CN114075218A - USP7 inhibitors - Google Patents

Abstract

The present application relates to inhibitors of USP7 of formula (I), methods for their preparation and their use in the treatment of neoplastic diseases. In the preparation process, the compound is obtained through a series of reactions such as substitution, coupling, reduction, deprotection and the like.

Description

USP7 inhibitors

technical field

The present application relates to a USP7 inhibitor, its preparation method and its therapeutic use in tumor diseases.

Background technique

Post-translational modification (PTM) is generally enzymatic modification of protein after protein biosynthesis. PTM includes methylation, acetylation, phosphorylation, glycosylation, ubiquitination, S-nitrosylation, etc. As one of the most studied PTMs, ubiquitination involves proteolytic machinery within the cell and regulates many physical activities within the cell. The process of adding ubiquitin to a substrate protein is called ubiquitination, which facilitates the degradation of the protein. The linked reaction can catalyze the ubiquitination of target proteins. First, ubiquitin is activated by E1 with the participation of adenosine triphosphate and transferred to E2 through a trans-sulfation reaction, and then binds to lysine or α-amino groups of substrate proteins in the presence of E3. Ultimately, protein tags with more than four ubiquitin molecules can be recognized and influenced by the 26S proteasome, where they are degraded, producing small polypeptides.

Deubiquitinating enzymes (DUBS) are responsible for removing ubiquitin and maintaining substrate stability by degrading ubiquitin. To date, about 100 DUBs have been identified and can be divided into five subclasses according to their Ub protease domains: ubiquitin-specific proteases (USPS), ubiquitin C-terminal hydrolases (UCHs), ovarian tumor proteases ( OTUS), Machado-Joseph disease protease (MJDS), a cysteine-dependent protease, and JAB1/MPN/Mov34 (JAMMS), a zinc metalloprotease.

With nearly 50 members, the USPS family is the largest of all the DUB subfamilies. These members all include conserved domains, the three main functional domains of the Cys, His, and Asp/Asn boxes, which are responsible for the reorganization of ubiquitin-binding molecules.

Among the USP family members, the ubiquitin-specific protease USP7, also known as herpes-associated ubiquitin-specific protease (HAUSP), is a unique deubiquitinase discovered in 1997. A new member of herpes simplex virus type 1 immediate early protein (Vmw110) interaction. Later, USP7 was found to interact with other viral proteins such as Epstein-Barr nuclear antigen 1 (EBNA1) of Epstein-Barr virus (EBV) and vIRF1 (viral interferon regulatory factor 1) of Kaposi's sarcoma-associated herpes virus (KSHV). ) protein, thus indicating that it is a general target of herpesviruses, and named it herpes-associated ubiquitin-specific protease. USP7, by far the most widely studied deubiquitinase, is thought to be an oncogene that promotes tumor growth and affects a patient's immune response to tumors.

USP7 is highly expressed in a variety of cancers and affects cancer disease progression. Furthermore, USP7 plays different roles in different tumors. In prostate cancer, high expression of USP7 is directly correlated with tumor aggressiveness. USP7 plays a key role in carcinogenesis through a p53-dependent pathway in non-small cell lung cancer (NSCLC). Studies have shown that, in vivo, changes in USP7 regulate colon cancer growth and apoptosis sensitivity. USP7 maintains the DNA damage response and promotes cervical cancer, and is positively associated with poor survival in cervical cancer patients. USP7 regulates human erythroid terminal differentiation by stabilizing GATA1, providing a certain treatment for leukemia. In short, USP7 plays an important role in a variety of pathological processes and is an excellent target from a therapeutic standpoint.

Not only does USP7 play a role in regulating cellular pathways such as viral proteins, immune responses, oncogenes, and DNA damage, but it is also aberrantly expressed in a variety of cancers, making it a promising target. However, due to the lack of protein co-crystal structure between USP7 and small molecule inhibitors, no effective and selective USP7 inhibitor has been found for a long time. Over the past few years, the crystal structures of some USP7 small molecule inhibitors and their complexes with USP7 have been published, which provide guidance for obtaining structure-based small molecule inhibitors. In recent years, although some USP7 small molecule inhibitors have been reported, these USP7 inhibitors have not yet entered clinical trials due to unsatisfactory in vivo efficacy data. Therefore, USP7 inhibitors with good in vivo activity need to be developed for the early treatment of cancer patients with abnormal USP7 expression.

The compound of the present invention is a USP7 deubiquitinase inhibitor with independent intellectual property rights. It can inhibit USP7 deubiquitinase with high selectivity, in order to safely and effectively treat tumor patients with abnormal USP7 expression.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof,

in,

One of Y ₁ , Y ₂ , Y ₃ and Y ₄ and Y ₅ is CR30, the remaining four are each independently selected from N and CR ₃ ,

R ₃₀ for

Rings A and B are aromatic rings,

X ₁ and X ₂ are each independently selected from CR ₄ and N,

X ₃ and X ₄ are each independently selected from C or N,

X ₅ and X ₆ are each independently selected from N, NR ₅ , O, S and CR ₆ , and X ₅ and X ₆ are not simultaneously CR ₆ ,

L is selected from -(CR ₁₂ R ₁₃ ) _n -, -O-, -S-, -NR ₁₀ -, -(CO)-, -(CO)NR ₁₀ -, -(CO)O-, -S( O) ₂ - and -S(O) ₂ NR ₁₀ -,

n is 0, 1, 2, 3, or 4,

_R9 is selected from H, halogen, -CN and _C1-6 alkyl, which may be optionally substituted by halogen,

R ₁ and R ₂ are each independently selected from H, halogen, -CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR ₁₀ , -NR ₁₀ R ₁₁ , C _{3 -8} cycloalkyl and 3-8 membered heterocycloalkyl, the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl may be optionally replaced by halogen, -CN, C _1-6 alkyl , C _2-6 alkenyl, C _2-6 alkynyl, -OR ₁₀ , -NR ₁₀ R ₁₁ , C _3-8 cycloalkyl, or 3-8 membered heterocycloalkyl substituted, or

R ₁ and R ₂ can be joined together to form C _3-12 cycloalkyl or 3-12 membered heterocycloalkyl, which may be optionally substituted by R ₅₀ ,

R ₅₀ is selected from halogen, -CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR ₁₀ , -NR ₁₀ R ₁₁ , C _3-8 cycloalkyl and 3- 8-membered heterocycloalkyl, the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl may be optionally replaced by halogen, -CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR ₁₀ , -NR ₁₀ R ₁₁ , C _3-8 cycloalkyl, or 3-8 membered heterocycloalkyl substituted,

R ₃ is selected from H, halogen, -CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR ₁₀ , -NR ₁₀ R ₁₁ , C _3-8 cycloalkyl and 3-8 membered heterocycloalkyl, the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl may be optionally replaced by halogen, -CN, C _1-6 alkyl, C _2-6 alkene group, C _2-6 alkynyl, -OR ₁₀ , -NR ₁₀ R ₁₁ , C _3-8 cycloalkyl, or 3-8 membered heterocycloalkyl,

R ₄ is each independently selected from H, halogen, -CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR ₁₀ , -NR ₁₀ R ₁₁ , C _3-8 ring Alkyl and 3-8 membered heterocycloalkyl, the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl may be optionally replaced by halogen, -CN, C _1-6 alkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, -OR ₁₀ , -NR ₁₀ R ₁₁ , C _3-8 cycloalkyl, or 3-8 membered heterocycloalkyl substituted,

R ₅ is each independently selected from H, -CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl and 3-8 membered heterocycloalkyl, The alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl groups may be optionally replaced by halogen, -CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR ₁₀ , -NR ₁₀ R ₁₁ , C _3-8 cycloalkyl, or 3-8 membered heterocycloalkyl substituted,

R ₆ is selected from H, halogen, -CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR ₁₀ , -NR ₁₀ R ₁₁ , C _3-8 cycloalkyl and 3-8 membered heterocycloalkyl, the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl may be optionally replaced by halogen, -CN, C _1-6 alkyl, C _2-6 alkene group, C _2-6 alkynyl, -OR ₁₀ , -NR ₁₀ R ₁₁ , C _3-8 cycloalkyl, or 3-8 membered heterocycloalkyl,

R ₇ is a 5-12-membered heteroaryl, 3-12-membered cycloalkyl or 3-12-membered heterocycloalkyl, and may be optionally substituted by R ₄₀ , the cycloalkyl and heterocycloalkyl may be any Optionally fused with 5-10 membered aryl or 5-12 membered heteroaryl, aryl or heteroaryl fused with cycloalkyl or heterocycloalkyl may be optionally substituted by _R40 ,

R ₄₀ is selected from (=O), halogen, -CN, -OR ₁₀ , -NR ₁₀ R ₁₁ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 ring Alkyl, or 3-8 membered heterocycloalkyl, the alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl may be optionally replaced by halogen, -CN, -OR ₁₀ , -NR ₁₀ R ₁₁ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR ₁₀ , -NR ₁₀ R ₁₁ , C _3-8 cycloalkyl, or 3-8 membered heterocycloalkane base substitution,

R ₁₀ and R ₁₁ are each independently selected from H, C _1-6 alkyl and C _3-8 cycloalkyl,

R ₁₂ and R ₁₃ are each independently selected from H, halogen and C _1-6 alkyl;

In another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof,

in,

Rings A and B are aromatic rings,

L is -(CH ₂ ) _n -,

n is 1, 2, 3, or 4,

X ₁ and X ₂ are each independently selected from CR ₄ and N,

X ₃ and X ₄ are each independently selected from C or N,

X ₅ and X ₆ are each independently selected from N, NR ₅ , O, S and CR ₆ , and X ₅ and X ₆ are not simultaneously CR ₆ ,

Y ₁ , Y ₂ , Y ₃ and Y ₄ are each independently selected from N and CR ₃ ,

_R9 is selected from H, halogen, -CN and _C1-6 alkyl, which may be optionally substituted by halogen,

R ₁ and R ₂ are each independently selected from H, C _1-6 alkyl, C _3-12 cycloalkyl and 3-12 membered heterocycloalkyl, which can be optionally substituted with halogen, -CN, -OR ₁₀ , -NR ₁₀ R ₁₁ , or C _1-6 alkyl, or

R ₁ and R ₂ can be joined together to form C _3-12 cycloalkyl or 3-12 membered heterocycloalkyl, which can be optionally substituted by halogen, -CN, -OR ₁₀ , -NR ₁₀ R ₁₁ , or C _1-6 alkyl substituted, which may be optionally substituted with halogen,

R ₃ is each independently selected from H, halogen, C _1-6 alkyl, C _3-8 cycloalkyl and 3-8 membered heterocycloalkyl, the alkyl, cycloalkyl and heterocycloalkyl may be any optionally substituted with halogen, -CN, -OR ₁₀ , -NR ₁₀ R ₁₁ , or C _1-6 alkyl,

R ₄ is each independently selected from H, halogen, and C _1-6 alkyl optionally substituted with halogen, -CN, -OR ₁₀ , or -NR ₁₀ R ₁₁ ,

R ₅ is selected from H, C _1-6 alkyl, C _3-8 cycloalkyl and 3-8 membered heterocycloalkyl,

R ₆ is selected from H, halogen, C _1-6 alkyl, C _3-8 cycloalkyl and 3-8 membered heterocycloalkyl,

R ₇ is 3-12-membered cycloalkyl or 3-12-membered heterocycloalkyl, and the cycloalkyl and heterocycloalkyl may be optionally substituted by (=O), or C _1-6 alkyl, so The alkyl group may be optionally substituted with halogen, -CN, -OR ₁₀ , or -NR ₁₀ R ₁₁ ,

R ₁₀ and R ₁₁ are each independently selected from H, C _1-6 alkyl and C _3-8 cycloalkyl;

In some embodiments, n is 1 or 2, preferably 1;

In some embodiments, X ₁ is CR ₄ and X ₂ is N, or X ₂ is CR ₄ and X ₁ is N, wherein

R ₄ is selected from H, halogen and C _1-6 alkyl, which may be optionally substituted with halogen, -CN, -OR ₁₀ , or -NR ₁₀ R ₁₁ , R ₁₀ and R ₁₁ are each independently selected From H, C _1-6 alkyl and C _3-8 cycloalkyl, preferably, R ₄ is H;

In some embodiments, X ₅ is NR ₅ , O, or S, X ₆ is CR ₆ , or X ₆ is NR ₅ , O, or S, and X ₅ is CR ₆ , wherein

R ₅ is selected from H, C _1-6 alkyl, C _3-8 cycloalkyl and 3-8 membered heterocycloalkyl, preferably H and C _1-6 alkyl, more preferably H,

R ₆ is selected from H, halogen, C _1-6 alkyl, C _3-8 cycloalkyl and 3-8 membered heterocycloalkyl, preferably H and C _1-6 alkyl, more preferably H;

In some embodiments, R ₇ is a 3-12 membered cycloalkyl or a 3-12 membered heterocycloalkyl, which may be optionally replaced by (=O), or C _{1- 6} alkyl substitution;

In some embodiments, R ₇ is

In some embodiments, each R ₃ is independently selected from H, halogen, and C _1-6 alkyl;

In some embodiments, R ₉ is selected from H and C _1-6 alkyl, which may be optionally substituted with halogen;

In some embodiments, R ₉ is H;

In some embodiments, Y ₁ , Y ₂ , Y ₃ and Y ₄ are each independently selected from CR ₃ , and R ₃ is each independently selected from H, halogen, C _1-6 alkyl, C _3-8 cycloalkyl and 3-8 membered heterocycloalkyl;

In some embodiments, Y ₁ , Y ₂ , Y ₃ and Y ₄ are each independently selected from CR ₃ , and R ₃ is each independently selected from H, halogen, and C _1-6 alkyl;

In some embodiments, the compound of formula (I) is the following compound, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof,

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, and optionally a pharmaceutically acceptable accepted carrier;

In another aspect, the present invention provides a method of treating a disease associated with USP7 activity, the method comprising administering to a subject an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, polymorph or isoform thereof Construct, or the pharmaceutical composition of the present invention; in some embodiments, the disease associated with USP7 activity is ovarian cancer, breast cancer, lung cancer, pancreatic cancer, kidney cancer, melanoma, liver cancer, colon cancer, sarcoma, Brain cancer, prostate cancer, leukemia, lymphoma, or multiple myeloma;

In some embodiments of the invention, the subject to which the invention relates is a mammal including a human;

In another aspect, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or a pharmaceutical composition of the present invention, prepared for the treatment of a disease associated with USP7 activity. Use in medicine for a disease; in some embodiments, the disease associated with USP7 activity is ovarian cancer, breast cancer, lung cancer, pancreatic cancer, kidney cancer, melanoma, liver cancer, colon cancer, sarcoma, brain cancer, prostate cancer cancer, leukemia, lymphoma, or multiple myeloma.

Detailed description of the invention

Exemplary embodiments utilizing the principles of the present invention are set forth in the following detailed description. The features and advantages of the present invention may be better understood by reference to the following summary.

It should be understood that the scope of protection for various aspects of the invention is to be determined by the following claims, and that methods and structures within the scope of these claims and their equivalents are intended to be within the scope of the present claims.

Unless otherwise defined, all technical and scientific terms herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, publications cited throughout this document are incorporated by reference in their entirety unless otherwise indicated.

It is to be understood that both the foregoing brief description and the following detailed description are exemplary and explanatory, and are not restrictive of any inventive subject matter. The use of the singular also includes the plural unless specifically stated otherwise. The use of "or", "or" means "and/or" unless stated otherwise. Furthermore, the use of the term "including" and other forms such as "comprising", "including" and "comprising" is not intended to be limiting.

certain chemical terms

The terms "optional", "optional" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes the occurrence and non-occurrence of said event or circumstance. For example, "optionally substituted alkyl" means "unsubstituted alkyl" or "substituted alkyl". Also, optionally substituted groups can be unsubstituted (eg: -CH2CH3 ₎ , fully substituted (eg: _{-CF2CF3 )} , monosubstituted (eg _{: -CH2CH2F )} or Any hierarchy between monosubstituted and fully substituted (eg _{: -CH2CHF2} , _-CF2CH3 , _-CFHCHF2 , etc. ₎ . Those skilled in the art will appreciate that for any group that does not introduce any substitution or substitution pattern that is sterically impossible and/or cannot be synthesized.

Unless otherwise stated, conventional methods within the skill of the art, such as mass spectrometry, nuclear magnetic resonance, high performance liquid chromatography, infrared and ultraviolet/visible spectroscopy, and pharmacological methods are employed. Unless specific definitions are presented, the relevant terms and experimental procedures and techniques in analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry are known in the art herein. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for use of the kit, or in a manner well known in the art or as described in the present invention. The techniques and methods described above can generally be carried out according to conventional methods well known in the art from the descriptions in the various general and more specific documents cited and discussed in this specification. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable moieties and compounds.

When substituents are described by conventional chemical formulae written from left to right, the substituents also include the chemically equivalent substituents obtained when the structural formula is written from right to left. For example, _-CH2O- is equivalent to _-OCH2- .

The terms "group", "chemical group" as used herein refer to a specific moiety or functional group of a molecule. Chemical groups are often thought of as chemical entities embedded or attached to a molecule.

Some chemical groups named herein may be represented by abbreviated notation for the total number of carbon atoms. For example, _C1 - _C6 alkyl describes an alkyl group, as defined below, having a total of 1 to 6 carbon atoms. The total number of carbon atoms shown in the abbreviated symbols does not include carbon atoms on possible substituents.

The compounds of the present invention may contain one or more (eg, one, two, three or four) isotopic substitutions. For example, in the compounds, H can be in any isotopic form, including ¹ H, ² H (D or deuterium), and ³ H (T or tritium); C can be in any isotopic form, including ¹² C, ¹³ C, and ¹⁴ C ; O can be in any isotopic form, including ¹⁶ O and ¹⁸ O, etc.

The terms "halogen", "halo" or "halide" refer to bromine, chlorine, fluorine or iodine.

As used herein, the terms "aromatic", "aromatic ring", "aromatic", "aromatic", "aromatic ring" refer to a planar ring or ring moieties having 4n+2 A delocalized electron conjugate system of electrons, where n is an integer. Aromatic rings can be formed from 5, 6, 7, 8, 9, or more than 9 atoms. Aromatic compounds can be optionally substituted and can be monocyclic or fused-ring polycyclic. The term aromatic compound includes all carbocyclic rings (eg, benzene rings) and rings containing one or more heteroatoms (eg, pyridine).

The term "heteroatom" or "hetero" as used herein, alone or as part of other components, refers to atoms other than carbon and hydrogen. The heteroatoms are independently selected from, but are not limited to, oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different from each other.

The term "fused" or "fused ring" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more bonds.

The term "spiro" or "spirocycle" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.

The term "alkyl" as used herein alone or as part of other components (eg, monoalkylamino) refers to an optionally substituted straight or branched monovalent saturated hydrocarbon having 1-12 carbon atoms, preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms, linked to the rest of the molecule by single bonds, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, n-nonyl, n-decyl, etc.

The term "alkenyl," as used herein, alone or in combination, refers to an optionally substituted straight chain or optionally substituted branched chain monovalent hydrocarbon group having one or more C=C double bonds and having from 2 to about 10 carbons atom, more preferably 2 to about 6 carbon atoms. Double bonds in these groups can be in either the cis or trans conformation and should be understood to encompass both isomers. Examples include, but are not limited to, vinyl (CH=CH ₂ ), 1-propenyl (CH ₂ CH=CH ₂ ), isopropenyl (C(CH ₃ )=CH ₂ ), butenyl, and 1,3-butanyl Dienyl, etc. Alkenyl groups as defined herein appearing in numerical ranges, such as "C2 _{- C6alkenyl} " or " _C2-6alkenyl ", refer to groups of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc. Atoms or alkenyl groups of 6 carbon atoms, alkenyl groups herein also encompass cases where no numerical range is specified.

The term "alkynyl" as used herein, alone or in combination, refers to an optionally substituted linear or branched monovalent hydrocarbon group having one or more C≡C triple bonds and having from 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1,3-butadiynyl, and the like. Alkynyl groups as defined herein appearing in numerical ranges, such as "C ₂ -C ₆ alkynyl" or "C _2-6 alkynyl", refer to groups of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc. Atoms or alkynyl groups of 6 carbon atoms, alkynyl groups herein also encompass unspecified numerical ranges.

The term "aryl" refers to an all-carbon monocyclic or fused ring having a fully conjugated pi-electron system, having 6-14 carbon atoms, preferably 6-12 carbon atoms, and most preferably 6 carbon atoms . Aryl groups may be unsubstituted or substituted with one or more substituents, examples of which include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxy, sulfonyl , sulfinyl, phosphoryl and heteroalicyclic groups. Non-limiting examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.

The term "heteroaryl" refers to a monocyclic or fused ring of 5-12 ring atoms, having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms containing 1, 2, 3 or 4 ring atoms selected from N, O, S, the remaining ring atoms are C, and have a fully conjugated π-electron system. Heteroaryl groups can be unsubstituted or substituted, including but not limited to alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxy, cyano, nitro, carbonyl and hetero Alicyclic. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, iso Quinolinyl, tetrazolyl, triazinyl.

The term "cycloalkyl" as used herein, alone or as part of other components, refers to a stable monovalent non-aromatic monocyclic or polycyclic hydrocarbon group containing only carbon and hydrogen atoms, which may include fused, spiro, or bridged rings Ring system, containing 3-15 ring carbon atoms, preferably containing 3-10 ring carbon atoms, more preferably containing 3-8 ring carbon atoms, which may be saturated or unsaturated, through a single bond to the rest of the molecule connected. Non-limiting examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

The terms "heterocyclyl," "heterocycloalkyl," and "heterocycle," as used herein alone or as part of other components, refer to a stable 3-18 membered monovalent non-aromatic ring comprising 2-12 carbon atoms, 1 -6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise specified, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may contain fused, spiro or bridged ring systems, with nitrogen, carbon or sulfur selectivity on the heterocyclyl group is oxidized, the nitrogen atom can be selectively quaternized, and the heterocyclic group can be partially or fully saturated. A heterocyclyl group can be attached to the rest of the molecule by a single bond through a carbon atom or a heteroatom in the ring. Heterocyclyl containing fused rings may contain one or more aromatic or heteroaromatic rings, as long as the attachment to the rest of the molecule is an atom on a non-aromatic ring. For the purposes of this application, the heterocyclyl is preferably a stable 4 -11 membered monovalent non-aromatic monocyclic or bicyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-8 membered monovalent non-aromatic monocyclic ring containing 1- 3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclyl include azepanyl, azetidinyl, decahydroisoquinolyl, dihydrofuranyl, indoline, dioxolane, 1,1 -Dioxy-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, Piperazinyl, piperidinyl, 4-piperidinyl, pyranyl, pyrazolidine, pyrrolidinyl, quinazinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl and the like.

As used herein, the term "polymorph" or "polymorph (phenomenon)" means that the compounds of the present invention have a variety of crystal lattice morphologies. Some of the compounds of the present invention may have more than one crystalline form, and the present invention encompasses all polymorphic forms or mixtures thereof.

Intermediate compounds of the compounds of the present invention and polymorphs thereof are also within the scope of the present invention.

Unless otherwise specified, the olefinic double bonds contained in the compounds of the present invention include both E and Z isomers.

It is understood that the compounds of the present invention may contain asymmetric centers. These asymmetric centers can independently be in the R or S configuration. Some of the compounds of the present invention may also exhibit cis-trans isomerism, as will be apparent to those skilled in the art. It is to be understood that the compounds of the present invention include their individual geometric and stereoisomers as well as their mixtures, including racemic mixtures. These isomers can be isolated from their mixtures by practicing or modifying known methods, such as chromatographic techniques and recrystallization techniques, or they can be prepared separately from the appropriate isomers of their intermediates.

The term "pharmaceutically acceptable salt" as used herein includes both added and base salts.

"Pharmaceutically acceptable addition salts" refers to those that retain the biological potency and properties of the compound's free base, are not biologically or otherwise undesirable, and are associated with inorganic acids such as, but not limited to, hydrochloric acid, hydrogen Bromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, Salts of capric acid, caproic acid, carbonic acid, cinnamic acid, citric acid, etc. "Pharmaceutically acceptable base-added salts" refers to those salts that retain the biological potency and properties of the free acid of the compound and are not biologically or otherwise undesirable. These salts are prepared by reacting the free acid with an inorganic or organic base. Salts formed by reaction with inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and manganese salts.

Organic bases that form salts include, but are not limited to, primary, secondary, tertiary, cyclic amines, and the like, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine , Dicyclohexylamine, ethylenediamine, purine, piperazine, piperidine, choline and caffeine. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

Crystallization often yields solvates of the compounds of the present invention. As used herein, the term "solvate" refers to a complex formed by combining one or more molecules of a compound of the present invention with one or more molecules of a solvent.

The solvent may be water, in which case the solvate is a hydrate. In addition, an organic solvent may be used. Accordingly, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms. The compounds of the present invention may be true solvates, but in other cases, the compounds of the present invention may only accidentally retain water or a mixture of water and some other solvent. The compounds of the present invention can be reacted in a solvent or precipitated or crystallized in a solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention.

As used herein, the term "pharmaceutical composition" refers to a formulation that combines a compound of the present invention with a vehicle generally accepted in the art for delivering a biologically active compound to a mammal, such as a human. This medium contains all pharmaceutically acceptable carriers.

The term "acceptable" as used herein in relation to a formulation, composition or ingredient means no persistent detrimental effect on the general health of the subject being treated.

As used herein, the term "pharmaceutically acceptable" refers to a substance (eg, a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, ie, the substance can be administered to an individual without causing adverse biological effects React or interact in an undesirable manner with any component contained in the composition.

"Pharmaceutically acceptable carrier" includes, but is not limited to, adjuvants, carriers, excipients, auxiliaries, deodorants, diluents, preservatives, Dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers.

As used herein, the terms "subject," "patient," "subject," or "individual" refer to an individual, including mammals and non-mammals, suffering from a disease, disorder, condition, or the like. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (eg, chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals , such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the related methods and compositions provided herein, the mammal is a human.

The term "treatment" as used herein refers to the treatment of an associated disease or disorder in mammals, particularly humans, including

(i) preventing mammals, particularly mammals who have been previously exposed to a disease or condition but have not been diagnosed with the disease or condition, from developing a corresponding disease or condition;

(ii) inhibiting the disease or disorder, i.e. controlling its development;

(iii) alleviating the disease or condition, i.e. causing regression of the disease or condition;

(iv) Relief of symptoms caused by a disease or disorder.

As used herein, the terms "disease" and "disorder" can be used interchangeably or have different meanings, because some specific diseases or conditions have no known causative agent (so the cause of the disease is not clear), so they cannot be considered as A disease can only be seen as an unwanted condition or syndrome which has more or less specific symptoms that have been confirmed by clinical researchers.

As used herein, the terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" refer to at least one agent or compound sufficient to alleviate, to some extent, one or more symptoms of the disease or disorder being treated upon administration. amount. The result can be a reduction and/or amelioration of signs, symptoms or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is that amount of a composition comprising a compound disclosed herein required to provide clinically significant relief of a condition. An effective amount appropriate in any individual case can be determined using techniques such as dose escalation assays.

The terms "administering," "administering," "administering," and the like, as used herein, refer to methods capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, the oral route, the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

Preparation of Compounds of the Invention

It will be appreciated that in the following description, combinations of substituent groups and/or variables of the formulae are only permissible if stable compounds are formed.

It will also be appreciated by those skilled in the art that functional groups of intermediate compounds may need to be protected with suitable protecting groups. Protecting groups can be added or removed by standard techniques known to those skilled in the art.

Example 1: 3-((7-(2-((4-Aminocyclohexene)methyl)-5-chloro-3-methylphenyl)thieno[3,2-b]pyridine-2- Synthesis of Trifluoroacetate Salt

Step 1: Synthesis of Compound 3

To a solution of compound 1 (6.00 g), compound 2 (6.29 g) and triphenylphosphine (11.84 g) in THF (150 mL) was added dropwise DIAD (9.14 g) at 0°C. Subsequently, the reaction solution was warmed to room temperature and stirred at room temperature overnight. The reaction solution was concentrated under vacuum, the obtained residue was dissolved in ethyl acetate (500 mL), washed with 5% Na ₂ CO ₃ aqueous solution (100 mL×3) and saturated brine (100 mL×3), and then washed with anhydrous Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained residue was purified by flash silica gel column chromatography (dichloromethane:methanol=100:1-100:2) to obtain 3 (11.7 g) as a pale yellow solid.

Step 2: Synthesis of Compound 5

A solution of compound 3 (1.00 g), compound 4 (1.62 g), Pd(dppf)Cl ₂ (234 mg) and anhydrous potassium acetate (940 mg) in dioxane (30 mL) was heated to 100 °C under nitrogen protection , and stirred at this temperature overnight. After cooling to room temperature, the reaction solution was directly used in the next reaction without further purification.

Step 3: Synthesis of Compound 7

To a mixture of compound 6 (24 g) and 3M aqueous sulfuric acid (80 mL) was slowly added dropwise an aqueous solution of NaNO ₂ (8.26 g) (40 mL) at 0°C. The reaction solution was stirred at 0°C for 30 minutes. Then at this temperature, an aqueous solution of KI (21.7 g) (80 mL) was slowly added dropwise. After the dropwise addition, the temperature of the reaction solution was raised to room temperature and stirred overnight. Dichloromethane (100 mL) was added to the reaction solution, the organic phase was separated, the aqueous phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined . The obtained organic phase was washed with saturated aqueous NaHCO (100 mL), saturated aqueous sodium thiosulfate (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was passed through a flash silica gel column layer Purification by precipitation (petroleum ether as mobile phase) gave compound 7 (28 g) as a white solid.

Step 4: Synthesis of Compound 10

To a solution of 2,2,6,6-tetramethylpiperidine (400 mg) in tetrahydrofuran (10 mL) was slowly added dropwise n-butyllithium solution (1.1 mL, 2.82 mmol) at -78°C. The reaction solution was reacted at this temperature for 30 minutes, and then a solution of compound 9 (628 mg) in tetrahydrofuran (5 mL) was added dropwise thereto. The reaction solution was reacted at -78°C for 30 minutes, and a solution of compound 8 (500 mg) in tetrahydrofuran (2 mL) was added thereto, and then the temperature of the reaction solution was slowly raised to room temperature and stirred overnight. To this was added saturated aqueous ammonium chloride (20 mL) to quench the reaction. The organic solvent was removed by concentration under reduced pressure, and ethyl acetate/water (50 mL/50 mL) was added thereto, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (20 mL×2). The organic phases were combined, the obtained organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by flash silica gel column chromatography (petroleum ether:ethyl acetate=20:1) to obtain compound 10 (143 mg) ).

Step 5: Synthesis of Compound 11

Under nitrogen protection, a mixture of compound 10 (143 mg), compound 7 (140 mg), tetrakistriphenylphosphine palladium (46 mg) and anhydrous sodium carbonate (89 mg) in dioxane/water (4 mL/1 mL) The mixture was heated to 80°C and stirred overnight. The reaction solution was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The obtained residue was separated and purified by flash silica gel column chromatography (petroleum ether:ethyl acetate=20:1) to obtain compound 11 (87 mg ).

Step 6: Synthesis of Compound 12

Under nitrogen protection, a mixture of compound 11 (87 mg), compound 5 (132 mg), tetrakistriphenylphosphine palladium (23 mg) and anhydrous sodium carbonate (45 mg) in dioxane/water (4 mL/1 mL) Heat to 80°C and stir overnight. The temperature was lowered to room temperature, the reaction solution was concentrated under reduced pressure, and the obtained residue was separated and purified by flash silica gel column chromatography (dichloromethane:ethyl acetate=5:1) to obtain compound 12 (85 mg).

Step 7: Synthesis of Compound 13

To a solution of compound 12 (85 mg) in dichloromethane (2 mL) was added dropwise trifluoroacetic acid (0.2 mL), and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and diluted with dichloromethane (30 mL). The obtained organic phase was washed with saturated aqueous sodium carbonate solution (10 mL×3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was separated and purified by flash silica gel column chromatography (dichloromethane: methanol = 20: 1 to 10:1) to obtain compound 13 (65 mg). ¹ H NMR (400 MHz, CDCl ₃ ), 8.50-8.66 (m, 1H), 7.70-8.24 (br, 3H), 7.44-7.59 (m, 1H) , 7.30(s, 1H), 7.21(s, 1H), 6.94-7.18(m, 1H), 5.90-6.02(m, 1H), 4.69-4.85(m, 2H), 2.96-3.10(m, 1H) , 2.32-2.43(m, 2H), 2.12-2.28(m, 5H), 1.85-2.10(m, 4H), 1.52-1.80(m, 2H), 1.21(s, 3H), 1.10(s, 3H) .

Example 2: 3-((7-(5-Chloro-3-methyl-2-((E)-2-((R)-pyrrol-2-yl)vinyl)phenyl)thieno[3 ,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

Step 1: Synthesis of Compound 15

To a solution of compound 14 (18.8 g) in tetrahydrofuran (200 mL) was slowly added borane dimethyl sulfide (2M, 64 mL) dropwise at 0°C. The reaction was then warmed to 50°C and heated overnight. The temperature of the reaction solution was lowered to 0°C, and methanol was slowly added dropwise thereto to quench the reaction. The reaction solution was concentrated, and the obtained residue was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate=5:1 to 3:1) to obtain compound 15 (16.2 g).

Step 2: Synthesis of Compound 16

To a solution of compound 15 (16.2 g) in dichloromethane (200 mL) was added PBr3 (37.2 g) at 0°C. Subsequently, the temperature of the reaction solution was raised to room temperature, and stirring was continued at room temperature overnight. The reaction solution was quenched with saturated aqueous sodium bicarbonate solution, the organic phase was separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by flash silica gel column chromatography (petroleum ether:ethyl acetate=100:1) to obtain compound 16 (21.3 g).

Step 3: Synthesis of Compound 17

To compound 16 (4.4 g) was added triethyl phosphite (15 mL), and the reaction solution was heated to 160° C. by microwave and reacted overnight. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The obtained residue was separated and purified by flash silica gel column chromatography (petroleum ether:ethyl acetate=3:1 to 1:1) to obtain compound 17 (5.0 g) as a colorless oil.

Step 4: Synthesis of Compound 19

To a solution of compound 17 (70 mg) in tetrahydrofuran (0.75 mL) at 0°C, LiHMDS (1 M, 0.26 mL) was slowly added dropwise. The resulting reaction solution was continuously stirred at this temperature for 30 minutes, and then a solution of compound 18 (50 mg) in tetrahydrofuran (0.25 mL) was added dropwise thereto. After the dropwise addition was completed, the temperature of the reaction solution was slowly raised to room temperature and stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride (0.1 mL). Concentrate under reduced pressure and add ethyl acetate/water (20 mL/20 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by flash silica gel column chromatography (dichloromethane:methanol=50:1) to obtain compound 19 (30 mg).

Step 6: Synthesis of Compound 20

A solution of compound 19 (30 mg), compound 5 (41 mg), tetrakistriphenylphosphine palladium (8 mg) and anhydrous sodium carbonate (14 mg) in dioxane/water (2 mL/0.5 mL) was prepared under nitrogen protection. The mixture was heated to 80°C and stirred overnight. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the obtained residue was separated and purified by flash silica gel column chromatography (petroleum ether:ethyl acetate=5:1 to 2:1) to obtain compound 20 (35 mg).

Step 7: Synthesis of Compound 21

To a solution of compound 20 (35 mg) in dichloromethane (2 mL) was added dropwise trifluoroacetic acid (0.2 mL), and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was separated and purified by flash silica gel column chromatography (dichloromethane:methanol=20:1 to 10:1) to obtain compound 21 (21 mg). ¹ H NMR (400 MHz, CDCl ₃ ), 8.78-10.04 (br, 2H), 8.60 (s, 1H), 7.50 (s, 1H), 7.24 (s, 1H), 7.15 (s, 1H), 7.09 (s , 1H), 6.50(d, J=15.6Hz, 1H), 5.20-5.38(m, 1H), 4.76(s, 2H), 3.66-3.78(m, 1H), 2.97-3.09(m, 2H), 2.35 (s, 2H), 2.27 (s, 3H), 1.34-1.82 (m, 4H), 1.21 (s, 3H), 1.09 (s, 3H).

Example 3: 3-((7-(5-Chloro-3-methyl-2-(pyrrolidin-3-ylenmethyl)phenyl)thieno[3,2-b]pyridin-2-yl )methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

The synthetic method of embodiment 3 is the same as that of embodiment 1. ¹ H NMR (400 MHz, CDCl ₃ ), 8.62-8.71 (m, 1H), 7.46-7.58 (m, 1H), 7.31-7.35 (m, 1H), 7.18-7.20 (m, 0.5H), 7.14-7.16 (m, 0.5H), 6.97-7.05 (m, 1H), 6.21-6.28 (m, 1H), 4.78 (s, 2H), 3.57-3.68 (m, 1H), 3.37-3.46 (m, 1H), 3.12-3.24(m, 2H), 2.45-2.53(m, 1H), 2.36-2.39(m, 2H), 2.28(s, 3H), 2.15-2.23(m, 1H), 1.23(s, 1.5H) , 1.22(s, 1.5H), 1.12(s, 1.5H), 1.10(s, 1.5H).

Example 4: 3-((7-(3,5-Dichloro-2-(piperidin-4-ylenmethyl)phenyl)thieno[3,2-b]pyridin-2-yl)methan base)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

The synthetic method of embodiment 4 is the same as that of embodiment 1. ¹ H NMR (400 MHz, CD ₃ OD), 8.66 (s, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.46-7.50 (m, 2H), 7.29 (d, J=4.4 Hz, 1H) , 6.22(s, 1H), 4.83(s, 2H), 2.60-3.14(m, 4H), 2.49(s, 2H), 1.76-2.45(m, 5H), 1.22(s, 3H), 1.08(s , 3H).

Example 5: 3-((7-(5-Chloro-3-fluoro-2-(piperidin-4-ylenmethyl)phenyl)thieno[3,2-b]pyridin-2-yl) Methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

The synthetic method of embodiment 5 is the same as that of embodiment 1. ¹ H NMR 12 (400 MHz, CD ₃ OD), 8.67 (d, J=4.8 Hz, 1H), 7.49 (s, 1H), 7.45 (dd, J=10.0 Hz, 2.0 Hz, 1H), 7.35 (d, J =2.0Hz, 1H), 7.29(d, J=4.8Hz, 1H), 5.97(s, 1H), 4.83(s, 2H), 2.97-3.01(m, 2H), 2.89-2.93(m, 2H) , 2.49 (s, 2H), 2.33-2.37 (m, 2H), 2.22-2.25 (m, 2H), 1.23 (s, 3H), 1.08 (s, 3H).

Example 6: 3-((7-(2-((8-azabicyclo[3.2.1]oct-3-ylen)methyl)-5-chloro-3-methylphenyl)thieno[ 3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

The synthetic method of embodiment 6 is the same as that of embodiment 1. ¹ H NMR (400 MHz, CDCl ₃ ), 9.28-9.62 (br, 2H), 8.64 (s, 1H), 7.55 (s, 1H), 7.30 (s, 1H), 7.21 (s, 1H), 7.04 (s , 1H), 6.24(s, 1H), 4.77(s, 2H), 3.74-4.13(m, 2H), 2.88-3.02(m, 1H), 2.42-2.56(m, 1H), 2.37-1.50(m , 11H), 1.22(s, 3H), 1.10(s, 3H).

Example 7: 3-((7-(5-Chloro-3-methyl-2-(1-(piperidin-4-ylalkenyl)ethyl)phenyl)thieno[3,2-b] Pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

The synthetic method of embodiment 7 is the same as that of embodiment 1. ¹ H NMR (400 MHz, DMSO-d ₆ ), 8.60 (d, J=4.8 Hz, 1H), 7.48 (s, 2H), 7.33 (s, 1H), 7.06 (d, J=5.2 Hz, 1H), 4.70-4.79(m, 2H), 2.70-2.80(m, 1H), 2.56(s, 2H), 2.46-2.55(m, 2H), 2.10-2.24(m, 4H), 1.91-2.05(m, 2H) ), 1.71-1.81 (m, 1H), 1.40-1.67 (m, 4H), 1.13 (s, 3H), 0.95 (s, 3H).

Example 8: 3-((7-(5-Chloro-3-methyl-2-((tetrahydro-4H-pyran-4-ylen)methyl)phenyl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

The synthetic method of embodiment 8 is the same as that of embodiment 1. ¹ H NMR (400 MHz, CDCl ₃ ), 8.62 (d, J=5.2 Hz, 1H), 7.53 (s, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.20-7.23 (m, 1H), 7.01(d, J=5.2Hz, 1H), 5.96(s, 1H), 4.79(s, 2H), 3.02-3.64(m, 3H), 2.52-2.88(m, 1H), 2.35(s, 2H) , 2.26 (s, 3H), 1.87-2.20 (m, 3H), 1.70-1.84 (m, 1H), 1.21 (s, 3H), 1.08 (s, 3H).

Example 9: 3-((7-(5-Chloro-3-methyl-2-((E)-2-((S)-pyrrolidin-2-yl)vinyl)phenyl)thieno[ 3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

The synthetic method of embodiment 9 is the same as that of embodiment 2. ¹ H NMR (400 MHz, CDCl ₃ ), 9.20-9.66 (br, 1H), 8.54-8.94 (m, 2H), 7.65 (s, 1H), 7.26 (d, J=1.2Hz, 1H), 7.21 (d , J=4.4Hz, 1H), 7.16 (d, J=2.0Hz, 1H), 6.54 (d, J=16.4Hz, 1H), 5.34-5.52 (m, 1H), 4.78 (s, 2H), 3.83 -3.92(m, 1H), 3.05-3.24(m, 2H), 2.38(s, 2H), 2.34(s, 3H), 1.48-1.82(m, 4H), 1.22(s, 3H), 1.12(s , 3H).

Example 10: 3-((7-(5-Chloro-2-(piperidin-4-ylenmethyl)phenyl)thieno[3,2-b]pyridin-2-yl)methyl)- 6,6-Dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

The synthesis method of Example 10 is the same as that of Example 1. ¹ H NMR (400 MHz, CDCl ₃ ), 8.69 (d, J=4.8 Hz, 1H), 7.53 (s, 1H), 7.42 (dd, J=8.0 Hz, 2.0 Hz, 1H), 7.33 (d, J= 2.4Hz, 1H), 7.19(d, J=8.4Hz, 1H), 7.05(d, J=4.8Hz, 1H), 5.96(s, 1H), 4.78(s, 2H), 3.09-3.13(m, 2H), 2.98-3.03 (m, 2H), 2.63-2.68 (m, 2H), 2.34-2.39 (m, 5H), 1.20 (s, 3H), 1.09 (s, 3H).

Example 11: 3-((7-(5-Chloro-3-methyl-2-(piperidin-4-ylenmethyl)phenyl)thieno[3,2-b]pyridine-2- yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

The synthesis method of Example 11 is the same as that of Example 1. ¹ H NMR (400 MHz, CDCl ₃ ), 8.63 (d, J=4.8 Hz, 1H), 7.52 (s, 1H), 7.30 (d, J=1.6 Hz, 1H), 7.18 (d, J=1.6 Hz, 1H), 6.97(d, J=4.8Hz, 1H), 6.07(s, 1H), 4.78(s, 2H), 2.6-3.18(m, 2H), 2.32-2.62(m, 4H), 1.78-2.30 (m, 7H), 1.21 (s, 3H), 1.10 (s, 3H).

Example 12: 3-((7-(5-Chloro-2-(fluoro(piperidin-4-ylenmethyl)methyl)-3-methylphenyl)thieno[3,2-b] Pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

The synthesis method of Example 12 is the same as that of Example 1. ¹ H NMR (400 MHz, CDCl ₃ ), 8.65 (d, J=4.4 Hz, 1H), 7.55-7.59 (m, 1H), 7.35-7.41 (m, 2H), 7.08-7.13 (m, 1H), 4.79 (s, 2H), 3.11-3.20 (m, 1H), 2.71-2.80 (m, 1H), 2.44-2.63 (m, 2H), 2.41 (s, 2H), 2.34 (s, 3H), 2.09-2.28 (m, 2H), 1.96-2.05 (m, 1H), 1.56-1.72 (m, 1H), 1.23 (s, 3H), 1.13 (s, 3H).

Example 13: 3-((7-(5-Chloro-3-methyl-2-((E)-2-((S)-pyrrolidin-3-yl)vinyl)phenyl)thieno[ 3,2-b]pyridin 2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

The synthesis method of Example 13 is the same as that of Example 2. ¹ H NMR (400 MHz, CDCl ₃ ), 8.76-9.50 (br, 2H), 8.71 (d, J=4.8 Hz, 1H), 7.62 (s, 1H), 7.26 (d, J=2.0 Hz, 1H), 7.17 (d, J=4.8Hz, 1H), 7.14 (d, J=2.0Hz, 1H), 6.32 (d, J=16.0Hz, 1H), 5.00 (dd, J=16.0Hz, 8.0Hz, 1H) , 4.79(s, 2H), 2.99-3.28(m, 3H), 2.65-2.77(m, 1H), 2.38(s, 2H), 2.31(s, 3H), 2.08-2.28(m, 1H), 1.52 -1.78 (m, 2H), 1.21 (s, 3H), 1.09 (s, 3H).

Example 14: (E)-3-((7-(2-(3-Amino-3-methylbut-1-en-1-yl)-5-chloro-3-methylphenyl)thieno [3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

The synthesis method of Example 14 is the same as that of Example 2. ¹ H NMR (400 MHz, CDCl ₃ ), 8.65 (d, J=5.2 Hz, 1H), 7.53 (s, 1H), 7.21 (d, J=2.0 Hz, 1H), 7.18 (d, J=2.0 Hz, 1H), 7.11(d, J=5.2Hz, 1H), 6.41(d, J=16.4Hz, 1H), 5.24(d, J=16.4Hz, 1H), 4.78(s, 2H), 2.35(s, 2H), 2.27 (s, 3H), 1.24 (s, 6H), 1.21 (s, 3H), 1.09 (s, 3H).

Example 15: 3-((7-(5-Chloro-3-methyl-2-((E)-2-((R)-morpholin-3-yl)vinyl)phenyl)thieno[ 3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

The synthesis method of Example 15 is the same as that of Example 2. ¹ H NMR (400 MHz, CDCl ₃ ), 8.68 (d, J=5.2 Hz, 1H), 7.54 (s, 1H), 7.25 (d, J=1.6 Hz, 1H), 7.15 (d, J=1.6 Hz, 1H), 7.11 (d, J=4.4Hz, 1H), 6.53 (d, J=16.8Hz, 1H), 5.26 (dd, J=16.8Hz, 6.8Hz, 1H), 4.78 (s, 2H), 3.64 -3.73(m, 1H), 3.44-3.54(m, 1H), 3.28-3.39(m, 1H), 2.98-3.24(m, 1H), 2.74-2.95(m, 3H), 2.37(s, 2H) , 2.35 (s, 3H), 1.22 (s, 3H), 1.11 (s, 3H).

Example 16: 3-((7-(5-Chloro-3-methyl-2-((E)-2-((R)-pyrrolidin-3-yl)vinyl)phenyl)thieno[ 3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

The synthesis method of Example 16 is the same as that of Example 2. ¹ H NMR (400 MHz, CDCl ₃ ), 8.82-9.44 (br, 2H), 8.74 (d, J=4.8 Hz, 1H), 7.68 (s, 1H), 7.28 (d, J=1.6 Hz, 1H), 7.19 (d, J=4.8Hz, 1H), 7.16 (d, J=1.6Hz, 1H), 6.33 (d, J=16.0Hz, 1H), 4.99 (dd, J=16.0Hz, 8.0Hz, 1H) , 4.80(s, 2H), 2.95-3.33(m, 3H), 2.66-2.78(m, 1H), 2.39(s, 2H), 2.32(s, 3H), 2.06-2.28(m, 1H), 1.52 -1.80 (m, 2H), 1.22 (s, 3H), 1.11 (s, 3H).

Example 17: 3-((7-(2-(azetidin-3-ylenmethyl)-5-chloro-3-methylphenyl)thieno[3,2-b]pyridine-2 -yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

The synthesis method of Example 17 is the same as that of Example 1. ¹ H NMR (400MHz, DMSO-d ₆ ), 8.72-9.22 (br, 2H), 8.69 (d, J=4.8Hz, 1H), 7.48-7.53 (m, 2H), 7.33 (d, J=2.0Hz) , 1H), 7.27(d, J=4.8Hz, 1H), 6.31(s, 1H), 4.76(s, 2H), 4.30(s, 2H), 3.73(s, 2H), 2.56(s, 2H) , 2.31 (s, 3H), 1.13 (s, 3H), 0.97 (s, 3H).

Example 18: (z)-3-((7-(5-Chloro-3-methyl-2-(piperidin-3-ylenmethyl)phenyl)thieno[3,2-b]pyridine -2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

The synthesis method of Example 18 is the same as that of Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ), 8.63 (d, J=4.8 Hz, 1H), 8.04-8.62 (br, 2H), 7.51 (s, 1H), 7.46 (s, 1H), 7.34 (s , 1H), 7.22-7.31(m, 1H), 6.23(s, 1H), 4.74(s, 2H), 3.05-3.21(m, 1H), 2.89-3.04(m, 1H), 2.70-2.86(m , 1H), 2.57(s, 2H), 2.42-2.55(m, 1H), 2.30(s, 3H), 2.10-2.25(m, 1H), 1.68-1.85(m, 1H), 1.52-1.66(m , 2H), 1.15 (s, 3H), 1.01 (s, 3H).

Example 19: 3-((7-(5-Chloro-2-((4-(dimethylamino)cyclohexenyl)methyl)-3-methylphenyl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

The synthesis method of Example 19 is the same as that of Example 1. ¹ H NMR (400 MHz, CD ₃ OD), 8.66 (d, J=4.8 Hz, 1H), 7.50 (s, 1H), 7.41 (s, 1H), 7.38 (s, 1H), 7.32 (d, J= 4.8Hz, 1H), 6.17(s, 1H), 4.88(s, 2H), 3.04-3.14(m, 1H), 2.65-2.78(m, 2H), 2.51(s, 6H), 2.29-2.38(m , 2H), 2.24 (s, 3H), 1.80-2.15 (m, 4H), 1.52-1.65 (m, 2H), 1.14 (s, 3H), 1.08 (s, 3H).

Example 20: 3-((7-(5-Chloro-3-methyl-2-((2,2,6,6-tetramethylpiperidin-4-en)methyl)phenyl)thieno [3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

The synthesis method of Example 20 is the same as that of Example 1. ¹ H NMR (400 MHz, CDCl ₃ ), 8.65 (d, J=4.8 Hz, 1H), 7.59 (s, 1H), 7.31 (s, 1H), 7.18-7.26 (m, 1H), 7.03 (d, J =4.8Hz, 1H), 6.32(s, 1H), 4.77(s, 2H), 2.36(s, 2H), 2.26(s, 3H), 1.88-2.06(m, 3H), 1.37-1.86(m, 7H), 1.27-1.36 (m, 3H), 1.21 (s, 3H), 1.10 (s, 3H), 0.98-1.09 (m, 3H).

Example 21: 3-((7-(5-Chloro-3-methyl-2-((E)-2-((S)-piperidin-2-yl)vinyl)phenyl)thieno[ 3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

The synthesis method of Example 21 is the same as that of Example 2. ¹ H NMR (400 MHz, DMSO-d ₆ ), 8.65 (d, J=4.8 Hz, 1H), 7.62-8.42 (br, 2H), 7.49 (d, J=2.0 Hz, 1H), 7.47 (s, 1H) ), 7.30 (d, J=2.0Hz, 1H), 7.22-7.29 (m, 1H), 6.48 (d, J=16.4Hz, 1H), 5.13 (dd, J=16.4Hz, 8.0Hz, 1H), 4.73(s, 2H), 3.32-3.42(m, 1H), 2.93-3.02(m, 1H), 2.63-2.73(m, 1H), 2.56(s, 2H), 2.35(s, 3H), 1.49- 1.58 (m, 1H), 1.36-1.45 (m, 1H), 1.17-1.32 (m, 4H), 1.15 (s, 3H), 1.02 (s, 3H).

Example 22: 3-((7-(5-Chloro-3-methyl-2-((E)-2-((S)-morpholin-3-yl)vinyl)phenyl)thieno[ 3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

The synthesis method of Example 22 is the same as that of Example 2. ¹ H NMR (400 MHz, DMSO-d ₆ ), 8.63 (d, J=5.2 Hz, 1H), 7.47 (s, 1H), 7.43 (d, J=2.0 Hz, 1H), 7.22-7.24 (m, 2H) ), 6.37(d, J=16.0Hz, 1H), 4.97(dd, J=16.0Hz, 6.8Hz, 1H), 4.73(s, 2H), 3.42-3.49(m, 1H), 3.20-3.28(m , 1H), 2.99-3.09(m, 1H), 2.90-2.97(m, 1H), 2.62-2.82(br, 1H), 2.50-2.58(m, 4H), 2.31(s, 3H), 2.12-2.21 (m, 1H), 1.14 (s, 3H), 0.99 (s, 3H).

Example 23: 3-((4-(5-Chloro-3-methyl-2-(piperidin-4-ylenmethyl)phenyl)thieno[2,3-b]pyridin-2-yl )methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

The synthesis method of Example 23 is the same as that of Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ), 8.54 (s, 1H), 7.90-8.40 (br, 2H), 7.48 (d, J=2.0 Hz, 1H), 7.13-7.42 (m, 2H), 6.86 -7.12(m, 1H), 6.14(s, 1H), 4.72(s, 2H), 2.82-3.02(m, 1H), 2.60-2.74(m, 1H), 2.56(s, 2H), 2.25(s , 3H), 2.01-2.22 (m, 2H), 1.54-1.92 (m, 3H), 1.32-1.50 (m, 1H), 1.15 (s, 3H), 1.01 (s, 3H).

Example 24: (E)-3-((7-(5-Chloro-3-methyl-2-(pyrrolidin-2-ylenmethyl)phenyl)thieno[3,2-b]pyridine -2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

The synthesis method of Example 24 is the same as that of Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ), 8.70 (d, J=4.4 Hz, 1H), 7.55 (d, J=1.6 Hz, 1H), 7.50 (s, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.35(d, J=5.2Hz, 1H), 6.90-7.30(br, 1H), 4.76(s, 2H), 2.57(s, 2H), 2.50(t, J=7.6Hz, 2H) ), 2.43(s, 3H), 2.26(t, J=6.8Hz, 2H), 1.40-1.47(m, 2H), 1.14(s, 3H), 1.01(s, 3H).

Example 25: 3-((7-(5-Chloro-3-methyl-2-((4-(methylamino)cyclohexenyl)methyl)phenyl)thieno[3,2-b ]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

Step 1: Synthesis of Compound 22

To a solution of compound 12 (100 mg) in tetrahydrofuran (2 mL) was added sodium hydride (10 mg) at 0°C. The reaction solution was further stirred at 0°C for 30 minutes, and then methyl iodide (92 mg) was slowly added dropwise thereto. Then the temperature of the reaction solution was raised to room temperature, and the reaction was continued for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was separated and purified by flash silica gel column chromatography (dichloromethane:methanol=100:1 to 100:3) to obtain Compound 22 (65 mg).

Step 2: Synthesis of Compound 23

To a solution of compound 22 (65 mg) in dichloromethane (3 mL) was added trifluoroacetic acid (0.3 mL) at room temperature. The reaction solution was further stirred at room temperature for 2 hours until the reaction was completed. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by flash silica gel column chromatography (dichloromethane:methanol=100:1 to 10:1) to obtain compound 23 (25 mg). ¹ H NMR (400 MHz, DMSO-d ₆ ), 8.58-8.69 (m, 1H), 8.22-8.50 (br, 2H), 7.44-7.50 (m, 2H), 7.33 (s, 1H), 7.11-7.23 ( m, 1H), 5.87-6.03 (m, 1H), 4.75 (s, 2H), 2.81-2.92 (m, 1H), 2.57 (s, 2H), 2.08-2.53 (m, 10H), 1.76-1.90 ( m, 2H), 1.40-1.58 (m, 2H), 1.14 (s, 3H), 0.99 (s, 3H).

Example 26: 3-((7-(5-Chloro-3-methyl-2-(piperidin-4-ylenmethyl)phenyl)thieno[3,2-b]pyridin-2-yl )methyl)thiazolidine-2,4-dione trifluoroacetate

Step 1: Synthesis of Compound 25

Like compound 24 (5.0 g), TBSCl (11.32 g) was added to a solution of imidazole (10.23 g) in dichloromethane (100 mL) at room temperature. The reaction solution was reacted at room temperature for 2 hours, then the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by flash silica gel column chromatography (dichloromethane:methanol=200:1 to 100:1) to obtain compound 25 (7.5 g) .

Step 2: Synthesis of Compound 26

Under nitrogen protection, a solution of compound 25 (1.00 g), compound 4 (1.62 g), Pd(dppf)Cl ₂ (234 mg) and anhydrous potassium acetate (940 mg) in dioxane (30 mL) was heated to 100 °C , and stirred at this temperature overnight. After cooling to room temperature, the reaction solution was directly used in the next reaction without further purification.

Step 3: Synthesis of Compound 28

Under nitrogen protection, a mixture of compound 26 (300 mg), compound 27 (320 mg), tetrakistriphenylphosphine palladium (90 mg) and anhydrous sodium carbonate (190 mg) in dioxane/water (8 mL/2 mL) Heat to 80°C and stir overnight. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the obtained residue was separated and purified by flash silica gel column chromatography (dichloromethane:methanol=100:1 to 100:3) to obtain compound 28 (200 mg).

Step 4: Synthesis of Compound 29

To a solution of compound 28 (150 mg) in tetrahydrofuran (3 mL) was added TBAF (100 mg) at room temperature. The reaction solution was continued to stir at room temperature overnight until the reaction was completed. The reaction solution was concentrated under reduced pressure, and the obtained residue was separated and purified by flash silica gel column chromatography (dichloromethane:methanol=100:1 to 100:3) to obtain compound 29 (124 mg).

Step 5: Synthesis of Compound 31

To a solution of compound 29 (124 mg), compound 30 (60 mg), triphenylphosphine (134 mg) in anhydrous tetrahydrofuran (2 mL) was added dropwise DIAD (103 mg) at 0°C. The reaction was then warmed to room temperature and stirred overnight. After completion of the reaction, the reaction solution was concentrated. The obtained residue was separated and purified by flash silica gel column chromatography (dichloromethane:methanol=200:1 to 100:1) to obtain Compound 31 (110 mg).

Step 6: Synthesis of Compound 32

To a solution of compound 31 (110 mg) in dichloromethane (5 mL) was added trifluoroacetic acid (0.5 mL) at room temperature. The reaction solution was further stirred at room temperature for 2 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by flash silica gel column chromatography (dichloromethane:methanol=100:1 to 10:1) to obtain compound 32 (43 mg). ¹ H NMR (400 MHz) , DMSO-d ₆ ), 8.50-8.78 (m, 3H), 7.52 (s, 1H), 7.49 (d, J=2.0Hz, 1H), 7.36 (s, 1H), 7.22 (d, J=4.4Hz) , 1H), 6.15(s, 1H), 4.95(s, 2H), 4.27(s, 2H), 2.86-3.06(m, 1H), 2.60-2.78(m, 1H), 2.36-2.53(m, 1H) ), 2.15-2.32 (m, 4H), 1.77-2.10 (m, 3H), 1.44-1.66 (m, 1H).

Example 27: (E)-3-((7-(2-(2-(1-aminocyclopropyl)vinyl)-5-chloro-3-methylphenyl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

The synthesis method of Example 27 is the same as that of Example 2. ¹ H NMR (400 MHz, CD ₃ OD), 8.62 (d, J=4.4 Hz, 1H), 7.47 (s, 1H), 7.39 (d, J=1.6 Hz, 1H), 7.27 (d, J=4.8 Hz , 1H), 7.22(d, J=2.0Hz, 1H), 6.44(d, J=16.4Hz, 1H), 5.11(d, J=16.4Hz, 1H), 4.81(s, 2H), 2.48(s , 2H), 2.40 (s, 3H), 1.22 (s, 3H), 1.08 (s, 3H), 0.78-0.91 (m, 4H).

Example 28: 3-((4-(5-Chloro-3-methyl-2-(piperidin-4-ylenmethyl)phenyl)-7-(hydroxymethyl)pyrrolo[1,2 -b]pyridazin-6-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

Step 1: Synthesis of Compound 34

To a solution of compound 33 (1 g) and cesium carbonate (3.1 g) in DMF (5 mL) was added SEMCl (1.7 g) at room temperature. The reaction solution was stirred at room temperature overnight until the reaction was completed. Subsequently, the reaction solution was poured into water (30 mL). The aqueous phase was extracted with ethyl acetate (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by flash silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to obtain compound 34 (1.2 g).

Step 2: Synthesis of Compound 35

To a solution of compound 34 (1 g) in anhydrous tetrahydrofuran (30 mL) was added dropwise a 2.5M solution of n-butyllithium in hexane (1.75 mL) at -78°C. After the dropwise addition was completed, the reaction solution was stirred at this temperature for 30 minutes, then anhydrous DMF (0.9 mL) was added dropwise to the reaction solution to slowly warm the reaction solution to -20°C, and the reaction was continued for 4 hours at this temperature. After the reaction was completed, saturated ammonium chloride solution (50 mL) was added to quench the reaction. Concentrate under reduced pressure to remove tetrahydrofuran. The resulting solution was extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried by adding anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to obtain compound 35 (670 mg).

Step 3: Synthesis of Compound 36

To a solution of Compound 35 (670 mg) in methanol (20 mL) was added sodium borohydride (104 mg) portionwise at 0°C, and the reaction solution was then warmed to room temperature. The reaction solution was further stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. Water (40 mL) was added to the obtained residue, and extracted with ethyl acetate (40 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography (petroleum ether:ethyl acetate=2:1) to obtain Compound 36 (430 mg).

Step 4: Synthesis of Compound 37

To a solution of compound 36 (430 mg), compound 2 (406 mg), and PPh3 (766 mg) in tetrahydrofuran (10 mL) was added dropwise DIAD (590 mg) at 0°C, followed by stirring at room temperature overnight. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was separated and purified by flash silica gel column chromatography (petroleum ether:ethyl acetate=10:1 to 4:1) to obtain compound 37 (530 mg).

Step 5: Synthesis of Compound 38

To a solution of compound 37 (510 mg) in tetrahydrofuran (10 mL) was added TBAF (480 mg) at room temperature, and the reaction solution was heated to 45° C. to react overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained residue was separated and purified by flash silica gel column chromatography (dichloromethane:methanol=100:1 to 20:1) to obtain Compound 39 (230 mg).

Step 6: Synthesis of Compound 39

To a solution of compound 39 (230 mg) and triethylamine (0.4 mL) in dichloromethane (5 mL) was added trifluoromethanesulfonic anhydride (0.2 mL) at 0°C. The reaction solution was continued to react at room temperature for 6 hours. After the reaction was completed, the reaction solution was poured into ice water (30 mL), and extracted with dichloromethane (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to obtain compound 39 (110 mg).

Step 7: Synthesis of Compound 40

Phosphorus oxychloride (40 μL) was slowly added dropwise to a solution of compound 39 (110 mg) in DMF (2 mL) at 0° C. After the dropwise addition, the reaction solution was warmed to room temperature, and the reaction was continued for 6 hours. The reaction solution was poured into ice water (15 mL), and extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate=2:1) to obtain compound 40 (80 mg).

Step 8: Synthesis of Compound 41

To a solution of compound 40 (80 mg) in methanol (2 mL) was added sodium borohydride (11 mg) portionwise at 0°C, and then the reaction solution was warmed to room temperature. The reaction solution was further stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. Water (10 mL) was added to the obtained residue, and extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography (petroleum ether:ethyl acetate=2:1) to obtain Compound 36 (43 mg).

Step 9: Synthesis of Compound 42

Under nitrogen protection, compound 41 (43 mg), compound 42 (50 mg), tetrakistriphenylphosphine palladium (11 mg) and anhydrous sodium carbonate (20 mg) were dissolved in dioxane/water (1 mL/0.2 mL) The mixture was heated to 80°C and stirred overnight. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the obtained residue was separated and purified by flash silica gel column chromatography (dichloromethane:methanol=20:1 to 5:1) to obtain compound 42 (5.3 mg). ¹ H NMR (400 MHz, CDCl ₃ ), 8.13 (d, J=4.4 Hz, 1H), 7.29 (s, 1H), 7.17 (s, 1H), 6.33 (d, J=4.4 Hz, 1H), 6.16 ( s, 1H), 6.08 (s, 1H), 5.14 (s, 2H), 4.66 (s, 2H), 1.84-3.34 (m, 13H), 1.19 (s, 3H), 1.05 (s, 3H).

Example 29: (E)-3-((7-(2-(2-(3-azabicyclo[3.1.0]hexane-6-yl)ethenyl)-5-chloro-3-methyl Phenyl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dionetri Fluoroacetate

The synthesis method of Example 29 is the same as that of Example 2. ¹ H NMR (400 MHz, CDCl ₃ ), 8.84-10.28 (br, 2H), 8.62 (d, J=4.4 Hz, 1H), 7.50 (s, 1H), 7.24 (d, J=2.0 Hz, 1H), 7.12 (d, J=2.0Hz, 1H), 7.04 (d, J=4.8Hz, 1H), 6.21 (d, J=16.0Hz, 1H), 4.78 (s, 2H), 4.64 (dd, J=16.0 Hz, 7.6Hz, 1H), 3.31(d, J=11.6Hz, 2H), 3.17-3.23(m, 2H), 2.38(s, 2H), 2.30(s, 3H), 1.56-1.60(m, 1H) ), 1.22(s, 3H), 1.11(s, 3H), 1.02-1.10(m, 2H).

Example 30: 3-((7-(5-Chloro-3-methoxy-2-(piperidin-4-ylenmethyl)phenyl)thieno[3,2-b]pyridine-2- yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

The synthesis method of Example 30 is the same as that of Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ), 8.56-8.80 (m, 3H), 7.48 (s, 1H), 7.26 (d, J=2.0Hz, 1H), 7.24 (d, J=5.2Hz, 1H) ), 7.10(d, J=2.0Hz, 1H), 5.94(s, 1H), 4.76(s, 2H), 3.84(s, 3H), 3.05-3.09(m, 4H), 2.57(s, 2H) , 2.39-2.42 (m, 4H), 1.14 (s, 3H), 0.99 (s, 3H).

Example 31: 3-((4-(5-Chloro-3-methyl-2-(piperidin-4-ylenmethyl)phenyl)thieno[2,3-d]pyrimidin-6-yl )methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione hydrochloride

The synthesis method of Example 31 is the same as that of Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ), 9.11 (s, 1H), 8.62-8.88 (br, 1H), 8.18-8.37 (br, 1H), 7.55 (d, J=2.0Hz, 1H), 7.42 (d, J=2.4Hz, 1H), 7.13(s, 1H), 6.23(s, 1H), 4.77(s, 2H), 2.82-2.99(m, 1H), 2.60-2.74(m, 1H), 2.58(s, 2H), 2.14-2.34(m, 5H), 1.73-1.99(m, 3H), 1.23-1.39(m, 1H), 1.16(s, 3H), 1.03(s, 3H).

Example 32: 3-((4-(5-Chloro-3-methyl-2-(piperidin-4-ylenmethyl)phenyl)thieno[3,2-d]pyrimidin-6-yl )methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione hydrochloride

The synthesis method of Example 32 is the same as that of Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ), 9.20 (s, 1H), 8.70-8.92 (m, 1H), 8.26-8.46 (m, 1H), 7.58 (s, 1H), 7.56 (d, J= 2.0Hz, 1H), 7.46(d, J=2.0Hz, 1H), 6.21(s, 1H), 4.83(s, 2H), 2.83-3.01(m, 1H), 2.61-2.73(m, 1H), 2.59(s, 2H), 2.37-2.53(m, 1H), 2.19-2.34(m, 4H), 1.77-2.18(m, 3H), 1.35-1.53(m, 1H), 1.15(s, 3H), 1.02 (s, 3H).

Example 33: 3-(2-((6,6-Dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-3-yl)methyl)thieno[ 3,2-b]pyridin-7-yl)-5-methyl-4-(piperidin-4-ylenmethyl)benzamide

The synthesis method of Example 33 is the same as that of Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ), 8.66 (d, J=4.8 Hz, 1H), 7.99 (s, 1H), 7.92 (s, 1H), 7.82 (s, 1H), 7.47 (s, 1H) ), 7.41(s, 1H), 7.21(d, J=4.4Hz, 1H), 6.25(s, 1H), 4.57(s, 2H), 2.84-3.06(m, 1H), 2.43-2.80(m, 4H), 2.32 (s, 3H), 1.60-2.30 (m, 5H), 1.22 (s, 3H), 1.17 (s, 3H).

Example 34: 3-((7-(2-((4-Amino-4-methylcyclohexenyl)methyl)-5-chloro-3-methylphenyl)thieno[3,2- b]Pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

The synthesis method of Example 34 is the same as that of Example 1. ¹ H NMR (400 MHz, CDCl ₃ ), 8.82-8.96 (m, 0.7H), 8.55-8.66 (m, 0.3H), 7.84-7.99 (m, 0.7H), 7.48-7.55 (m, 0.3H), 7.17-7.36(m, 3H), 5.92-6.06(m, 1H), 4.76-4.90(m, 2H), 2.44(s, 2H), 2.24(s, 3H), 1.54-2.19(m, 8H), 1.38(s, 3H), 1.24(s, 3H), 1.11(s, 3H).

Example 35: 3-(2-((6,6-Dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-3-yl)methyl)thieno[ 3,2-b]pyridin-7-yl)-5-methyl-4-(piperidin-4-ylenmethyl)benzonitrile

The synthesis method of Example 35 is the same as that of Example 1. ¹ H NMR (400MHz, DMSO-d ₆ ), 8.28-9.04 (m, 3H), 7.89 (s, 1H), 7.81 (s, 1H), 7.50 (s, 1H), 7.26 (d, J=4.4Hz , 1H), 6.23(s, 1H), 4.76(s, 2H), 2.87-3.04(m, 1H), 2.50-2.76(m, 4H), 2.26-2.36(m, 4H), 1.74-2.14(m , 3H), 1.35-1.58 (m, 1H), 1.14 (s, 3H), 1.00 (s, 3H).

Example 36: 3-((7-(5-Chloro-2-((1-ethylpiperidin-4-ylalkenyl)methyl)-3-methylphenyl)thieno[3,2- b]Pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione hydrobromide

To a solution of the compound of Example 11 (100 mg) and potassium carbonate (82 mg) in tetrahydrofuran (1 mL) was added methyl bromide (65 mg). The reaction solution was reacted at room temperature overnight, then the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by flash silica gel column chromatography (dichloromethane:methanol=30:1 to 5:1) to obtain the compound of Example 36 (35 mg) . ¹ H NMR (400 MHz, CDCl ₃ ), 11.10-12.10 (br, 1H), 8.69 (s, 1H), 7.58 (s, 1H), 7.33 (s, 1H), 7.26 (s, 1H), 7.07 (s , 1H), 6.17(s, 1H), 4.80(s, 2H), 3.18-3.42(m, 1H), 2.62-3.14(m, 4H), 2.33-2.56(m, 3H), 2.12-2.29(m , 4H), 1.53-2.03 (m, 3H), 1.18-1.26 (m, 6H), 1.15 (s, 3H).

Example 37: 3-((4-(5-Chloro-3-methyl-2-(piperidin-4-ylenmethyl)phenyl)pyrro[2,1-f][1,2,4 ]triazin-6-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

Step 1: Synthesis of Compound 46

Under nitrogen protection, a mixture of compound 44 (150 mg), compound 45 (447 mg), tetrakistriphenylphosphine palladium (77 mg) and anhydrous sodium carbonate (141 mg) in dioxane/water (4 mL/1 mL) Heat to 80°C and stir overnight. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the obtained residue was separated and purified by flash silica gel column chromatography (dichloromethane:methanol=200:1 to 50:1) to obtain compound 42 (110 mg).

Step 2: Synthesis of Compound 47

To a solution of compound 47 (110 mg) in tetrahydrofuran (5 mL) was added dropwise a solution of DIBAl-H in toluene (0.75 mL, 1 M) at 0°C under nitrogen protection. The temperature of the reaction solution was then raised to room temperature, and stirring was continued at room temperature for 2 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium sulfate solution, the obtained mixture was filtered through celite, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by flash silica gel column chromatography (dichloromethane:methanol=100:1 to 100:3) to obtain compound 47 (42 mg).

Step 3: Synthesis of Compound 48

To a solution of compound 47 (42 mg), compound 2 (25 mg), and PPh3 (47 mg) in tetrahydrofuran (1 mL) was added dropwise DIAD (36 mg) at 0°C. The reaction solution was reacted at room temperature overnight. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was separated and purified by flash silica gel column chromatography (dichloromethane:methanol=200:1 to 100:1) to obtain compound 48 (21 mg).

Step 4: Synthesis of Compound 49

To a solution of compound 48 (21 mg) in dichloromethane (1 mL) was added trifluoroacetic acid (0.1 mL) at room temperature. The reaction solution was further stirred at room temperature for 2 hours until the reaction was completed. Saturated aqueous sodium bicarbonate solution (5 mL) was added to quench the reaction, and the aqueous phase was extracted with dichloromethane (5 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by flash silica gel column chromatography (dichloromethane:methanol=20:1 to 5:1) to obtain compound 23 (7.4 mg). ¹ H NMR (400 MHz, CD ₃ OD), 8.45(s, 1H), 7.95(s, 1H), 7.49(s, 1H), 7.40(s, 1H), 6.58(s, 1H), 6.32(s, 1H) 1H), 4.62(s, 2H), 2.82-2.98(m, 1H), 2.52-2.65(m, 1H), 2.13-2.48(m, 8H), 1.97-2.11(m, 1H), 1.78-1.91( m, 1H), 1.52-1.62 (m, 1H), 1.21 (s, 3H), 1.03 (s, 3H).

Example 38: 1-((7-(5-Chloro-3-methyl-2-(piperidin-4-ylenmethyl)phenyl)thieno[3,2-b]pyridin-2-yl )methyl)pyrrolidine-2,5-dione

The synthesis method of Example 38 is the same as that of Example 26. ¹ H NMR (400 MHz, CD ₃ OD), 8.63 (d, J=4.4 Hz, 1H), 7.49 (s, 1H), 7.43 (d, J=2.0 Hz, 1H), 7.34 (s, 1H), 7.26 (d, J=4.8Hz, 1H), 6.33(s, 1H), 4.94(s, 2H), 2.99-3.15(m, 1H), 2.77-2.92(m, 1H), 2.75(s, 4H), 2.32-2.60(m, 2H), 2.30(s, 3H), 2.10-2.26(m, 1H), 1.85-2.09(m, 2H), 1.64-1.83(m, 1H).

Example 39: 3-((7-(5-Chloro-3-methyl-2-(piperidin-4-ylenmethyl)phenyl)thieno[3,2-b]pyridin-2-yl )methyl)-1-(2,2,2-trifluoroethyl)pyrimidine-2,4(1H,3H)-dione trifluoroacetate

The synthesis method of Example 39 is the same as that of Example 26. ¹ H NMR (400 MHz, DMSO-d ₆ ), 8.63 (d, J=4.8 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.46-7.51 (m, 2H), 7.35 (s, 1H) ), 7.20(d, J=4.8Hz, 1H), 6.14(s, 1H), 5.89(d, J=8.4Hz, 1H), 5.24(s, 2H), 4.69(q, J=9.2Hz, 2H ), 2.86-3.05 (m, 1H), 2.58-2.77 (m, 1H), 2.23 (s, 3H), 1.75-2.19 (m, 4H), 1.36-1.66 (m, 2H).

Example 40: (E)-3-((7-(2-(2-(azetidin-3-yl)ethenyl)-5-chloro-3-methylphenyl)thieno[3, 2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

The synthesis method of Example 40 is the same as that of Example 2. LC-MS (ESI): [M+H] 492.3.

Example 41: 3-((7-(5-Chloro-2-((hexahydrocyclopentano[c]pyrrol-5(1H)-ylen)methyl)-3-methylphenyl)thiophene [3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

The synthesis method of Example 41 is the same as that of Example 1. ¹ H NMR (400MHz, DMSO-d ₆ ), 8.68-8.92 (br, 2H), 8.63 (d, J=4.8Hz, 1H), 7.46-7.48 (m, 2H), 7.31 (d, J=1.6Hz) , 1H), 7.19(d, J=4.4Hz, 1H), 6.09(s, 1H), 4.75(s, 2H), 3.16-3.25(m, 1H), 3.02-3.15(m, 1H), 2.56( s, 2H), 2.32-2.52(m, 2H), 2.10-2.31(m, 5H), 1.90-2.04(m, 2H), 1.38-1.64(m, 2H), 1.14(s, 3H), 0.97( s, 3H).

Example 42: 2-((7-(5-Chloro-3-methyl-2-(piperidin-4-ylenmethyl)phenyl)thieno[3,2-b]pyridin-2-yl )methyl)isoindole-1,3-dione trifluoroacetate

The synthesis method of Example 42 is the same as that of Example 26. ¹ H NMR (400 MHz, CD ₃ OD), 8.63 (d, J=4.4 Hz, 1H), 7.87-7.90 (m, 2H), 7.81-7.84 (m, 2H), 7.53 (s, 1H), 7.41 ( d, J=2.0Hz, 1H), 7.34 (s, 1H), 7.25 (d, J=4.8Hz, 1H), 6.31 (s, 1H), 5.14 (s, 2H), 2.97-3.14 (m, 1H) ), 2.68-2.87 (m, 1H), 2.06-2.57 (m, 6H), 1.54-2.06 (m, 3H).

Example 43: 3-(2-((6,6-Dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]yl-3-yl)methyl)thieno[3 , 2-b]pyridin-7-yl)-4-((1-ethylpiperidin-4-ylen)methyl)-5-methylbenzonitrile

The synthesis method of Example 43 is the same as that of Example 36. ¹ H NMR (400 MHz, DMSO-d ₆ ), 8.63-8.70 (m, 1H), 7.89 (s, 1H), 7.81 (s, 1H), 7.50 (s, 1H), 7.19-7.30 (m, 1H) , 6.04-6.36(m, 1H), 4.76(s, 2H), 2.66-3.12(m, 4H), 2.57(s, 2H), 2.18-2.54(m, 7H), 1.70-2.01(m, 2H) , 1.14 (s, 3H), 0.96-1.11 (m, 6H).

Example 44: 2-((7-(5-Chloro-3-methyl-2-(piperidin-4-ylenmethyl)phenyl)thieno[3,2-b]pyridin-2-yl )methyl)tetrahydrocyclopenteno[c]pyrrole-1,3(2H,3aH)-dione trifluoroacetate

The synthesis method of Example 44 is the same as that of Example 26. ¹ H NMR (400 MHz, DMSO-d ₆ ), 8.64 (d, J=4.8 Hz, 1H), 8.38-8.58 (br, 1H), 8.12-8.29 (br, 1H), 7.50 (d, J=2.0 Hz) , 1H), 7.47(s, 1H), 7.35-7.40(m, 1H), 7.22(d, J=4.8Hz, 1H), 6.19(s, 1H), 4.82(s, 2H), 3.20-3.26( m, 2H), 2.87-3.04 (m, 1H), 2.55-2.72 (m, 1H), 2.40-2.51 (m, 1H), 2.18-2.32 (m, 4H), 1.92-2.10 (m, 1H), 1.70-1.90(m, 5H), 1.58-1.68(m, 1H), 1.32-1.52(m, 1H), 1.02-1.20(m, 2H).

Example 45: 2-((7-(5-chloro-3-methyl-2-(piperidin-4-ylenmethyl)phenyl)thieno[3,2-b]pyridine-2- yl)methyl)hexahydro-1H-isoindole-1,3(2H)-dione trifluoroacetate

The synthesis method of Example 45 is the same as that of Example 26. ¹ H NMR (400 MHz, DMSO-d ₆ ), 8.64 (d, J=4.8 Hz, 1H), 8.35-8.54 (br, 1H), 8.07-8.27 (br, 1H), 7.49-7.50 (m, 2H) , 7.36-7.39(m, 1H), 7.22(d, J=4.4Hz, 1H), 6.20(s, 1H), 4.85(s, 2H), 2.86-3.06(m, 3H), 2.38-2.74(m , 2H), 2.14-2.33 (m, 4H), 1.65-2.14 (m, 5H), 1.30-1.61 (m, 5H), 1.14-1.28 (m, 2H).

Example 46: (3aR,4S,7R,7aS)-2-((7-(5-chloro-3-methyl-2-(piperidin-4-ylenmethyl)phenyl)thieno[3 ,2-b]pyridin-2-yl)methyl)hexahydro-1H-4,7-methyleneisoindole-1,3(2H)-dione trifluoroacetate

The synthesis method of Example 46 is the same as that of Example 26. ¹ H NMR (400 MHz, CDCl ₃ ), 9.60-9.98 (br, 1H), 8.58-9.01 (m, 2H), 7.65-7.72 (m, 1H), 7.34-7.38 (m, 1H), 7.14-7.24 ( m, 2H), 6.10(s, 1H), 4.90(s, 2H), 2.99-3.16(m, 1H), 2.81-2.98(m, 1H), 2.56-2.76(m, 5H), 3.41-3.56( m, 1H), 2.01-2.37 (m, 6H), 1.78-1.99 (m, 1H), 1.58-1.72 (m, 3H), 1.16-1.36 (m, 2H), 0.99-1.05 (m, 1H).

Example 47: 1-((7-(5-Chloro-3-methyl-2-(piperidin-4-ylenmethyl)phenyl)thieno[3,2-b]pyridin-2-yl )methyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione

The synthesis method of Example 47 is the same as that of Example 26. ¹ H NMR (400 MHz, CD ₃ OD), 8.60 (d, J=4.8 Hz, 1H), 7.86 (s, 1H), 7.53 (s, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.30 (s, 1H), 7.22(s, 1H), 6.29(s, 1H), 5.41(s, 2H), 3.95(s, 3H), 3.51(s, 3H), 3.01-3.15(m, 1H), 2.75-2.91 (m, 1H), 2.31-2.60 (m, 2H), 2.28 (s, 3H), 1.92-2.25 (m, 3H), 1.67-1.85 (m, 1H).

Example 48: 1-((7-(5-Chloro-3-methyl-2-(piperidin-4-ylenmethyl)phenyl)thieno[3,2-b]pyridin-2-yl )methyl)-3,3-dimethylpyrrolidine-2,5-dione trifluoroacetate

The synthesis method of Example 48 is the same as that of Example 26. ¹ H NMR (400 MHz, CDCl ₃ ), 8.84-9.72 (br, 2H), 8.61-8.71 (m, 1H), 7.53 (s, 1H), 7.33 (s, 1H), 7.21 (s, 1H), 7.01 -7.07(m, 1H), 6.10(s, 1H), 4.89(s, 2H), 3.57-4.12(m, 1H), 2.73-3.17(m, 2H), 2.32-2.64(m, 4H), 1.80 -2.31 (m, 6H), 1.29 (s, 6H).

Example 49: (3aR,4S,7R,7aS)-2-((7-(5-chloro-3-methyl-2-piperidin-4-ylenmethyl)phenyl)thieno[3, 2-b]pyridin-2-yl)methyl)-3a,4,7,7a-tetrahydro-1H-4,7-methyleneisoindole-1,3(2H)-dionetrifluoroethyl acid salt

The synthesis method of Example 49 is the same as that of Example 26. ¹ H NMR (400 MHz, CDCl ₃ ), 9.33-9.70 (br, 1H), 8.79-9.12 (br, 1H), 8.60-8.74 (m, 1H), 7.43-7.56 (m, 1H), 7.34 (s, 1H), 7.21(s, 1H), 7.02-7.11(m, 1H), 6.10(s, 1H), 5.98(s, 2H), 4.74(s, 2H), 3.62-4.27(m, 2H), 3.30 (s, 2H), 2.74-3.16 (m, 2H), 2.34-2.65 (m, 2H), 1.99-2.31 (m, 6H), 1.80-1.98 (m, 1H), 1.71 (d, J=8.4Hz) , 1H), 1.52 (d, J=8.4Hz, 1H).

Example 50: 4-(4-Chloro-2-(2-((6,6-Dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hex-3-yl) Methyl)thieno[3,2-b]pyridin-7-yl)-6-methylphenylene)piperidine-1-carbonitrile

To a solution of the compound of Example 11 (100 mg), DIEA (62 μL) in dichloromethane (5 mL) was added BrCN (40 mg). The reaction solution was reacted at room temperature overnight, then the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by flash silica gel column chromatography (dichloromethane:methanol=200:1 to 50:1) to obtain the compound of Example 50 (34 mg) ). ¹ H NMR (400 MHz, CD ₃ OD), 8.57-8.67 (m, 1H), 7.50 (s, 1H), 7.41 (s, 1H), 7.30 (s, 1H), 7.24 (d, J=4.8 Hz, 1H), 6.18(s, 1H), 4.83(s, 2H), 3.06-3.21(m, 1H), 2.78-2.93(m, 1H), 2.52-2.68(m, 1H), 2.48(s, 2H) , 2.15-2.32(m, 4H), 1.96-2.12(m, 2H), 1.81-1.95(m, 1H), 1.56-1.72(m, 1H), 1.22(s, 3H), 1.07(s, 3H) .

Example 51: 3-((7-(5-Chloro-3-methyl-2-((1-methylpiperidin-4-ylen)methyl)phenyl)thieno[3,2-b ]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

The synthesis method of Example 51 is the same as that of Example 36. ¹ H NMR (400 MHz, CD ₃ OD), 8.61-8.68 (m, 1H), 7.50 (s, 1H), 7.44 (d, J=1.6 Hz, 1H), 7.32 (s, 1H), 7.26 (d, J=4.8Hz, 1H), 4.83(s, 2H), 3.01-3.22(m, 1H), 2.78-2.98(m, 1H), 2.56-2.75(m, 4H), 2.38-2.55(m, 4H) , 2.31 (s, 3H), 1.72-2.28 (m, 3H), 1.62-1.84 (m, 1H), 1.23 (s, 3H), 1.10 (s, 3H).

Example 52: 3-((7-(2-((2-azaspiro[3.3]hept-6-ylen)methyl)-5-chloro-3-methylphenyl)thieno[3, 2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

The synthesis method of Example 52 is the same as that of Example 1. ¹ H NMR (400 MHz, CD ₃ OD), 8.62 (d, J=4.4 Hz, 1H), 7.47 (s, 1H), 7.39 (d, J=2.0 Hz, 1H), 7.24-7.26 (m, 2H) , 6.11(s, 1H), 4.83(s, 2H), 3.81(d, J=10.8Hz, 2H), 3.72(d, J=10.8Hz, 2H), 2.73(s, 2H), 2.49(s, 2H), 2.27-2.32 (m, 5H), 1.23 (s, 3H), 1.09 (s, 3H).

Example 53: (3aR,4S,7R,7aS)-2-((7-(5-chloro-3-methyl-2-(piperidin-4-ylenmethyl)phenyl)thieno[3 ,2-b]pyridin-2-yl)methyl)-3a,7a-dimethylhexahydro-1H-4,7-epoxyisoindole-1,3(2H)-dionetrifluoroacetic acid Salt

The synthesis method of Example 53 is the same as that of Example 26. ¹ H NMR (400 MHz, CDCl ₃ ), 9.52-9.94 (br, 1H), 8.44-8.86 (m, 2H), 7.56 (s, 1H), 7.33 (s, 1H), 7.23 (s, 1H), 7.04 -7.09(m, 1H), 6.11(s, 1H), 4.83-4.95(m, 2H), 4.55(s, 2H), 2.75-3.21(m, 4H), 2.33-2.54(m, 1H), 2.23 (s, 3H), 1.82-2.22 (m, 3H), 1.75-1.81 (m, 2H), 1.62-1.70 (m, 2H), 1.13 (s, 6H).

Example 54: 3-((7-(5-Chloro-3-methyl-2-(piperidin-4-ylenmethyl)phenyl)thieno[3,2-b]pyridin-2-yl )methyl)-3-azabicyclo[3.2.0]hept-2,4-dione trifluoroacetate

The synthesis method of Example 54 is the same as that of Example 26. ¹ H NMR (400 MHz, CDCl ₃ ), 9.33-9.61 (br, 1H), 8.78-9.08 (br, 1H), 8.62-8.73 (m, 1H), 7.59 (s, 1H), 7.33 (d, J= 2.0Hz, 1H), 7.22(s, 1H), 7.07(d, J=4.0Hz, 1H), 6.11(s, 1H), 4.96(s, 2H), 3.85-4.24(m, 2H), 3.28- 3.36(m, 2H), 2.97-3.17(m, 1H), 2.75-2.95(m, 1H), 2.60-2.71(m, 2H), 2.36-2.58(m, 2H), 2.24(s, 3H), 2.02-2.22 (m, 4H).

Example 55: 3-((7-(5-Chloro-2-((1-ethylazetidin-3-ylen)methyl)-3-methylphenyl)thieno[3, 2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

The synthesis method of Example 55 is the same as that of Example 36. ¹ H NMR (400 MHz, CDCl ₃ ), 8.73 (d, J=4.8 Hz, 1H), 7.58 (s, 1H), 7.32 (s, 1H) , 7.22(s, 1H), 7.08(d, J=4.8Hz, 1H), 6.32(s, 1H), 4.80(s, 2H), 3.28-4.64(m, 4H), 2.55-2.69(m, 2H) ), 2.37(s, 2H), 2.34(s, 3H), 1.23(s, 3H), 1.12(s, 3H), 1.03(t, J=7.2Hz, 3H).

Example 56: 3-((7-(5-Chloro-2-((1-isopropylpiperidin-4-ylen)methyl)-3-methylphenyl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

The synthesis method of Example 56 is the same as that of Example 36. ¹ H NMR (400 MHz, CDCl ₃ ), 8.62 (d, J=4.4 Hz, 1H), 7.48 (s, 1H), 7.28 (s, 1H), 7.24 (s, 1H), 7.04 (d, J=4.0 Hz, 1H), 6.11(s, 1H), 4.69-4.89(m, 2H), 2.76-3.11(m, 3H), 2.29-2.64(m, 4H), 2.08-2.25(m, 4H), 1.68- 1.92 (m, 2H), 1.18-1.23 (m, 4H), 1.12 (s, 3H), 1.04 (d, J=6.8Hz, 6H).

Example 57: 3-((7-(5-Chloro-2-((1-(cyclopropylmethyl)piperidin-4-ylen)methyl)-3-methylphenyl)thieno[3 ,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

The synthesis method of Example 57 is the same as that of Example 36. ¹ H NMR (400 MHz, CDCl ₃ ), 8.62 (d, J=4.8 Hz, 1H), 7.50 (s, 1H), 7.30 (d, J=1.6 Hz, 1H), 7.23-7.27 (m, 1H), 7.04(d, J=4.8Hz, 1H), 6.11(s, 1H), 4.79(s, 2H), 2.99-3.21(m, 1H), 2.62-2.88(m, 2H), 2.08-2.52(m, 10H), 1.72-1.98(m, 2H), 1.22(s, 3H), 1.12(s, 3H), 0.85-1.05(m, 1H), 0.56-0.65(m, 2H), 0.09-0.21(m, 2H).

Example 58: 3-((7-(5-Chloro-3-methyl-2-((E)-2-((S)-morpholin-2-yl)vinyl)phenyl)thieno[ 3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

The synthesis method of Example 58 is the same as that of Example 2. ¹ H NMR (400 MHz, CDCl ₃ ), 8.67-8.75 (m, 1H), 7.61 (s, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.12-7.18 (m, 2H), 6.54 (d , J=16.4Hz, 1H), 5.03 (dd, J=16.4Hz, 4.8Hz, 1H), 4.82 (s, 2H), 4.15-4.23 (m, 1H), 3.86-3.99 (m, 2H), 3.24 -3.34(m, 1H), 2.90-3.05(m, 1H), 2.50-2.59(m, 1H), 2.44(d, J=5.2Hz, 1H), 2.40(d, J=5.2Hz, 1H), 2.28-2.37 (m, 4H), 1.22 (s, 3H), 1.12 (s, 3H).

Example 59: 3-((7-(5-Chloro-3-methyl-2-((8-methyl-8-azabicyclo[3.2.1]oct-3-ylen)methyl)benzene yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

The synthesis method of Example 59 is the same as that of Example 36. ¹ H NMR (400 MHz, CDCl ₃ ), 8.68 (d, J=4.8 Hz, 1H), 7.57 (s, 1H), 7.31 (d, J= 2.0Hz, 1H), 7.18-7.26(m, 1H), 7.04-7.12(m, 1H), 6.25-6.37(m, 1H), 4.74-4.83(m, 2H), 3.20-3.69(m, 3H) , 2.60(s, 3H), 2.15-2.44(m, 6H), 1.94-2.10(m, 2H), 1.48-1.91(m, 4H), 1.22(s, 3H), 1.11(s, 3H).

Example 60: 3-(2-((6,6-Dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hex-3-yl)methyl)thieno[3 ,2-b]pyridin-7-yl)-4-((1-isopropylpiperidin-4-ylen)methyl)-5-methylbenzonitrile trifluoroacetate

The synthesis method of Example 60 is the same as that of Example 36. ¹ H NMR (400 MHz, DMSO-d ₆ ), 8.68 (s, 1H), 7.75-7.92 (m, 2H), 7.50 (s, 1H), 7.16-7.38 (m, 1H), 6.29 (s, 1H) , 4.77(s, 2H), 3.12-3.40(m, 2H), 2.68-3.10(m, 2H), 2.51-2.63(m, 3H), 2.20-2.40(m, 4H), 2.03-2.19(m, 1H), 1.54-1.87 (m, 2H), 1.15 (s, 3H), 0.86-1.14 (m, 9H).

Example 61: 3-((7-(2-((6-Aminospiro[3.3]hept2-ylen)methyl)-5-chloro-3-methylphenyl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

The synthesis method of Example 61 is the same as that of Example 1. ¹ H NMR (400 MHz, CD ₃ OD), 8.59-8.61 (m, 1H), 7.47 (s, 1H), 7.36-7.38 (m, 1H), 7.24-7.26 (m, 2H), 6.03-6.06 (m , 1H), 4.84(s, 1.2H), 4.83(s, 0.8H), 2.50-2.53(m, 0.8H), 2.49(s, 0.8H), 2.48(s, 1.2H), 2.43-2.46( m, 1.2H), 2.30(s, 3H), 1.88-2.09(m, 6H), 1.74-1.82(m, 1H), 1.23(s, 1.2H), 1.22(s, 1.8H), 1.07(s , 1.2H), 1.06 (s, 1.8H).

Example 62: 3-((7-(5-Chloro-2-((1-cyclopropylpiperidin-4-ylen)methyl)-3-methylphenyl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

The synthesis method of Example 62 is the same as that of Example 36. ¹ H NMR (400 MHz, CD ₃ OD), 8.60 (d, J=5.2 Hz, 1H), 7.47 (s, 1H), 7.41 (d, J=2.0 Hz, 1H), 7.30-7.33 (m, 1H) , 7.24(d, J=5.2Hz, 1H), 6.17(s, 1H), 4.83(s, 2H), 2.70-2.87(m, 1H), 2.41-2.60(m, 3H), 2.13-2.35(m , 5H), 1.40-1.91 (m, 4H), 1.26-1.35 (m, 1H), 1.22 (s, 3H), 1.08 (s, 3H), 0.39-0.58 (m, 4H).

Example 63: 3-((7-(5-Chloro-3-methyl-2-(piperidin-4-ylenmethyl)phenyl)thieno[3,2-b]pyridin-2-yl )methyl)oxazoline-2,4-dione trifluoroacetate

The synthesis method of Example 63 is the same as that of Example 26. ¹ H NMR (400 MHz, CDCl ₃ ), 8.67-9.68 (br, 2H), 8.66 (s, 1H), 7.61 (s, 1H), 7.32 (d, J=2.0 Hz, 1H), 7.22 (s, 1H) ), 7.03(d, J=4.4Hz, 1H), 6.12(s, 1H), 4.89-5.01(m, 2H), 4.75(s, 2H), 2.96-3.14(m, 1H), 2.74-2.92( m, 1H), 2.33-2.54 (m, 2H), 2.23 (s, 3H), 1.79-2.22 (m, 4H).

Example 64: 3-((7-(5-Chloro-2-((1-isopropylazetidin-3-ylen)methyl)-3-methylphenyl)thieno[3 ,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

The synthesis method of Example 64 is the same as that of Example 36. ¹ H NMR (400 MHz, CDCl ₃ ), 8.70 (d, J=4.4 Hz, 1H), 7.55 (s, 1H), 7.31 (d, J=1.6 Hz, 1H), 7.21 (d, J=1.6 Hz, 1H), 7.07(d, J=5.2Hz, 1H), 6.29(s, 1H), 4.79(s, 2H), 3.98-4.40(m, 2H), 3.30-3.86(m, 2H), 2.55-2.66 (m, 1H), 2.36(s, 2H), 2.34(s, 3H), 1.22(s, 3H), 1.11(s, 3H), 1.01(d, J=6.4Hz, 6H).

Example 65: 6,6-Dimethyl-3-((7-(3-methyl-5-nitro-2-(piperidin-4-ylenmethyl)phenyl)thieno[3, 2-b]pyridin-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

The synthesis method of Example 65 is the same as that of Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ), 8.69 (d, J=5.2 Hz, 1H), 8.18-8.40 (m, 3H), 8.13 (s, 1H), 7.53 (s, 1H), 7.30 (d , J=4.8Hz, 1H), 6.30(s, 1H), 4.77(s, 2H), 2.90-3.04(m, 1H), 2.60-2.74(m, 1H), 2.57(s, 2H), 2.44- 2.56(m, 1H), 2.39(s, 3H), 2.20-2.35(m, 1H), 1.72-2.13(m, 3H), 1.33-1.53(m, 1H), 1.14(s, 3H), 1.00( s, 3H).

Example 66: 6,6-Dimethyl-3-((7-(3-methyl-2-(piperidin-4-ylenmethyl)-5-(trifluoromethyl)phenyl)thiophene [3,2-b]pyridin-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-2,4-dione

The synthesis method of Example 66 is the same as that of Example 1. ¹ H NMR (400 MHz, CDCl ₃ ), 8.65 (d, J=4.8 Hz, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 7.44 (s, 1H), 7.01 (d, J=4.8 Hz, 1H), 6.12(s, 1H), 4.78(s, 2H), 2.95-3.15(m, 1H), 2.74-2.94(m, 1H), 2.37-2.56(m, 2H), 2.36(s, 2H), 2.31 (s, 3H), 1.75-2.24 (m, 4H), 1.20 (s, 3H), 1.09 (s, 3H).

Example 67: 3-((7-(5-Chloro-3-methyl-2-(piperidin-4-ylenmethyl)phenyl)thieno[3,2-b]pyridin-2-yl )methyl)-1-methylimidazoline-2,4-dione trifluoroacetate

The synthesis method of Example 67 is the same as that of Example 26. ¹ H NMR (400 MHz, CDCl ₃ ), 8.74-9.76 (br, 2H), 8.63 (d, J=4.8 Hz, 1H), 7.54 (s, 1H), 7.31 (d, J=1.6 Hz, 1H), 7.20(s, 1H), 6.98(d, J=4.8Hz, 1H), 6.10(s, 1H), 4.89(s, 2H), 3.90(s, 2H), 2.98-3.17(m, 1H), 2.97 (s, 3H), 2.76-2.96 (m, 1H), 2.32-2.65 (m, 4H), 2.22 (s, 3H), 1.86-2.21 (m, 2H).

Example 68: 3-((7-(5-Chloro-3-methyl-2-((1-(2,2,2-trifluoroethyl)azetidin-3-ylene)methan yl)phenyl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-di ketone

The synthesis method of Example 68 is the same as that of Example 36. ¹ H NMR (400 MHz, CDCl ₃ ), 8.69 (d, J=4.0 Hz, 1H), 7.55 (s, 1H), 7.27 (s, 1H), 7.18 (s, 1H), 7.06 (d, J=4.0 Hz, 1H), 6.06(s, 1H), 4.79(s, 2H), 3.72-3.80(m, 2H), 3.16-3.26(m, 2H), 2.79(q, J=9.6Hz, 2H), 2.34 (s, 2H), 2.32 (s, 3H), 1.20 (s, 3H), 1.07 (s, 3H).

Example 69: 3-((7-(2-((3-Azaspiro[5.5]undec-9-ylen)methyl)-5-chloro-3-methylphenyl)thieno[ 3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

The synthesis method of Example 69 is the same as that of Example 1. ¹ H NMR (400MHz, _CD3OD ), 8.58 (d, J=5.2Hz, 1H), 7.45 (s, 1H), 7.39 (d, J=2.4Hz, 1H), 7.31 (d, J=2.4HZ) , 1H), 7.24(d, J=4.8Hz, 1H), 6.03(s, 1H), 4.83(s, 2H), 2.90-3.08(m, 4H), 2.49(s, 2H), 2.26(s, 3H), 1.85-2.16(m, 2H), 1.40-1.72(m, 6H), 1.24-1.35(m, 2H), 1.23(s, 3H), 1.10(s, 3H), 0.73-0.88(m, 2H).

Example 70: 3-((7-(2-((2-Azaspiro[3.5]nonan-7-ylen)methyl)-5-chloro-3-methylphenyl)thieno[3 ,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

The synthesis method of Example 70 is the same as that of Example 1. ¹ H NMR (400 MHz, CD ₃ OD), 8.56 (d, J=5.2 Hz, 1H), 7.44 (s, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.29 (d, J=2.0 Hz) , 1H), 7.22(d, J=5.2Hz, 1H), 6.06(s, 1H), 4.82(s, 2H), 3.45-3.71(m, 4H), 2.50(s, 2H), 2.26(s, 3H), 1.84-1.98 (m, 1H), 1.38-1.80 (m, 6H), 1.23 (s, 3H), 1.10 (s, 3H), 0.83-0.88 (m, 1H).

Example 71: 3-(2-((6,6-Dimethyl-2,4-dioxo-3-aza[3.1.0]hexane-3-yl)methyl)thieno[3 , 2-b]pyridin-7-yl)-5-methyl-4-((1-methylpiperidin-4-ylen)methyl)benzonitrile

The synthesis method of Example 71 is the same as that of Example 36. ¹ H NMR (400 MHz, CD ₃ OD), 8.65 (d, J=5.2 Hz, 1H), 7.78 (s, 1H), 7.70 (s, 1H), 7.49 (s, 1H), 7.28 (d, J= 5.2Hz, 1H), 6.36(s, 1H), 4.83(s, 2H), 2.86-3.07(m, 1H), 2.60-2.83(m, 2H), 2.54(s, 3H), 2.49(s, 2H) ), 2.37(s, 3H), 2.08-2.24(m, 1H), 1.86-2.07(m, 1H), 1.50-1.80(m, 2H), 1.23(s, 3H), 1.09(s, 3H), 0.83-0.89 (m, 1H).

Example 72: 3-(2-((6,6-Dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-3-yl)methyl)thieno[ 3,2-b]pyridin-7-yl)-5-methyl-4-((8-methyl-8-azabicyclo[3.2.1]oct-3-ylen)methyl)benzonitrile

The synthesis method of Example 72 is the same as that of Example 36. ¹ H NMR (400 MHz, CDCl ₃ ), 8.68-8.74 (m, 1H), 7.63 (s, 1H), 7.50-7.60 (m, 2H), 7.06-7.11 (m, 1H), 6.35 (s, 1H) , 4.76-4.85(m, 2H), 3.34-3.64(m, 3H), 2.92-3.10(m, 1H), 2.72-2.79(m, 1H), 2.59(s, 2H), 2.39(s, 3H) , 2.30(s, 3H), 1.97-2.11(m, 2H), 1.66-1.85(m, 2H), 1.24(s, 3H), 1.13(s, 3H), 0.76-0.85(m, 1H).

Example 73: 4-(Azacyclobutyl-3-ylenmethyl)-3-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[ 3.1.0]Hexan-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)-5-methylbenzonitrile

The synthesis method of Example 73 is the same as that of Example 1. ¹ H NMR (400 MHz, CDCl ₃ ), 8.69 (d, J=4.8 Hz, 1H), 7.56 (s, 1H), 7.55 (s, 1H), 7.49 (s, 1H), 7.04 (d, J=4.8 Hz, 1H), 6.04-6.08(m, 1H), 4.81(s, 2H), 3.98-4.02(m, 2H), 3.40-3.48(m, 2H), 2.39(s, 3H), 2.36(s, 2H), 1.21 (s, 3H), 1.07 (s, 3H).

Example 74: 4-((1-Cyclopropylpiperidin-4-ylen)methyl)-3-(2-((6,6-dimethyl-2,4-dioxo-3- Azabicyclo[3.1.0]hexane-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)-5-methylbenzonitrile

The synthesis method of Example 74 is the same as that of Example 36. ¹ H NMR (400 MHz, CD ₃ OD), 8.64 (d, J=4.4 Hz, 1H), 7.75 (s, 1H), 7.68 (s, 1H), 7.49 (s, 1H), 7.28 (d, J= 4.8Hz, 1H), 6.24(s, 1H), 4.83(s, 2H), 2.76-2.94(m, 1H), 2.48(s, 2H), 2.36(s, 3H), 2.21-2.35(m, 2H) ), 1.95-2.10 (m, 1H), 1.47-1.94 (m, 5H), 1.22 (s, 3H), 1.08 (s, 3H), 0.44-0.59 (m, 4H).

Example 75: 3-((7-(5-Chloro-3-methyl-2-(piperidin-4-ylenmethyl)phenyl)thieno[3,2-b]pyridin-2-yl )methyl)-1-(2,2,2-trifluoroethyl)imidazoline-2,4-dione trifluoroacetate

The synthesis method of Example 75 is the same as that of Example 26. ¹ H NMR (400 MHz, CDCl ₃ ), 8.90-9.66 (br, 2H), 8.66 (s, 1H), 7.57 (s, 1H), 7.32 (d, J=2.0 Hz, 1H), 7.22 (s, 1H) ), 6.99-7.05(m, 1H), 6.11(s, 1H), 4.94(s, 2H), 4.07(s, 2H), 3.92-4.04(m, 2H), 2.73-3.17(m, 4H), 2.33-2.52 (m, 2H), 2.23 (s, 3H), 1.99-2.22 (m, 2H).

Example 76: 3-((7-(5-Chloro-2-((1-(cyclopropylmethyl)azetidin-3-ylen)methyl)-3-methylphenyl) Thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

The synthesis method of Example 76 is the same as that of Example 36. ¹ H NMR (400 MHz, DMSO-d ₆ ), 8.66 (d, J=4.8 Hz, 1H), 7.46-7.51 (m, 2H), 7.32 (d, J=1.6 Hz, 1H), 7.26 (d, J =4.8Hz, 1H), 6.23(s, 1H), 4.76(s, 2H), 4.14-4.28(m, 2H), 3.61-3.75(m, 4H), 2.54(s, 2H), 2.30(s, 3H), 1.12 (s, 3H), 0.96 (s, 3H), 0.88-0.95 (m, 1H), 0.38-0.44 (m, 2H), 0.12-0.16 (m, 2H).

Example 77: 3-(2-((6,6-Dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-3-yl)methyl)thieno[ 3,2-b]pyridin-7-yl)-4-((1-isopropylazetidin-3-ylen)methyl)-5-methylbenzonitrile

The synthesis method of Example 77 is the same as that of Example 36. ¹ H NMR (400 MHz, CDCl ₃ ), 8.74 (d, J=2.8 Hz, 1H), 7.61 (s, 1H), 7.57 (s, 1H), 7.51 (s, 1H), 7.09 (d, J=2.8 Hz, 1H), 6.36(s, 1H), 4.79(s, 2H), 3.04-4.63(m, 4H), 2.63-2.78(m, 1H), 2.42(s, 3H), 2.36(s, 2H) , 1.22 (s, 3H), 1.11 (s, 3H), 0.97-1.10 (m, 6H).

Example 78: 3-(2-((6,6-Dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-3-yl)methyl)thieno[ 3,2-b]pyridin-7-yl)-4-((1-ethylazetidin-3-ylen)methyl)-5-methylbenzonitrile hydrochloride

The synthesis method of Example 78 is the same as that of Example 36. ¹ H NMR (400 MHz, DMSO-d ₆ ), 10.41-10.97 (br, 1H), 8.71 (d, J=4.8 Hz, 1H), 7.90 (s, 1H), 7.78 (s, 1H), 7.52 (s , 1H), 7.32(d, J=5.2Hz, 1H), 6.36(s, 1H), 4.76(s, 2H), 4.20-4.36(m, 2H), 3.71-3.91(m, 2H), 2.72- 2.83 (m, 2H), 2.56 (s, 2H), 2.36 (s, 3H), 1.14 (s, 3H), 0.99 (s, 3H), 0.87 (t, J=7.2Hz, 3H).

Example 79: 4-((4-Aminocyclohexene)methyl)-3-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1. 0]Hexan-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)-5-methylbenzonitrile

The synthesis method of Example 79 is the same as that of Example 1. ¹ H NMR (400 MHz, CDCl ₃ ), 8.52-8.63 (m, 1H), 7.59 (s, 1H), 7.44-7.56 (m, 2H), 7.03-7.12 (m, 1H), 6.00 (s, 1H) , 4.69-4.84(m, 2H), 2.94-3.05(m, 1H), 2-38(s, 2H), 2.28(s, 3H), 2.15-2.25(m, 1H), 1.82-2.10(m, 4H), 1.36-1.80 (m, 3H), 1.21 (s, 3H), 1.09 (s, 3H).

Example 80: 3-(2-((6,6-Dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-3-yl)methyl)thieno[ 3,2-b]pyridin-7-yl)-4-((4-(dimethylamino)cyclohexylene)methyl)-5-methylbenzonitrile

The synthesis method of Example 80 is the same as that of Example 36. ¹ H NMR (400 MHz, CDCl ₃ ), 8.56-8.70 (m, 1H), 7.46-7.60 (m, 3H), 6.93-7.11 (m, 1H), 5.93-6.04 (m, 1H), 4.76-4.85 ( m, 2H), 2.46-2.62 (m, 1H), 2.12-2.42 (m, 12H), 1.80-2.06 (m, 4H), 1.42-1.75 (m, 3H), 1.23 (s, 3H), 1.13 ( s, 3H).

Example 81 : 3-(2-((2,5-dioxopyrrolidin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-5-methyl-4 -(Piperidin-4-ylenmethyl)benzonitrile

The synthesis method of Example 81 is the same as that of Example 26.¹H NMR (400MHz, CD₃OD), 8.65(d, J=4.8Hz, 1H), 7.78(s, 1H), 7.71(s, 1H), 7.49(s, 1H), 7.29(d, J=5.2Hz, 1H), 6.41( s, 1H), 4.94(s, 2H), 3.02-3.17(m, 1H), 2.76-2.93(m, 1H), 2.75(s, 4H), 2.48-2.61(m, 1H), 2.31-2.46( m, 4H), 2.14-2.28 (m, 1H), 1.89-2.10 (m, 2H), 1.64-1.84 (m, 2H).

Example 82: 1-((7-(5-Chloro-3-methyl-2-(piperidin-4-ylenmethyl)phenyl)thieno[3,2-b]pyridin-2-yl )methyl)-3,3,4,4-tetramethylpyrrolidine-2,5-dione trifluoroacetate

The synthesis method of Example 82 is the same as that of Example 26. ¹ H NMR (400 MHz, DMSO-d ₆ ), 8.64 (d, J=4.8 Hz, 1H), 8.22-8.50 (br, 2H), 7.50 (s, 1H), 7.47 (s, 1H), 7.39 (s , 1H), 7.22(d, J=4.0Hz, 1H), 6.20(s, 1H), 4.85(s, 2H), 2.86-3.02(m, 1H), 2.40-2.70(m, 2H), 2.16- 2.34 (m, 4H), 1.68-2.09 (m, 3H), 1.30-1.50 (m, 1H), 1.05 (s, 12H).

Biological activity test:

1. In vitro enzymatic activity assay of compounds inhibiting USP7

The enzymatic activity detection of USP7 in this patent is carried out by a fast fluorescence method, using Ubiquitin-Rhodamine110 as an alternative substrate for the reaction and optimized to establish a high-throughput screening platform. Assays for the inhibitory activity of compounds against USP7 were performed on this platform. The specific method is as follows: Compounds were diluted 5-fold with 100% DMSO starting from 1mM (7 concentrations in total), and 2μL of each concentration was added to 48μL of reaction buffer (20mM Tris, pH 8.0, 2mM CaCl2, 1mM Reduced glutathione, 0.01% (v/v) Triton X-100, 0.01% (w/v) BSA) was diluted and mixed. 5 μL of the final diluted compound was added to a black 384-well plate (OptiPlate-384, Cat. No. 6007270, purchased from PerkinElmer), followed by 10 μL of His-USP7 (final concentration 0.05 nM). After the 384-well plate was placed in an incubator at 23°C for 30 minutes, 5 μL of the surrogate substrate Ubiquitin-Rhodamine 110 (Cat. No. U-555, purchased from Boston Biochem, final concentration 10nM) was added to each well, and the reaction was continued in the 23°C incubator. 1.5 hours. Add 5 μL of citric acid to each well to stop the reaction (Cat. No. 77-92-9, purchased from Sinopharm Group, final concentration 10 mM), and read the fluorescence value (excitation 485nm/emission 535nm) using BMGClariostar Microplate Reader. The IC50 value of the compound for the inhibition of USP7 enzymatic activity was calculated using GraphPad Prism software.

Table 1. Inhibitory effect of example compounds on USP7

2. Activity assay of compounds inhibiting the proliferation of RS4;11 cells

(货号G7570，购自Promega)试剂，室温摇床反应5-10分钟。在BMG ClariostarMicroplate Reader上读取化学发光值，数据使用GraphPad Prism软件进行处理，计算得到该化合物对细胞增殖抑制的IC50值。Human acute lymphoblastic leukemia cell line RS4; 11 cells were used RPMI-1640 medium plus 10% fetal bovine serum (FBS, purchased from Biological Industries, BI) and 1% penicillin/streptomycin (P/S, purchased from Thermo Fisher Scientific) at 37°C, 5% CO ₂ . RS4;11 cells were plated in 96-well plates (Cat. #3917, from CORNING) at a concentration of 4000 cells/195 μL/well. After 24 hours, the compounds were diluted and mixed by 3 times with 100% DMSO starting from 10 mM (10 concentrations in total), and then 4 μL of each concentration was added to 96 μL of RPMI-1640 medium for dilution and mixing. 5 μL of each concentration of the diluted compound was added to the plated cell suspension, and the compound was incubated with the cells for 72 hours (3 days) in a cell incubator. Then add 35 μL of Cell-Titer

(Cat. No. G7570, purchased from Promega) reagent, shake at room temperature for 5-10 minutes. The chemiluminescence value was read on the BMG Clariostar Microplate Reader, and the data was processed using GraphPad Prism software to calculate the IC50 value of the compound for inhibiting cell proliferation.

Table 2. Inhibitory effect of compounds on RS4;11 cell line

Claims (11)

1. A compound of formula (II) or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof,

wherein,

Y₁、Y₂、Y₃and Y₄And Y₅One of which is CR30, the remaining four of which are each independently selected from N and CR₃，

R₃₀Is composed of

The A ring and the B ring are aromatic rings,

X₁and X₂Each independently selected from CR₄And a combination of N and N, wherein,

X₃and X₄Each independently selected from the group consisting of C or N,

X₅and X₆Each independently selected from N, NR₅O, S and CR₆And X₅And X₆Not being CR at the same time₆，

L is selected from- (CR)₁₂R₁₃)_n-、-O-、-S-、-NR₁₀-、-(CO)-、-(CO)NR₁₀-、-(CO)O-、-S(O)₂-and-S (O)₂NR₁₀-，

n is 0, 1, 2, 3, or 4,

R₉selected from H, halogen, -CN and C_1-6An alkyl group, which may be optionally substituted with halogen,

R₁and R₂Each independently selected from H, halogen, -CN, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -O-R₁₀、-NR₁₀R₁₁、C_3-8Cycloalkyl and 3-8 membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl optionally being substituted by halogen, -CN, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -O-R₁₀、-NR₁₀R₁₁、C_3-8Cycloalkyl, or 3-to 8-membered heterocycloalkyl, or

R₁And R₂Can be connected together to form C_3-12Cycloalkyl or 3-12 membered heterocycloalkyl, which cycloalkyl and heterocycloalkyl may optionally be substituted by R₅₀The substitution is carried out by the following steps,

R₅₀selected from halogen, -CN, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -O-R₁₀、-NR₁₀R₁₁、C_3-8Cycloalkyl and 3-8 membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl optionally being substituted by halogen, -CN, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -O-R₁₀、-NR₁₀R₁₁、C_3-8Cycloalkyl, or 3-8 membered heterocycloalkyl,

R₃selected from H, halogen, -CN, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -O-R₁₀、-NR₁₀R₁₁、C_3-8Cycloalkyl and 3-8 membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl optionally being substituted by halogen, -CN, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -O-R₁₀、-NR₁₀R₁₁、C_3-8Cycloalkyl, or 3-8 membered heterocycloalkyl,

R₄each independently selected from H, halogen, -CN, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -O-R₁₀、-NR₁₀R₁₁、C_3-8Cycloalkyl and 3-8 membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl optionally being substituted by halogen, -CN, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -O-R₁₀、-NR₁₀R₁₁、C_3-8Cycloalkyl, or 3-8 membered heterocycloalkyl,

R₅each independently selected from H, -CN, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl and 3-8 membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl optionally being substituted by halogen, -CN, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -O-R₁₀、-NR₁₀R₁₁、C_3-8Cycloalkyl, or 3-8 membered heterocycloalkyl,

R₆selected from H, halogen, -CN, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -O-R₁₀、-NR₁₀R₁₁、C_3-8Cycloalkyl and 3-8 membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl optionally being substituted by halogen, -CN, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -O-R₁₀、-NR₁₀R₁₁、C_3-8Cycloalkyl, or 3-8 membered heterocycloalkyl,

R₇is 5-12 membered heteroaryl, 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl and may optionally be substituted by R₄₀Substituted, said cycloalkyl and heterocycloalkyl being optionally fused with a 5-to 10-membered aryl or 5-to 12-membered heteroaryl, the aryl or heteroaryl fused with cycloalkyl or heterocycloalkyl being optionally substituted with R₄₀The substitution is carried out by the following steps,

R₄₀selected from (═ O), halogen, -CN, -O-R₁₀、-NR₁₀R₁₁、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl, or 3-8 membered heterocycloalkyl, which alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl may optionally be substituted with halogen, -CN, -O-R₁₀、-NR₁₀R₁₁、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -O-R₁₀、-NR₁₀R₁₁、C_3-8Cycloalkyl, or 3-8 membered heterocycloalkyl,

R₁₀and R₁₁Each independently selected from H, C_1-6Alkyl and C_3-8A cycloalkyl group,

R₁₂and R₁₃Each independently selected from H, halogen and C_1-6An alkyl group.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, having a structure according to formula (I),

wherein,

the A ring and the B ring are aromatic rings,

l is- (CH)₂)_n-，

n is 1, 2, 3, or 4,

X₁and X₂Each independently selected from CR₄And a combination of N and N, wherein,

X₃、X₄each independently selected from the group consisting of C or N,

X₅and X₆Each independently selected from N, NR₅O, S and CR₆And X₅And X₆Not being CR at the same time₆，

Y₁、Y₂、Y₃And Y₄Each independently selected from N and CR₃，

R₉Selected from H, halogen, -CN and C_1-6An alkyl group, which may be optionally substituted with halogen,

R₁and R₂Each independently selected from H, C_1-6Alkyl radical, C_3-12Cycloalkyl and 3-12 membered heterocycloalkyl, said alkyl, cycloalkyl and heterocycloalkyl being optionally substituted by halogen, -CN, -O-R₁₀、-NR₁₀R₁₁Or C_1-6Alkyl is substituted, or

R₁And R₂Can be connected together to form C_3-12Cycloalkyl or 3-12 membered heterocycloalkyl, which cycloalkyl and heterocycloalkyl may optionally be substituted by halogen, -CN, -O-R₁₀、-NR₁₀R₁₁Or C_1-6Alkyl substituted, which alkyl may optionally be substituted by halogen,

R₃each independently selected from H, halogen, C_1-6Alkyl radical, C_3-8Cycloalkyl and 3-8 membered heterocycloalkyl, said alkyl, cycloalkyl and heterocycloalkyl being optionally substituted by halogen, -CN, -O-R₁₀、-NR₁₀R₁₁Or C_1-6The substitution of the alkyl group is carried out,

R₄each independently selected from H, halogen and C_1-6Alkyl, which may optionally be substituted by halogen, -CN, -O-R₁₀or-NR₁₀R₁₁The substitution is carried out by the following steps,

R₅selected from H, C_1-6Alkyl radical, C_3-8Cycloalkyl and 3-to 8-membered heterocycloalkyl,

R₆selected from H, halogen, C_1-6Alkyl radical, C_3-8Cycloalkyl and 3-to 8-membered heterocycloalkyl,

R₇is a 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl, which cycloalkyl and heterocycloalkyl may optionally be substituted (═ O), or C_1-6Alkyl substituted, said alkyl being optionally substituted by halogen, -CN, -O-R₁₀or-NR₁₀R₁₁And the substitution is carried out on the compound,

R₁₀and R₁₁Each independently selected from H, C_1-6Alkyl and C_3-8A cycloalkyl group.

3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, wherein

n is 1 or 2, and n is a hydrogen atom,

X₁and X₂Are both CH.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, wherein X₅Is NR₅O or S, X₆Is CR₆Or X₆Is NR₅O or S, X₅Is CR₆，

R₅Selected from H, C_1-6Alkyl radical, C_3-8Cycloalkyl and 3-to 8-membered heterocycloalkyl,

R₆selected from H, halogen, C_1-6Alkyl radical, C_3-8Cycloalkyl and 3-8 membered heterocycloalkyl.

5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, wherein R₇Is a 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl, which cycloalkyl and heterocycloalkyl may optionally be substituted (═ O), or C_1-6Alkyl substitution.

6. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, wherein R₉Selected from H, halogen and C_1-6Alkyl, which may be optionally substituted with halogen.

7. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, wherein Y₁、Y₂、Y₃And Y₄Each independently selected from CR₃，R₃Each independently selected from H, halogen and C_1-6An alkyl group.

8. A compound, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof,

9. a pharmaceutical composition comprising a compound according to any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, and optionally a pharmaceutically acceptable carrier.

10. Use of a compound according to any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, or a pharmaceutical composition according to claim 9, in the manufacture of a medicament for the treatment of a disease associated with USP7 activity.

11. The use according to claim 10, wherein the disease associated with USP7 activity is ovarian cancer, breast cancer, lung cancer, pancreatic cancer, renal cancer, melanoma, liver cancer, colon cancer, sarcoma, brain cancer, prostate cancer, leukemia, lymphoma, or multiple myeloma.