DMSO-d6) δ9.52(s,1H),8.71(s,1H),8.53(s,1H),7.70(d,J=8.2Hz,2H),7.47(d,J=8.2Hz,2H ),7.24(s,1H),5.80(s,2H),3.85(s,3H),2.05(s,3H),1.65(br,1H),1.10-1.02(m,2H),0.92-0.75(m,2H). MS m / z 531.1[M+H] + .

[0218] Example 25: Preparation of Compound 40

[0219] Compound 34-b (20 mg, 0.03 mmol), 4-ethynyl-2-fluoropyridine (6 mg, 0.05 mmol), cuprous iodide (1 mg, 0.06 mmol), bistriphenylphosphine palladium dichloride (2 mg, 0.003 mmol), and pyridine (7 mg, 0.09 mmol) were dissolved in N,N-dimethylformamide (0.5 mL). The reaction mixture was placed in a sealed tube and heated to 65 ° C. under a nitrogen atmosphere and stirred for 3 hours. The reaction was monitored by TLC. After the reaction solution was cooled to room temperature, it was filtered and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=20:1, 2% ammonia water) to give compound 40 (4.03 mg, yield 21%) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ9.51(s,1H),8.69(s,1H),8.53(s,1H),8.31(d,J=5.1Hz,1H),7.82-7.78(m,2H),7.59(s,1H),7.55- 7.49(m,2H),7.39-7.37(m,1H),7.31(br,1H),5.82(s,2H),3.82(s,3H),1.61(m,1H),1.04-0.99(m,2H),0.82-0.77(m,2H). MS m / z 612.1[M+H] + .

[0220] Example 26: Preparation of Compound 41

[0221] Compound 1-a (30 mg, 0.061 mmol), compound 41-a (40 mg, 0.152 mmol), and cesium carbonate (60 mg, 0.183 mmol) were dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature for 3.5 hours. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 30:1) to afford compound 41 (2.85 mg, 8% yield) as a white solid. 1H NMR (500MHz, DMSO-d6) δ9.51(s,1H),8.71(s,1H),8.51(s,1H),7.99(d,J=1.0Hz,1H),7.56(d,J=8.3Hz,2H),7.41(d ,J=8.3Hz,2H),5.77(s,2H),3.85(s,3H),3.63(s,3H),1.69–1.61(m,1H),1.09–1.01(m,4H),0.89–0.80(m,4H)ppm. MS m / z 591.2[M+H] + .

[0222] Example 27: Preparation of Compound 42

[0223] Compound 38 (36 mg, 0.069 mmol), 4-iodopyridine (43 mg, 0.208 mmol), palladium acetate (2 mg, 0.007 mmol), and tri(o-methylphenyl)phosphine (4 mg, 0.014 mmol) were dissolved in N,N-dimethylformamide (2 mL), and triethylamine (21 mg, 0.208 mmol) was added. The reaction solution was stirred at 100°C overnight. After the reaction was completed, the mixture was cooled to room temperature, diluted with water, and quenched. The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 30:1) to obtain compound 42 (3.39 mg, 8% yield) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ9.51(s,1H),8.71(s,1H),8.56–8.53(m,3H),8.53(s,1H),7.78(d,J=14.4Hz,1H),7.67(d,J=8.3Hz,2H), 7.50–7.44(m,4H),7.23(d,J=14.4Hz,1H),5.80(s,2H),3.83(s,3H),1.71–1.61(m,1H),1.07–1.01(m,2H),0.85–0.81(m,2H)ppm. MS m / z 596.2[M+H] + .

[0224] Example 28: Preparation of Compound 43

[0225] Compound 29-b (209 mg, 1.23 mmol) was dissolved in DMF (3 mL), and tert-butyldiphenylsilyl chloride (375 mg, 1.35 mmol) and imidazole (251 mg, 3.69 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:10) to obtain compound 43-a (290 mg, 58% yield) as a colorless oil.

[0226] Compound 43-a (290 mg, 0.71 mmol) was dissolved in tetrahydrofuran (5 mL) and lithium aluminum hydride (54 mg, 1.42 mmol) was slowly added under ice. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was diluted with tetrahydrofuran (20 mL) and quenched with sodium sulfate decahydrate. Stirring was continued at room temperature for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 43-b (243 mg, 96% yield), which was used directly in the next reaction.

[0227] Compound 43-b (243 mg, 0.66 mmol) was dissolved in tetrahydrofuran (5 mL) and sodium hydride (79 mg, 1.98 mmol, 60%) was slowly added under ice-cooling. The reaction mixture was stirred for 0.5 hours, and then iodomethane (469 mg, 3.30 mmol) was added dropwise. The reaction mixture was heated and stirred at 50°C overnight. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:10) to obtain compound 43-c (133 mg, 53% yield) as a colorless oil.

[0228] Compound 43-c (81 mg, 0.21 mmol) was dissolved in tetrahydrofuran (3 mL), and tetrabutylammonium fluoride solution in tetrahydrofuran (0.1 mL, 4 M) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. Then, p-toluenesulfonyl chloride (60 mg, 0.32 mmol) and sodium hydride (17 mg, 0.42 mmol, 60%) were added to the reaction mixture under ice-bath. The reaction mixture was stirred under ice-bath for 0.5 hour. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The mixture was separated and purified by silica gel column chromatography to obtain compound 43-d (44 mg, 70% yield) as a colorless oil.

[0229] Compound 1-a (21 mg, 0.04 mmol) and compound 43-d (38 mg, 0.13 mmol) were dissolved in acetonitrile (1 mL), and cesium carbonate (28 mg, 0.09 mmol) was added. The reaction mixture was heated and stirred at 90°C overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The product was purified by preparative thin-layer plate separation (ethyl acetate:petroleum ether = 1:1) to afford compound 43 as a white solid (5 mg, 19% yield). 1H NMR(500MHz,DMSO-d6)δ9.51(s,1H),8.71(s,1H),8.53(s,1H),8.28(d,J= 1.0Hz,1H),7.55(d,J=8.3Hz,2H),7.41(d,J=8.3Hz,2H),5.79(s,2H),4.82 -4.74(m,1H),3.85(s,3H),3.69(s,2H),3.23-3.11(m,5H),3.07-3.01(m, 2H),1.68-1.62(m,1H),1.50(s,3H),1.08-1.04(m,2H),0.87-0.84(m,2H). MS m / z 617.2[M+H] + .

[0230] Example 29: Preparation of Compound 44

[0231] Compound 34-b (20 mg, 0.03 mmol), 4-ethynyl-2-fluoropyridine (6 mg, 0.05 mmol), cuprous iodide (1 mg, 0.06 mmol), bistriphenylphosphine palladium dichloride (2 mg, 0.003 mmol), and pyridine (7 mg, 0.09 mmol) were dissolved in N,N-dimethylformamide (0.5 mL). The reaction mixture was placed in a sealed tube and heated to 65 ° C under a nitrogen atmosphere and stirred for 3 hours. The reaction was monitored by TLC. After the reaction mixture was cooled to room temperature, it was filtered and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=20:1, 2% ammonia water) to give compound 44 (3.92 mg, 22% yield) as a white solid. 1 H NMR (500MHz, DMSO-d6) δ9.51(s,1H),8.71(s,1H),8.53(s,1H),7.73(d,J=8.6Hz,2H),7.48(d,J=8.6Hz,2H),7.33(s,1H),5.81( s,2H),4.75-4.69(m,2H),4.50-4.44(m,2H),4.16-4.10(m,1H),3.85(s,3H),1.64(m,1H),1.08-1.02(m,2H),0.87-0.83(m,2H). MS m / z 573.1[M+H] + .

[0232] Example 30: Preparation of Compound 45

[0233] Compound 34 (5 mg, 0.01 mmol), acetic acid (1 mg, 0.02 mmol), and N,N-diisopropylethylamine (4 mg, 0.03 mmol) were dissolved in acetonitrile (0.5 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (11 mg, 0.03 mmol) was added. After addition, the system was allowed to react at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated and purified by preparative silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain Compound 45 (2.67 mg, 50% yield) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ9.51(s,1H),8.71(s,1H),8.53(s,1H),7.73(d,J=8 .5Hz,2H),7.47(d,J=8.5Hz,2H),7.34(s,1H),5.80(s,2H),4.35(t,J=8.2H z,1H),4.09(t,J=8.4Hz,1H),4.04-4.00(m,1H),3.85(s,3H),3.75-3.67(m ,2H),1.71(s,3H),1.67-1.62(m,1H),1.08-1.03(m,2H),0.87-0.83(m,2H). MS m / z 614.2[M+H] + .

[0234] Example 31: Preparation of Compound 46

[0235] Compound 34-b (4 mg, 0.006 mmol), 3-ethynylpyridine (1.93 mg, 0.018 mmol), cuprous iodide (1 mg, 0.006 mmol), bistriphenylphosphine palladium dichloride (2 mg, 0.003 mmol), and pyridine (2 mg, 0.03 mmol) were dissolved in N,N-dimethylformamide (0.5 mL). The reaction mixture was placed in a sealed tube and heated to 65°C under a nitrogen atmosphere and stirred for 3 hours. The reaction was monitored by TLC. After the reaction mixture was cooled to room temperature, it was filtered and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia water) to obtain compound 46 (2 mg, 54% yield) as a white solid. 1H NMR(500MHz,DMSO-d6)δ9.51(s,1H),8.69(s,1H),8.66-8.63(m,2H),8.53(s,1H),7.91-7.87(m,1H),7.83-7.79(m,2H), 7.54-7.49(m,3H),7.49-7.44(m,1H),5.82(s,2H),3.81(s,3H),1.65-1.57(m,1H),1.04-0.99(m,2H),0.88-0.82(m,2H). MS m / z 594.1[M+H] + .

[0236] Example 32: Preparation of Compound 47

[0237] Compound 34-b (100 mg, 0.156 mmol), trimethylethynylsilane (46 mg, 0.468 mmol), cuprous iodide (3 mg, 0.016 mmol), bistriphenylphosphine palladium dichloride (11 mg, 0.016 mmol), and pyridine (36 mg, 0.468 mmol) were dissolved in N,N-dimethylformamide (0.5 mL). The reaction mixture was placed in a sealed tube and heated to 65°C under a nitrogen atmosphere and stirred for 3 hours. The reaction was monitored by TLC. After the reaction mixture was cooled to room temperature, it was filtered and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to obtain compound 47-a (80 mg, yield 87%).

[0238] Compound 47-a (20 mg, 0.034 mmol), 3-iodothiophene (14 mg, 0.068 mmol), bistriphenylphosphine palladium dichloride (2 mg, 0.003 mmol), and cesium carbonate (33 mg, 0.10 mmol) were dissolved in N,N-dimethylformamide (0.5 mL). The reaction mixture was placed in a sealed tube and heated to 80 ° C under a nitrogen atmosphere and stirred for 0.5 hours. TLC monitored the completion of the reaction. After the reaction mixture was cooled to room temperature, it was filtered and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane: methanol = 20:1) to give compound 47 (5.72 mg, yield 28%). 1H NMR(500MHz,DMSO-d6)δ9.51(s,1H),8.70(s,1H),8.53(s,1H),7.93(dd,J=2.9,1.2Hz,1H),7.80-7.75(m,2H),7.68-7.64(m,1H),7.53-7 .49(m,2H),7.42(s,1H),7.15(dd,J=5.0,1.2Hz,1H),5.81(s,2H),3.82(s,3H),1.65-1.59(m,1H),1.05-0.99(m,2H),0.90-0.82(m,2H). MS m / z 599.0[M+H] + .

[0239] Example 33: Preparation of Compound 48

[0240] Compound 47-a (15 mg, 0.03 mmol) and compound 48-a (17 mg, 0.06 mmol) (synthesis of 48-a follows the method described in article DOI:10.1039 / d0sc02213f) were dissolved in tetrahydrofuran (1.0 mL). Triethylamine (9 mg, 0.09 mmol), cuprous chloride (2 mg, 0.02 mmol), copper acetylacetonate (5 mg, 0.02 mmol), and cesium fluoride (23 mg, 0.15 mmol) were added. The mixture was irradiated with a blue light lamp under a nitrogen atmosphere and stirred overnight at room temperature. The reaction mixture was filtered, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (ethyl acetate 100%) to afford compound 48 (2.5 mg, 16% yield) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ9.51(s,1H),8.71(s,1H),8.52(s,1H),7.75-7.66(m,2H),7.52-7.43(m,2H),7.30(s,1H),5.80(s,2H), 3.85(s,3H),3.28-3.21(m,1H),3.03-2.89(m,2H),2.63-2.52(m,2H),1.68-1.61(m,1H),1.09-1.00(m,2H),0.88-0.80(m,2H). MS m / z 607.1[M+H] + .

[0241] Example 34: Preparation of Compound 49

[0242] Compound 1-a (92 mg, 0.19 mmol), (2-bromoethynyl)triisopropylsilane (247 mg, 0.95 mmol), 2-(2-pyridine)-benzimidazole (7 mg, 0.04 mmol), cuprous iodide (4 mg, 0.02 mmol), and cesium carbonate (124 mg, 0.38 mmol) were dissolved in dioxane (2 mL). The reaction mixture was heated and stirred at 100°C under a nitrogen atmosphere overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:1) to obtain compound 49-a (52 mg, 41% yield) as a white solid. MS m / z 673.3 [M+H] + .

[0243] Compound 49-a (30 mg, 0.04 mmol) was dissolved in DMF (2 mL) and cesium fluoride (33 mg, 0.22 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer plate separation (ethyl acetate:petroleum ether = 1:1) to obtain compound 49 as a white solid (14 mg, yield 61%). MS m / z 517.1 [M+H] + .

[0244] Example 35: Preparation of Compound 50

[0245] Compound 49-a (22 mg, 0.03 mmol) was dissolved in tetrahydrofuran (2 mL), and tetrabutylammonium fluoride (1 M, 0.10 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by preparative thin-layer plate separation (ethyl acetate:petroleum ether = 1:1) to afford compound 50 (1 mg, 7% yield) as a white solid. 1 H NMR (500MHz, CD3OD) δ9.40(s,1H),8.64(s,1H),8.41(s,1H),7.93(s,1H),7.66-7.63(m,2H),7.55-7.51(m,2H),6.86(dd,J=76. 6,3.9Hz,1H),6.48(dd,J=29.9,3.9Hz,1H),5.81(s,2H),3.92(s,3H),1.70-1.65(m,1H),1.18-1.14(m,2H),0.92-0.88(m,2H). MS m / z 537.1[M+H] + .

[0246] Example 35: Preparation of Compound 51

[0247] Compound 49 (6 mg, 0.01 mmol) was dissolved in tetrahydrofuran (1 mL), and acetone (1 mg, 0.02 mmol) and sodium amide (1 mg, 0.03 mmol) were added. The reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by preparative thin-layer plate separation (ethyl acetate:petroleum ether = 1:1) to afford compound 51 (0.7 mg, 10% yield) as a white solid. 1 H NMR(500MHz,CD3OD)δ9.40(s,1H),8.64(s,1H),8.42(s,1H),8.00-7.96(m,3H),7.53-7.49(m,2H) ,5.81(s,2H),3.91(s,3H),1.68-1.65(m,1H),1.48(s,6H),1.17-1.14(m,2H),0.92-0.89(m,2H). MS m / z 575.1[M+H] + .

[0248] Example 36: Preparation of Compound 52

[0249] Anhydrous chromium chloride (1.66 g, 13.50 mmol) was dissolved in tetrahydrofuran (20 mL). A solution of tert-butyl 3-formylazetidine-1-carboxylate (500 mg, 2.70 mmol) and iodoform (2.13 g, 5.40 mmol) in tetrahydrofuran (10 mL) was added dropwise under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 52-a (226 mg, 27% yield) as a colorless oil.

[0250] Compound 1-a (50 mg, 0.10 mmol), compound 52-a (63 mg, 0.20 mmol), 2-(2-pyridine)-benzimidazole (4 mg, 0.02 mmol), cuprous iodide (2 mg, 0.01 mmol), and cesium carbonate (65 mg, 0.20 mmol) were dissolved in dioxane (2 mL). The reaction mixture was heated and stirred at 100°C overnight under a nitrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain compound 52-b (10 mg, 15% yield) as a white solid. MS m / z 674.3 [M+H] + .

[0251] Compound 52-b (10 mg, 0.01 mmol) was dissolved in dichloromethane (2 mL) and a 4 M solution of hydrogen chloride in dioxane (0.2 mL) was added dropwise under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour. The pH of the reaction mixture was adjusted to 8-10 with aqueous ammonia and concentrated under reduced pressure. The crude product was purified by preparative thin-layer plate separation to obtain compound 52 (7 mg, 82% yield) as a white solid. MS m / z 574.1 [M+H] + .

[0252] Example 37: Preparation of Compound 53

[0253] Compound 52 (6 mg, 0.01 mmol) was dissolved in methanol (1 mL), and paraformaldehyde (1 mg, 0.03 mmol), anhydrous zinc chloride (3 mg, 0.02 mmol), and sodium cyanoborohydride (2 mg, 0.03 mmol) were added. The reaction mixture was stirred at room temperature overnight, quenched with water, and extracted with ethyl acetate (3×5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer plate separation to obtain compound 53 (3 mg, 49% yield) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ9.52(s,1H),8.72(s,1H),8.53(s,1H),8.34(s,1H),7.6 3-7.57(m,2H),7.46-7.41(m,2H),6.85(d,J=13.9Hz,1H),6.40(dd,J=13.9,8.9H z,1H),5.79(s,2H),3.86(s,3H),3.59-3.53(m,2H),3.27-3.20(m,1H),3.14-3. 08(m,2H),2.32(s,3H),1.69-1.63(m,1H),1.09-1.05(m,2H),0.89-0.84(m,2H). MS m / z 588.2[M+H] + .

[0254] Example 38: Preparation of Compound 54

[0255] Compound 1-a (35 mg, 0.07 mmol), compound 54-a (47 mg, 0.213 mmol), 2-dicyclohexylphosphino-2',6'-diisopropyl-1,1'-biphenyl (6 mg, 0.014 mmol), (2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II)methanesulfonate (6 mg, 0.007 mmol), and cesium carbonate (69 mg, 0.213 mmol) were dissolved in 1,4-dioxane solution (1 mL). The reaction mixture was placed in a sealed tube and heated to 100°C under a nitrogen atmosphere with stirring for 3 hours. The reaction was monitored for completion by TLC. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=25:1) to give compound 54 (31 mg, yield 75%). 1 H NMR (500 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.71 (s, 1H), 8.53 (s, 1H), 8.29 (d, J = 1.0 Hz, 1H), 7.59 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H), 5.93 (s, 1H), 5.77 (s, 2H), 3.84 (s, 3H), 1.69-1.61 (m, 2H), 1.10 (d, J = 6.0 Hz, 1H), 1.07-1.02 (m, 3H), 0.94 (d, J = 6.0 Hz, 1H), 0.88-0.82 (m, 3H). The solvent peak contains one hydrogen. MS m / z 587.2 [M+H] + .

[0256] Example 39: Preparation of Compounds 55 and 56

[0257] 2-Fluoropyridine-4-carboxaldehyde (100 mg, 0.80 mmol) was dissolved in methanol (3 mL). Dimethyl (1-diazo-2-oxopropyl)phosphonate (230 mg, 1.20 mmol) was added dropwise, followed by potassium carbonate (21 mg, 1.60 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction solution was quenched with water, and the mixed solution was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer plate separation (ethyl acetate: petroleum ether = 1:20) to give compound 55-a (23 mg, 22% yield) as a white solid.

[0258] Compound 1-a (50 mg, 0.10 mmol), compound 55-a (23 mg, 0.19 mmol), and cesium carbonate (65 mg, 0.20 mmol) were dissolved in acetonitrile (2 mL). The reaction mixture was heated and stirred at 90°C overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified on a preparative thin-layer plate (methanol:dichloromethane = 1:20) to obtain compound 55 (11 mg, yield 21%) and compound 56 (3 mg, yield 6%).

[0259] Compound 55: 1 H NMR(500MHz,DMSO-d6)δ9.51(s,1H),8.71(s,1H),8.55-8.54(m,1H),8.53(s ,1H),8.21(d,J=5.2Hz,1H),7.89(d,J=14.4Hz,1H),7.69-7.65(m,2H),7.50 -7.46(m,2H),7.45-7.43(m,1H),7.32(s,1H),7.29(d,J=14.4Hz,1H),5.80( s,2H),3.83(s,3H),1.68-1.63(m,1H),1.06-1.03(m,2H),0.86-0.82(m,2H). MS m / z 614.0[M+H] + .

[0260] Compound 56: 1 H NMR(500MHz,DMSO-d6)δ9.51(s,1H),8.71(s,1H),8.52(s,1H),8.01(d,J= 5.2Hz,1H),7.92-7.91(m,1H),7.60-7.56(m,2H),7.37(m,2H),7.27(d,J=8 .8Hz,1H),6.74(d,J=8.8Hz,1H),6.68-6.65(m,1H),6.54(s,1H),5.74(s, 2H),3.84(s,3H),1.67-1.63(m,1H),1.07-1.04(m,2H),0.87-0.84(m,2H). MS m / z 614.0[M+H] + .

[0261] Example 40: Preparation of Compound 57

[0262] Compound 1-a (50 mg, 0.101 mmol) and compound 3-ethynylpyridine (21 mg, 0.203 mmol) were dissolved in acetonitrile (1 mL), and cesium carbonate (99 mg, 0.304 mmol) was added. The mixture was heated to 80°C for 14 hours. After the reaction was completed, water was added to the reaction solution and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a crude product. The crude product was purified by thin layer chromatography on silica gel plates (dichloromethane: methanol = 25:1) to obtain compound 57 (3.42 mg, yield 5.6%). 1 H NMR(500MHz,DMSO-d6)δ9.50(s,1H),8.71(s,1H),8.51(s,1H),8.38(dd,J=4.7,1.5Hz ,1H),8.08(d,J=2.0Hz,1H),7.88(s,1H),7.65(d,J=8.3Hz,2H),7.34(d,J=8.3Hz,2H) ,7.22-7.19(m,1H),7.17(d,J=8.8Hz,1H),7.10(d,J=8.0Hz,1H),6.75(d,J=8.8Hz,1H ),5.73(s,2H),3.83(s,3H),1.67-1.61(m,1H),1.07-1.01(m,2H),0.87-0.81(m,3H). MS m / z596.1[M+H] + .

[0263] Example 41: Preparation of Compounds 58 and 63

[0264] Compound 1-a (50 mg, 0.10 mmol), 2-ethynylpyridine (21 mg, 0.19 mmol), and cesium carbonate (65 mg, 0.20 mmol) were dissolved in acetonitrile (2 mL). The reaction mixture was heated and stirred at 90°C overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer plate separation (methanol:dichloromethane = 1:20) to obtain compound 63 (2 mg, 3% yield). 1H NMR(500MHz,DMSO-d6)δ9.52(s,1H),8.71(s,1H),8.63(s,1H),8.53(s,1H),8.51- 8.49(m,1H),7.86(d,J=14.0Hz,1H),7.82-7.78(m,1H),7.64(d,J=8.2Hz,2H),7.48 (d,J=8.2Hz,2H),7.38(d,J=7.8Hz,1H),7.33(d,J=14.0Hz,1H),7.30-7.27(m,1H), 5.82(s,2H),3.84(s,3H),1.68-1.64(m,1H),1.06-1.02(m,2H),0.87-0.82(m,2H). MS m / z 596.0[M+H] + .

[0265] Compound 58 (9 mg, yield 15%). 1 H NMR(500MHz,DMSO-d6)δ9.50(s,1H),8.71(s,1H),8.51(s,1H),8.39-8.37(m,1H ),7.87-7.86(m,1H),7.66(dd,J=8.1,1.7Hz,3H),7.35(d,J=8.3Hz,2H),7.22-7. 19(m,1H),7.08(d,J=9.1Hz,1H),7.03(d,J=7.9Hz,1H),6.70(d,J=9.1Hz,1H),5. 73(s,2H),3.83(s,3H),1.67-1.61(m,1H),1.07-1.03(m,2H),0.86-0.82(m,2H). MS m / z 596.0[M+H] + .

[0266] Example 42: Preparation of Compounds 59 and 60

[0267] Compound 1-a (50 mg, 0.101 mmol) and compound 5-ethynylpyrimidine (21 mg, 0.203 mmol) were dissolved in acetonitrile (1 mL), and cesium carbonate (99 mg, 0.304 mmol) was added. The mixture was heated to 80°C for 14 hours. After the reaction was completed, water was added to the reaction solution and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a crude product. The crude product was purified by thin layer chromatography on silica gel plates (dichloromethane: methanol = 25:1) to obtain compound 59 (2 mg, yield 3.3%). 1H NMR (500MHz, DMSO-d6) δ9.51(s,1H),9.10(s,1H),8.95(s,2H),8.71(s,1H),8.54-8.51(m,2H),7.82(d,J=14.5Hz,1H),7.69(d,J=8.2Hz ,2H),7.47(d,J=8.2Hz,2H),7.24(d,J=14.5Hz,1H),5.80(s,2H),3.83(s,3H),1.68-1.63(m,1H),1.07-1.02(m,2H),0.88-0.81(m,2H). MS m / z 597.0[M+H] + .

[0268] Compound 60 (5.86 mg, yield 9.7%): 1 H NMR (500MHz, DMSO-d6) δ9.50(s,1H),8.98(s,1H),8.71(s,1H),8.51(s,1H),8.23(s,2H),7.97(d,J=0.9Hz,1H),7.64(d,J=8.3Hz,2H),7.36(d, J=8.3Hz,2H),7.25(d,J=8.8Hz,1H),6.73(d,J=8.8Hz,1H),5.74(s,2H) ,3.85(s,3H),1.67-1.61(m,1H),1.08-1.02(m,2H),0.87-0.81(m,2H). MS m / z 597.0[M+H] + .

[0269] Example 43: Preparation of Compounds 61 and 62

[0270] Anhydrous chromium chloride (864 mg, 7.03 mmol) was dissolved in tetrahydrofuran (10 mL). A solution of 1-tert-butyloxycarbonylpiperidine-4-carboxaldehyde (500 mg, 2.34 mmol) and iodoform (1.85 g, 4.69 mmol) in tetrahydrofuran (10 mL) was added dropwise under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 61-a (210 mg, 26% yield) as a colorless oil.

[0271] Compound 1-a (100 mg, 0.203 mmol), compound 61-a (137 mg, 0.41 mmol), 2-(2-pyridine)-benzimidazole (8 mg, 0.041 mmol), cuprous iodide (4 mg, 0.02 mmol), and cesium carbonate (132 mg, 0.41 mmol) were dissolved in dioxane (2 mL). The reaction mixture was heated and stirred at 100°C overnight under a nitrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain compound 61-b (22 mg, 15% yield) as a white solid. MS m / z 702.3 [M+H] + .

[0272] Compound 61-b (22 mg, 0.03 mmol) was dissolved in dichloromethane (2 mL) and a 4 M solution of hydrogen chloride in dioxane (0.2 mL) was added dropwise under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour. The pH of the reaction mixture was adjusted to 8-10 with aqueous ammonia and concentrated under reduced pressure. The crude product was purified by preparative thin-layer plate separation to obtain compound 62 (10 mg, 53% yield) as a white solid. MS m / z 602.2 [M+H] + .

[0273] Compound 62 (10 mg, 0.016 mmol) was dissolved in methanol (1 mL), and paraformaldehyde (1.5 mg, 0.048 mmol) was added, followed by acetic acid (1 drop). The mixture was stirred at room temperature for 30 minutes, and then sodium cyanoborohydride (2 mg, 0.032 mmol) was added. The reaction mixture was stirred at room temperature overnight, quenched with water, and extracted with ethyl acetate (3 x 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer plate separation to afford compound 61 (1.89 mg, 18% yield) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ9.51(s,1H),8.72(s,1H),8.52(s,1H),8.28(s,1H),7.61( d,J=8.3Hz,2H),7.44(d,J=8.3Hz,2H),6.77(d,J=14.0Hz,1H),6.17(dd,J=14.1,7 .4Hz,1H),5.78(s,2H),3.86(s,3H),2.81-2.71(m,2H),2.18(s,3H),2.13-2.04(m ,2H),2.02-1.85(m,3H),1.69-1.59(m,3H),1.10-1.03(m,2H),0.90-0.78(m,2H). MS m / z 616.0[M+H] + .

[0274] Example 44: Preparation of Compound 64

[0275] Compound 64-a (100 mg, 0.55 mmol) was dissolved in toluene (2.0 mL), and azobisisobutyronitrile (25 mg, 0.15 mmol) and tributyltin (1 mL, 3.7 mmol) were added. Under nitrogen, the mixture was stirred at 90°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to afford 64-b (250.0 mg, 97% yield) as a yellow oil.

[0276] Compound 64-b (250 mg, 0.53 mmol) was dissolved in dichloromethane (10 mL), and elemental iodine (147 mg, 0.58 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with aqueous potassium fluoride and aqueous sodium thiosulfate, extracted with dichloromethane, and the organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to afford compound 64-c (150.0 mg, 91% yield) as a pale yellow solid. MS m / z 334.1 [M+Na]+.

[0277] Compound 64-c (60 mg, 0.19 mmol) and compound 1-a (30 mg, 0.06 mmol) were dissolved in DMSO (2.0 mL), and cuprous oxide (3 mg, 0.02 mmol) and N1,N2-bis(furan-2-ylmethyl)oxaldamide (5 mg, 0.02 mmol) were added. The mixture was stirred overnight at 100°C under a nitrogen atmosphere. The reaction system was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (ethyl acetate 100%) to give compound 64-d (20 mg, 49% yield) as a yellow solid. MS m / z 676.3 [M+H] + .

[0278] Compound 64-d (20 mg, 0.03 mmol) was dissolved in dichloromethane (2.0 mL), trifluoroacetic acid (1.0 mL) was added at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, redissolved in methanol (5.0 mL), ammonia (1.0 mL) was added, stirred for 5 minutes, and concentrated under reduced pressure again. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give compound 64 (10 mg, yield 59%) as a white solid. MS m / z 575.9 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ9.51(s,1H),8.71(s,1H),8.53(s,1H),8.27(s,1H),7.66-7.61(m,2H),7.45-7.41(m,2H),6.90(d,J=14. 1Hz,1H),6.32(d,J=14.1Hz,1H),5.79(s,2H),3.85(s,3H),1.69-1.62(m,1H),1.16(s,6H),1.08-1.03(m,2H),0.88-0.84(m,2H).

[0279] Example 45: Preparation of Compound 65

[0280] Compound 36 (5 mg, 0.01 mmol) was placed in a sealed tube, tetrahydrofuran (1.0 mL) was added, and sodium hydroxide (2 mg, 0.05 mmol) was added at 0°C. The mixture was slowly warmed to room temperature and stirred for 30 minutes. Iodomethane (10 mg, 0.07 mmol) was then added, and the reaction mixture was heated to 70°C and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (100% methyl tert-butyl ether) to obtain compound 65 (1.8 mg, 35% yield) as a white solid. MS m / z 590.9 [M+H] + .

[0281] Example 46: Preparation of Compound 66

[0282] Compound 4-c (18 mg, 0.03 mmol) was dissolved in 1,2-dichloroethane, and diethylaminosulfur trifluoride (19 mg, 0.12 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour, quenched with water, and extracted with dichloromethane (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer plate separation (ethyl acetate:petroleum ether = 1:1) to afford compound 66 (8 mg, 44% yield) as a white solid. 1H NMR (500MHz, DMSO-d6) δ9.51(s,1H),8.71(s,1H),8.53(s,1H),8.29(d,J=1.2Hz,1H),7.59-7.53(m,2H),7.42-7.37(m,2H),5.79(s, 2H),3.85(s,3H),2.64-2.54(m,2H),2.48-2.39(m,2H),1.94-1.87(m,1H),1.69-1.62(m,2H),1.08-1.04(m,2H),0.87-0.83(m,2H). MS m / z 565.8[M+H] + .

[0283] Example 47: Preparation of Compound 67

[0284] Chromium chloride (323 mg, 2.63 mmol) was placed in a 25 mL single-necked flask and tetrahydrofuran (2 mL) was added. A mixture of compound 67-a (50 mg, 0.44 mmol) and iodoform (345 mg, 0.88 mmol) in tetrahydrofuran (3 mL) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 3 hours. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to afford 67-b (30.0 mg, 29% yield) as a yellow oil.

[0285] Compound 67-b (30 mg, 0.13 mmol) and compound 1-a (20 mg, 0.04 mmol) were dissolved in DMSO (2.0 mL), and cuprous oxide (3 mg, 0.02 mmol) and N1,N2-bis(furan-2-ylmethyl)oxaldamide (5 mg, 0.02 mmol) were added. The mixture was stirred at 100 degrees Celsius overnight under a nitrogen atmosphere. The mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to afford compound 67 (1.01 mg, 4% yield) as a white solid. MS m / z 603.0 [M+H] + .

[0286] Example 48: Preparation of Compound 68

[0287] Compound 24-b (125 mg, 0.64 mmol) was dissolved in methanol (3 mL), and sodium borohydride (36 mg, 0.96 mmol) was slowly added under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by preparative thin-layer plate separation (ethyl acetate:petroleum ether = 1:5) to obtain compound 68-a (102 mg, 81% yield).

[0288] Compound 68-a (15 mg, 0.07 mmol), compound 1-a (18 mg, 0.04 mmol), N,N'-bis(furan-2-ylmethyl)oxaldamide (2 mg, 0.01 mmol), cuprous oxide (1 mg, 0.01 mmol), and cesium carbonate (39 mg, 0.12 mmol) were dissolved in N,N-dimethylformamide (1 mL). The reaction mixture was stirred and heated at 110°C under a nitrogen atmosphere for 3 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer plate separation (ethyl acetate:dichloromethane = 1:1) to obtain compound 68 (5 mg, 24% yield) as a white solid. 1 H NMR(500MHz,DMSO-d)δ9.51(s,1H),8.72(s,1H),8.53(s,1H),8.34(d, J=1.0Hz,1H),7.62-7.58(m,2H),7.45-7.42(m,2H),6.87(dd,J=14.0,1.4Hz,1H),6.29(dd,J=14.0,5.1Hz,1H),5.80(s,2H),5.01 (d,J=4.4Hz,1H),4.32-4.27(m,1H),3.85(s,3H),1.68-1.63(m,1H),1.17(d,J=6.5Hz,3H),1.07-1.04(m,2H),0.88-0.85(m,2H). MS m / z 563.0[M+H] + .

[0289] Example 49: Inhibition of USP1 Enzyme Activity by Compounds

[0290] Method 1: Dilute the control compound ML323 to 1 mM in DMSO, then serially dilute it in DMSO in a 4-fold series for a total of 10 concentrations. Dilute the test compound in DMSO in a 3-fold series for a total of 10 concentrations. Prepare 1× assay buffer, and use this buffer to prepare a 2× working solution of USP1 & UAF1 and a 2× working solution of substrate. Use an Echo to transfer 120 nL / well of the test compound to a 384-well plate, using 1% DMSO as a vehicle control and 10 μM ML323 as a positive control. Add 6 μL of the 2× USP1 & UAF1 solution to each well, shake for 30 seconds, and incubate at 25°C for 15 minutes. Initiate the reaction by adding 6 μL of the 2× substrate solution to each well, seal the plate, and incubate at 25°C for 60 minutes. Read fluorescence using an Envision 2105. The IC value of each compound was calculated as follows: Inhibition rate (%) = (DMSO well control reading - compound well reading) / (DMSO well control reading - positive control reading) × 100%. 50 The values ​​were analyzed by nonlinear regression method using Graphpad Prism 8 software, and the formula was: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 =X)*HillSlope). Y is the inhibition rate, and X is the Log value of the compound concentration. The enzyme inhibition activity data of some representative compounds are shown in Table 1.

[0291] Method 2: The test compound was diluted in a gradient with DMSO. Prepare 1× detection buffer (modified Tris buffer), and use the detection buffer to prepare USP1&UAF1 enzyme working solution and substrate (Ubiquitin Rhodamine 110Protein, CF (Ub-Rho)) working solution. Use Echo to transfer the test compound to a 384-well plate with a final DMSO concentration of 1%. Add 10 μL of USP1 enzyme solution to each well and incubate at room temperature for 1 hour. Add 10 μL of substrate solution to each well to start the reaction, centrifuge for 30 seconds, and shake for 30 seconds. Use SpectraMax Paradigm to read the fluorescence value continuously for 30 minutes. Calculate according to the following formula: Inhibition rate (%) = (DMSO well control reading - compound well reading) / (DMSO well control reading - solvent control reading) × 100%. IC of each compound 50 The values ​​were analyzed by nonlinear regression method using XL-Fit software, and the formula was: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 =X)*HillSlope). Y is the inhibition rate, and X is the Log value of the compound concentration. The enzyme inhibition activity data of some representative compounds are shown in Table 1.

[0292] Table 1: Inhibitory activity of compounds against USP1 enzyme

[0293] Example 50: Inhibition of MDA-MB-468 Cell Proliferation by Compounds

[0294] Select well-growing MDA-MB-468 cells and digest them with trypsin. Add fresh culture medium, mix thoroughly, and centrifuge at 1000 rpm for 5 minutes. Seed 1500 cells per well in a 96-well plate and incubate overnight at 37°C. The next day, remove the plate, administer the compound using a five-fold serial dilution, and incubate in a 37°C incubator for 168 hours.

[0295] After the cell culture plate was removed and equilibrated to room temperature, 100 μL of CellTiter Glo assay reagent was added to each well. The plate was shaken in the dark for 2 minutes, incubated for 10 minutes, and the chemiluminescence value was measured using Enspire. Calculate the inhibition rate (%) using the following formula: (1-(compound RLU - blank control RLU) / (DMSO control RLU - blank control RLU)) × 100%. The blank control wells contain only normal culture medium without cells, while the DMSO wells contain cells without compound and 0.5% DMSO. Use XLFit to draw the inhibition rate curve and calculate the IC 50 The cell inhibitory activity data of some representative compounds are shown in Table 2.

[0296] Table 2: Inhibitory activity of compounds on MDA-MB-468 cell proliferation

[0297] Example 51: Pharmacokinetics in rats

[0298] Method 1: Instrument: Waters XEVO TQ-S LC-MS / MS. All measurement data were collected and processed by Masslynx V4.1 software, and calculated and processed using Microsoft Excel. Pharmacokinetic parameters were calculated using WinNonLin 8.0 software using the statistical moment method. The main kinetic parameters included were T max 、T 1 / 2 、C max , AUC 0-24hChromatographic column: ACQUITY UPLC BEH C18 (2.1 mm × 50 mm, 1.7 μm); column temperature: 40°C; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 0.350 mL / min; gradient elution: 0.50 min: 10% B; 1.50 min: 90% B; 2.50 min: 90% B; 2.51 min: 10% B; 3.50 min: stop. Injection volume: 1 μL.

[0299] Animals: Three male Sprague-Dawley rats, weighing 200-220 g, were housed in the laboratory of the Experimental Animal Center for two days before use. They were fasted for 12 hours before and 4 hours after dosing, with free access to water during the experiment. Blood samples were collected at designated intervals after gavage.

[0300] Solvent: 0.4% ethanol + 0.4% Tween 80 + 99.2% (0.5% methylcellulose M450) Preparation of oral administration solution: Accurately weigh the compound, add it to the solvent, and sonicate at room temperature for 5 minutes to completely dissolve the drug to prepare a 0.3 mg / ml solution.

[0301] Drug samples: Typically, multiple structurally similar samples (molecular weights differing by at least 2 units) are collected, accurately weighed, and administered together (cassette PK). This allows for simultaneous screening of multiple compounds and comparison of their oral absorption rates. Single administration is also used to study the pharmacokinetics of drug samples in rats.

[0302] Blood was collected from the orbital cavity at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours after oral administration. Fifty microliters of plasma was added to 200 microliters of acetonitrile (containing the internal standard verapamil, 2 ng / mL). The mixture was vortexed for 3 minutes and centrifuged at 20,000 rcf at 4°C for 10 minutes. The supernatant was then analyzed by LC-MS / MS.

[0303] The compound is accurately weighed and prepared into different concentrations, and quantitative analysis is performed on the mass spectrometer to establish a standard curve. Then the concentration of the compound in the plasma is tested to obtain the concentration of the compound at different time points. All the measurement data are collected and processed by relevant software, and the pharmacokinetic parameters are calculated using the statistical moment method (mainly including the kinetic parameter T max 、T 1 / 2 、C max , AUC 0-24h The kinetic parameters of some representative compounds are shown in Table 3.

[0304] Method 2: Instrument: SCIEX Triple Quad 6500+ triple quadrupole liquid chromatography-mass spectrometry, operating software: Analyst 1.7.2 (Applied Biosystems, Inc.); ExionLC liquid chromatography system; data were calculated and processed using Microsoft Excel. Pharmacokinetic parameters were calculated using WinNolin 8.2 software using the statistical moment method. These parameters primarily included Tmax, T1 / 2, Cmax, and AUC0-24h. Chromatographic column: Synergi 4μm Fusion-RP Luna C18 2mm*50mm, 4μm; column temperature 40°C; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile, flow rate 0.8 mL / min, gradient elution: 0.10 min: 15% B; 1.6 min: 95% B; 1.90 min: 95% B; 1.91 min: 15% B; 2.20 min: 15% B. Injection volume: 1 μL.

[0305] Animals: Three male Sprague-Dawley rats, weighing 200-220 g, were housed in the laboratory of the Experimental Animal Center for three days before use. They were fasted for 12 hours before and 4 hours after dosing, with free access to water during the experiment. Blood samples were collected at designated intervals after gavage.

[0306] Solvent: 0.4% ethanol + 0.4% Tween 80 + 99.2% (0.5% methylcellulose M450) Preparation of oral administration solution: accurately weigh the compound, add it to the solvent, vortex and sonicate until the compound is uniformly suspended, and prepare a drug solution of corresponding concentration.

[0307] Drug samples: Typically, multiple structurally similar samples (molecular weights differing by at least 2 units) are collected, accurately weighed, and administered together (cassette PK). This allows for simultaneous screening of multiple compounds and comparison of their oral absorption rates. Single administration is also used to study the pharmacokinetics of drug samples in rats.

[0308] Blood was collected from the jugular vein at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours after oral administration. 20 μL of plasma sample (blank sample and internal standard blank sample plus 20 μL of blank plasma) was transferred to a 1.5 mL centrifuge tube, and 200 μL of internal standard (50% methanol in acetonitrile (concentration 100 ng / mL)) solution was added (double blank sample plus 200 μL of 50% methanol in acetonitrile solution). The sample was vortexed for 5 minutes and centrifuged at 14,000 rpm and 4°C for 5 minutes. 80 μL of the sample was transferred to 80 μL of water, mixed thoroughly, and analyzed by LC-MS / MS.

[0309] The compound is accurately weighed and prepared into different concentrations, and quantitative analysis is performed on the mass spectrometer to establish a standard curve. Then the concentration of the compound in the plasma is tested to obtain the concentration of the compound at different time points. All the measurement data are collected and processed by relevant software, and the pharmacokinetic parameters are calculated using the statistical moment method (mainly including the kinetic parameter T max 、T 1 / 2 、C max , AUC 0-24h The pharmacokinetic data of some representative compounds are shown in Table 3.

[0310] Table 3 Pharmacokinetic parameters in rats

[0311] *Note: Compounds 53 and 59 were tested using Method 2, while the remaining compounds were tested using Method 1.

[0312] Example 52: Pharmacokinetics in mice

[0313] Instrument: SCIEX Triple Quad 6500+ triple quadrupole liquid chromatography-mass spectrometry (LC-MS / MS), operating software: Analyst 1.7.2 (Applied Biosystems, Inc.); ExionLC liquid chromatography system; data were calculated and processed using Microsoft Excel. Pharmacokinetic parameters were calculated using WinNolin 8.2 software using the statistical moment method. These parameters included Tmax, T1 / 2, Cmax, and AUC0-24h. Chromatographic column: Synergi 4μm Fusion-RP Luna C18 2mm*50mm, 4μm; column temperature 40°C; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile, flow rate 0.8 mL / min, gradient elution: 0.10 min: 15% B; 1.6 min: 95% B; 1.90 min: 95% B; 1.91 min: 15% B; 2.20 min: 15% B. Injection volume: 1 μL.

[0314] Animals: Three ICR male mice, weighing 25-30 g, were purchased and housed in the laboratory of the Experimental Animal Center for three days before use. They were fasted for 12 hours before and 4 hours after dosing, with free access to water during the experiment. Blood samples were collected at designated intervals after gavage.

[0315] Solvent: 0.4% ethanol + 0.4% Tween 80 + 99.2% (0.5% methylcellulose M450) Preparation of oral administration solution: accurately weigh the compound, add it to the solvent, vortex and sonicate until the compound is uniformly suspended, and prepare a drug solution of corresponding concentration.

[0316] Drug samples: Typically, multiple structurally similar samples (molecular weights differing by at least 2 units) are collected, accurately weighed, and administered together (cassette PK). This allows for simultaneous screening of multiple compounds and comparison of their oral absorption rates. Single administration is also used to study the pharmacokinetics of drug samples in mice.

[0317] Cheek blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours after oral administration. 20 μL of plasma sample (blank sample and internal standard blank sample plus 20 μL of blank plasma) was transferred to a 1.5 mL centrifuge tube, and 200 μL of internal standard (50% methanol in acetonitrile (concentration 100 ng / mL)) solution was added (double blank sample plus 200 μL of 50% methanol in acetonitrile). The sample was vortexed for 5 minutes and centrifuged at 6000 g at 4°C for 3 minutes. 80 μL of the sample was transferred to 80 μL of water, mixed thoroughly, and analyzed by LC-MS / MS.

[0318] The compound is accurately weighed and prepared into different concentrations, and quantitative analysis is performed on the mass spectrometer to establish a standard curve. Then the concentration of the compound in the plasma is tested to obtain the concentration of the compound at different time points. All the measurement data are collected and processed by relevant software, and the pharmacokinetic parameters are calculated using the statistical moment method (mainly including the kinetic parameter T max 、T 1 / 2 、C max , AUC 0-24h The pharmacokinetic data of some representative compounds are shown in Table 4.

[0319] Table 4 Pharmacokinetic parameters in mice

[0320] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound having a structure represented by the following formula (I), or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate thereof: In formula (I): B is selected from formula (Ia) or formula (Ib): The site where A is linked in the compound of formula (Ia) or formula (Ib) and formula (I); represents the site where formula (Ia) or formula (Ib) is linked to the benzene ring in the compound of formula (I); Each R 1 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, CN; m is selected from 0, 1, or 2; Each R 2 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, CN; n is selected from 0, 1, 2, 3, or 4; R 3 and R 4 each independently selected from hydrogen, halogen, C 1-4 alkyl; or R 3 and R 4 together with the same carbon atom to which they are attached form a 3- to 6-membered ring structure, which ring structure optionally contains 0 or 1 heteroatom selected from N, O, S; Each R 5 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, CN; p is selected from 0, 1, or 2; Each R 6 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 2-4 alkynyl, 3- to 6-membered heterocyclic group, 3- to 6-membered heterocyclic group-C 2-4 alkynyl, CN, OR f , SR f , NR d R d , C(O)R g , C(O)OR f , or S(O)2R g ; q is selected from 0, 1, 2, or 3; A is selected from formula (Ic), formula (Id), formula (Ie), formula (If), or formula (Ig): represents the site where formula (Ic), formula (Id), formula (Ie), formula (If), or formula (Ig) is linked to B in the compound of formula (I); represents a single bond or a double bond; Each R a is independently selected from hydrogen, halogen, C 1-4 alkyl, C 2-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 8-membered heterocyclic group, aryl, heteroaryl, CN, C(O)R g , C(O)OR f , C(O)NR d R d , or S(O)2NR d R d ; The alkyl, cycloalkyl, 3- to 8-membered heterocyclic group, aryl and heteroaryl described in R a are optionally substituted by one or more groups selected from the group consisting of: halogen, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 8-membered heterocyclic group, aryl, heteroaryl, CN, OR f , SR f , NR d R d , C(O)R g , C(O)OR f , OC(O)R g , C(O)NR d R d , NR d C(O)R g , NR d , C(O)NR d R d , OC(O)NR d R d , NR d , C(O)OR f , OC(O)OR f , S(O)2NR d R d , NR d , S(O)2R g , or NR d , S(O)2NR d R d ; Or the cycloalkyl and 3- to 8-membered heterocyclic group described in R a are optionally substituted by =T, where T is selected from O or CR m R n ; R m and R n each independently is selected from hydrogen, halogen, or C 1-4 alkyl; Each R b is independently selected from hydrogen, halogen, C 1-4 alkyl; or two Rs b together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; each k is independently selected from 0, 1, 2, or 3; R c selected from hydrogen, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl, CN, C(O)R g , C(O)OR f , C(O)NR d R d ; the alkyl, alkenyl or alkynyl is optionally substituted with one or more groups selected from the group consisting of halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, CN, OR f , SR f , NR d R d , C(O)R g , C(O)OR f , OC(O)R g , C(O)NR d R d , NR d C(O)R g , S(O)2NR d R d , or NR d S(O)2R g ; Each R d is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl; Each R d’ is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, hydroxy, C 1-4 alkoxy, or CN; each t is independently selected from 0, 1, 2, 3, or 4; k 1 、k 2 、k 3 、and k 4 are each independently selected from 0, 1, 2, 3, 4 or 5; D is selected from a chemical bond, O, NR e , or CR b R b ; wherein, R e is selected from hydrogen or C 1-4 alkyl; R b is defined as described above; M is selected from O or CR h R i ; wherein, R h and R i are each independently selected from hydrogen, halogen, or C 1-4 alkyl; said alkyl is optionally substituted with one or more groups selected from the group consisting of: halogen, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, aryl, heteroaryl, CN, OR f , SR f , NR d R d , C(O)R g , C(O)OR f , OC(O)R g , C(O)NR d R d , NR d C(O)R g , NR d , C(O)NR d R d , OC(O)NR d R d , NR d , C(O)OR f , OC(O)OR f , S(O)2NR d R d , NR d , S(O)2R g , or NR d , S(O)2NR d R d ; or R h and R i together with the carbon atom to which they are attached form a 3- to 8-membered ring structure, which ring structure optionally contains 0, 1, or 2 heteroatoms selected from N, O, S; X 1 、 X 2 、 X 3 、 X 4 、 and X 5 each independently is selected from N or CR k ; provided that, X 1 、 X 2 、 X 3 、 X 4 、 and X 5 at most two of which are selected from N; each R k each independently is selected from hydrogen, halogen, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, CN, OR f 、 SR f 、 NR d R d 、 C(O)R g 、 or C(O)OR f ; Each of the above Rs d is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, or a 3- to 6-membered heterocyclic group; each R f is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, a 3- to 6-membered heterocyclic group, aryl, or heteroaryl; each R g is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, a 3- to 6-membered heterocyclic group, aryl, or heteroaryl; Wherein, each of the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, cyclic structure, aryl and heteroaryl is optionally and independently substituted with 1-3 substituents independently selected from the group consisting of: halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, aryl, heteroaryl, CN, NO2, OR f , SR f , NR d R d , C(O)R g , C(O)OR f , C(O)NR d R d , NR d C(O)R g , S(O)2R g , or NR d S(O)2R g , provided that the chemical structure formed is stable and meaningful; wherein, R d , R f , and R g are as defined above; Unless otherwise specified, the above-mentioned aryl is an aromatic group containing 6 - 12 carbon atoms; heteroaryl is a 5 - to 15 - membered heteroaromatic group; the cyclic structure is a saturated or unsaturated cyclic group containing or not containing heteroatoms.

2. The compound according to claim 1, characterized in that, Formula (I) is Formula (IIa) or Formula (IIb): The definitions of the groups in formula (IIa) or formula (IIb) are as described in claim 1.

3. The compound according to claim 2, wherein Formula (I) is Formula (IIc) or Formula (IId): Each R a are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 2-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, CN, C(O)R g 、C(O)OR f , or C(O)NR d R d ; R a The alkyl, cycloalkyl, 3- to 8-membered heterocyclyl, aryl and heteroaryl groups described in the above are optionally substituted by one or more groups selected from the group consisting of halogen, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, CN, OR f , SR f NR d R d 、C(O)R g 、C(O)OR f 、OC(O)R g 、C(O)NR d R d NR d C(O)R g , or NR d S(O)2R g ; or R a The cycloalkyl and 3- to 8-membered heterocyclyl groups are optionally substituted by =T, wherein T is selected from CR m R n ; R m and R n are each independently selected from hydrogen, halogen, or C 1-4 alkyl; R d 、R f 、and R g are defined as described in claim 1.

4. The compound according to claim 3, characterized in that, Formula (I) is Formula (IIe) or Formula (IIf): Each R a is independently selected from hydrogen, halogen, C 1-4 alkyl, C 2-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2- 4-alkynyl, C 3-6 cycloalkyl, 3- to 8-membered heterocyclic group, aryl, heteroaryl, CN, C(O)R g , C(O)OR f , or C(O)NR d R d ; R a The alkyl, cycloalkyl, 3- to 8-membered heterocyclic group, aryl and heteroaryl as described in 3-6 are optionally substituted by one or more groups selected from the group consisting of: halogen, C f cycloalkyl, 3- to 8-membered heterocyclic group, aryl, heteroaryl, CN, OR d , NR d R a ; or the cycloalkyl and 3- to 8-membered heterocyclic group as described in m are optionally substituted by =T, where T is selected from CR n R m and R n are each independently selected from hydrogen, halogen, or C 1-4 alkyl; R d 、R f 、and R g are defined as described in claim 1.

5. The compound according to claim 4, wherein Each R in formula (IIe) or formula (IIf) a is independently a group selected from the following group:

6. The compound according to claim 1, wherein Formula (I) is Formula (IIIa) or Formula (IIIb): Each R a are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 2-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, CN, C(O)R g 、C(O)OR f , or C(O)NR d R d ; R a The alkyl, cycloalkyl, 3- to 8-membered heterocyclyl, aryl and heteroaryl groups described in the above are optionally substituted by one or more groups selected from the group consisting of halogen, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, CN, OR f , SR f NR d R d 、C(O)R g 、C(O)OR f 、OC(O)R g 、C(O)NR d R d NR d C(O)R g , or NR d S(O)2R g ; or R a The cycloalkyl and 3- to 8-membered heterocyclyl groups are optionally substituted by =T, wherein T is selected from CR m R n ; R m and R n are each independently selected from hydrogen, halogen, or C 1-4 alkyl; R d 、R f 、and R g are defined as described in claim 1.

7. The compound according to claim 6, wherein Each R in formula (IIIa) or formula (IIIb) a is independently selected from hydrogen, halogen, C 1-4 alkyl, C 2-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 8-membered heterocyclic group, aryl, heteroaryl, CN, C(O)R g , C(O)OR f , or C(O)NR d R d ; The alkyl, cycloalkyl, 3- to 8-membered heterocyclic group, aryl and heteroaryl described in R a are optionally substituted by one or more groups selected from the group consisting of: halogen, C 3-6 cycloalkyl, 3- to 8-membered heterocyclic group, aryl, heteroaryl, CN, OR f , NR d R d ; Or the cycloalkyl and 3- to 8-membered heterocyclic group described in R a are optionally substituted by =T, where T is selected from CR m R n ; R m and R n are each independently selected from hydrogen, halogen, or C 1-4 alkyl; R d 、R f 、and R g are defined as described in claim 1.

8. [Corrected according to Rule 26 on 29.03.2024] The compound according to claim 7, characterized in that, Each R in formula (IIIa) or formula (IIIb) a is independently selected from the group consisting of:

9. The compound according to claim 1, wherein Formula (I) is Formula (IVa) or Formula (IVb): The definitions of the groups in formula (IVa) or formula (IVb) are as described in claim 1.

10. The compound according to any one of claims 1 and 4, characterized in that, Formula (I) is Formula (V): R c selected from halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, CN, C(O)R g , C(O)OR f , C(O)NR d R d ; the alkyl, alkenyl or alkynyl is optionally substituted with one or more groups selected from the group consisting of halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, CN, OR f , SR f , NR d R d , C(O)R g , C(O)OR f , OC(O)R g , C(O)NR d R d , NR d C(O)R g , or NR d S(O)2R g ; k 1 selected from 1, 2, 3, or 4; R d’ , the definition of t is as described in claim 1; R d 、R f 、and R g are defined as described in claim 1.

11. The compound according to claim 1, wherein Formula (I) is Formula (VIa) or Formula (VIb): The definitions of the groups in formula (VIa) or formula (VIb) are as described in claim 1.

12. The compound according to claim 1, wherein Formula (I) is Formula (VIIa) or Formula (VIIb): The definitions of the groups in formula (VIIa) or formula (VIIb) are as described in claim 1.

13. The compound according to claim 1, wherein Formula (I) is Formula (VIIIa) or Formula (VIIIb): X 1 、X 2 、X 3 、X 4 、 and X 5 are each independently selected from N or CR k ; provided that, X 1 、X 2 、X 3 、X 4 、 and X 5 at most two are selected from N; each R k is independently selected from hydrogen, halogen, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, CN, OR f 、SR f 、NR d R d 、C(O)R g 、 or C(O)OR f ; R d 、R f 、and R g are defined as described in claim 1.

14. The compound according to claim 1, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof, selected from one of the following groups: "*" represents a chiral center.

15. A pharmaceutical composition, characterized in that, Comprising the compound according to any one of claims 1 to 14, or its optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, solvates, and a pharmaceutically acceptable carrier.

16. Use of a compound according to any one of claims 1 to 14, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof, characterized in that, For preparing a pharmaceutical composition for treating a disease, disorder or condition related to USP1 activity or expression level.

17. The use according to claim 16, characterized in that, The disease, disorder or condition is selected from the group consisting of: breast cancer, non - small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, colon cancer, colorectal cancer, thyroid cancer, embryonal rhabdomyosarcoma, cutaneous granular cell tumor, melanoma, liver cancer, rectal cancer, bladder cancer, throat cancer, pancreatic cancer, prostate cancer, glioblastoma, ovarian cancer, endometrial cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, skin cancer, gastric cancer, mesothelioma, osteosarcoma, acute myeloid leukemia, myelofibrosis, B - cell lymphoma, T - cell lymphoma, monocytic leukemia, hypereosinophilic syndrome, multiple myeloma and other various solid tumors and hematological tumors.

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