CN114075218A - USP7 inhibitor - 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 inhibitor

Technical Field

The present application relates to a USP7 inhibitor, a process for its preparation and its therapeutic use in the treatment of neoplastic diseases.

Background

PTMs include methylation, acetylation, phosphorylation, glycosylation, ubiquitination, S-nitrosylation, and the like. As one of the most studied PTMs, ubiquitination involves the proteolytic mechanism within the cell and regulates many physical activities within the cell. A cascade of ubiquitin activating enzyme (E1), ubiquitin conjugating enzyme (E2) and ubiquitin ligase (E3) can catalyze ubiquitination of a target protein. First, ubiquitin is activated by E1 in the presence of adenosine triphosphate and transferred to E2 by a transsulfuration reaction, and then bound to lysine or α -amino group of substrate protein in the presence of E3. Finally, protein markers with more than four ubiquitin molecules can be identified and influenced by the 26S proteasome, where they are degraded, producing small polypeptides.

Deubiquitinase (DUBS) is responsible for removing ubiquitin and maintaining the stability of the substrate by degrading ubiquitin. To date, approximately 100 DUBs have been identified, which 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), cysteine-dependent protease Machado-Joseph disease protease (MJDS) and zinc metalloprotease JAB1/MPN/Mov34 (JAMMS).

The USPS family, which has nearly 50 members, is the largest of all DUB subfamilies. These members all include conserved domains, namely the three major functional domains of the Cys, His and Asp/Asn cassettes, which are responsible for the recombination of ubiquitin binding molecules.

Among the members of the USP family, the ubiquitin-specific protease USP7, also known as herpes associated ubiquitin-specific protease (HAUSP), is a unique deubiquitinase found in 1997, a new member of the ubiquitin-specific protease family that interacts with the herpes simplex virus type 1 immediate early protein (Vmw 110). Subsequently, USP7 was found to interact with other viral proteins, such as Epstein-Barr nuclear antigen 1(EBNA1) of Epstein-Barr virus (EBV) and vrrf 1 (viral interferon regulatory factor 1) protein of kaposi's sarcoma-associated herpes virus (KSHV), thus indicating that it is a universal target for herpes viruses and was named herpes-associated ubiquitin-specific protease. To date, USP7 is the most widely studied deubiquitinase and is considered to be an oncogene that promotes tumor growth and affects the patient's immune response to tumors.

USP7 is highly expressed in a variety of cancers and affects the progression of cancer diseases. In addition, 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 the development of cancer through the p 53-dependent pathway in non-small cell lung cancer (NSCLC). Studies have shown that changes in USP7 modulate the growth and apoptosis sensitivity of colon cancer in vivo. USP7 maintains DNA damage response and promotes cervical cancer, and is positively correlated with low survival rate of cervical cancer patients. USP7 provides certain treatments for leukemia by stabilizing GATA1 to regulate human erythroid terminal differentiation. In short, USP7 plays an important role in a variety of pathological processes and is a good target from a therapeutic point of view.

USP7 not only has a role in regulating cellular pathways such as viral proteins, immune responses, oncogenes and DNA damage, but also is abnormally expressed in various cancers, and thus is a promising target. However, no effective selective USP7 inhibitor has been found for a long time due to the lack of protein co-crystal structure between USP7 and small molecule inhibitors. For several years, the crystal structures of some USP7 small molecule inhibitors and complexes thereof with USP7 were published sequentially, and these structures provide guidance for obtaining structure-based small molecule inhibitors. In recent years, although some USP7 small-molecule inhibitors are reported, the USP7 inhibitors have unsatisfactory in vivo efficacy data, so that no USP7 small-molecule inhibitor enters clinical trials at present. Therefore, a USP7 inhibitor with good in vivo activity is in high demand to be developed for the early treatment of patients with tumors aberrantly expressing USP 7.

The compound belongs to the invention is a USP7 deubiquitinase inhibitor with proprietary intellectual property rights. It can inhibit USP7 deubiquitinase with high selectivity, so as to treat patients with tumors with abnormal USP7 expression safely and effectively.

Disclosure of Invention

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

wherein the content of the first and second substances,

Y₁、Y₂、Y₃and Y₄And Y₅One of them is CR30, the remaining oneFour 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;

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

wherein the content of the first and second substances,

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, aryl, heteroaryl, and heteroaryl,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;

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

in some embodiments, X₁Is CR₄，X₂Is N, or X₂Is CR₄，X₁Is N, wherein

R₄Selected from H, halogen and C_1-6Alkyl, which may optionally be substituted by halogen, -CN, -O-R₁₀or-NR₁₀R₁₁Substituted, R₁₀And R₁₁Each independently selected from H, C_1-6Alkyl and C_3-8Cycloalkyl, preferably R₄Is H;

in some embodiments, X₅Is NR₅O or S, X₆Is CR₆Or X₆Is NR₅O or S, X₅Is CR₆Wherein

R₅Selected from H, C_1-6Alkyl radical, C_3-8Cycloalkyl and 3-8 membered heterocycloalkyl, preferably H and C_1-6The alkyl group, more preferably H,

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

in some embodiments, 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;

in some embodiments, R₇Is composed of

In some embodiments, R₃Each independently selected from H, halogen and C_1-6An alkyl group;

in some embodiments, R₉Selected from H and C_1-6Alkyl, which may be optionally substituted with halogen;

in some embodiments, R₉Is H;

in some embodiments, Y₁、Y₂、Y₃And Y₄Each independently selected from CR₃，R₃Each independently selected from H, halogen, C_1-6Alkyl radical, C_3-8Cycloalkyl and 3-8 membered heterocycloalkyl;

in some embodiments, Y₁、Y₂、Y₃And Y₄Each independently selected from CR₃，R₃Each independently selected from H, halogen and C_1-6An alkyl group;

in some embodiments, the compound of formula (I) is a 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 carrier;

in another aspect, the present invention provides a method of treating a disease associated with activity of USP7, said method comprising administering to a subject an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or a pharmaceutical composition of the present invention; in some embodiments, 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;

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 the use of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or a pharmaceutical composition of the present invention, in the manufacture of a medicament for the treatment of a disease associated with activity of USP 7; in some embodiments, 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.

Detailed Description

Exemplary embodiments utilizing the principles of the present invention are set forth in the following detailed description of the invention. 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 the various aspects of the invention is defined by the claims and that methods and structures within the scope of these claims and their equivalents are intended to be covered thereby.

Unless defined otherwise, all technical and scientific terms used 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, and publications cited herein are incorporated by reference in their entirety unless otherwise indicated.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, explanatory and are not restrictive of any inventive subject matter. The use of the singular forms also includes the plural unless specifically stated otherwise. The use of "or", "or" means "and/or" unless stated otherwise. Furthermore, the term "comprising" as well as other forms, such as "includes," "including," and "containing," are not 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 instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" means "unsubstituted alkyl" or "substituted alkyl". And, optionally substituted groups may be unsubstituted (e.g.: CH)₂CH₃) Fully substituted (e.g.: -CF₂CF₃) Monosubstituted (e.g.: -CH₂CH₂F) Or any level between mono-and fully substituted (e.g.: -CH₂CHF₂、-CF₂CH₃、-CFHCHF₂One skilled in the art will appreciate that any substitution or substitution pattern for any group containing one or more substituents that is not sterically impossible and/or cannot be synthesized is not introduced.

Unless otherwise indicated, conventional methods within the skill of the art are employed, such as mass spectrometry, nuclear magnetism, high performance liquid chromatography, infrared and ultraviolet/visible spectroscopy, and pharmacological methods. Unless specific definitions are set forth, the nomenclature used herein in the analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry, as well as the laboratory procedures and techniques, are those known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the instructions of the kit from the manufacturer, or according to the methods known in the art or the instructions of the present invention. The techniques and methods described above can generally be practiced according to conventional methods well known in the art, as described in various general and more specific documents referred to and discussed in this specification. In the present specification, groups and substituents thereof may be selected by one skilled in the art to provide stable moieties and compounds.

When a substituent is described by a general formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the formula is written from right to left. For example, -CH₂O-is equivalent to-OCH₂-。

As used herein, the terms "group", "chemical group" or "chemical group" refer to a particular portion or functional group of a molecule. Chemical groups are often considered as chemical entities embedded in or attached to a molecule.

Some of the chemical groups named herein may be referred to by a shorthand notation for the total number of carbon atoms. E.g. C₁-C₆Alkyl describes an alkyl group, as defined below, having a total of 1 to 6 carbon atoms. The total number of carbon atoms indicated by shorthand notation does not include carbon atoms on possible substituents.

The compounds of the invention may contain one or more (e.g. one, two, three or four) isotopic substitutions. For example, in the compounds, H may be in any isotopic form, including¹H、²H (D or deuterium) and³h (T or tritium); c may be in any isotopic form, including¹²C、¹³C and¹⁴c; o may be in any isotopic form, including¹⁶O and¹⁸o, and the like.

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

The terms "aromatic", "aromatic ring", "aromatic" and "aromatic-cyclic" as used herein refer to a planar ring portion of one or more rings having a delocalized electron-conjugated system of 4n +2 electrons, where n is an integer. The aromatic ring may be formed of 5, 6, 7, 8, 9 or more atoms. The aromatic compound may be optionally substituted and may be monocyclic or fused-ring polycyclic. The term aromatic compound includes all carbocyclic rings (e.g., benzene rings) and rings containing one or more heteroatoms (e.g., pyridine).

The term "heteroatom" or "hetero" as used herein alone or as part of another component refers to atoms other than carbon and hydrogen. The heteroatoms are independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin, but are not limited to these atoms. 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 terms "fused" or "fused ring" as used herein, alone or in combination, refer to a cyclic structure in which two or more rings share one or more bonds.

The term "spiro" or "spirocyclic" 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 another component (e.g., monoalkylamino) refers to an optionally substituted straight or optionally substituted branched chain monovalent saturated hydrocarbon having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, attached to the rest of the molecule by a single bond, e.g., 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, and the like.

The term "alkenyl" as used herein, alone or in combination, refers to an optionally substituted straight or optionally substituted branched chain monovalent hydrocarbon radical having one or more C ═ C double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The double bond in these groups may be in either the cis or trans conformation and should be understood to encompass both isomers. Examples include, but are not limited to, ethenyl (CH ═ CH)₂) 1-propenyl (CH)₂CH＝CH₂) Isopropenyl (C (CH)₃)＝CH₂) Butenyl, 1, 3-butadienyl and the like. When a numerical range is present for alkenyl as defined herein, e.g. "C₂-C₆Alkenyl "or" C_2-6The "alkenyl group" means an alkenyl group which may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, and the alkenyl group herein also covers the case where no numerical range is specified.

The term "alkynyl", as used herein, alone or in combination, refers to an optionally substituted straight or branched chain monovalent hydrocarbon radical having one or more C ≡ C triple bonds and having 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, 1, 3-butadiynyl, and the like. When a numerical range occurs for alkynyl as defined herein, for example "C₂-C₆Alkynyl "or" C_2-6Alkynyl "refers to an alkynyl group that can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, and alkynyl groups herein also encompass instances where no numerical range is specified.

The term "aryl" refers to an all-carbon monocyclic or fused ring having a fully conjugated pi-electron system, having 6 to 14 carbon atoms, preferably 6 to 12 carbon atoms, 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, halo, hydroxy, sulfonyl, sulfinyl, phosphoryl, and heteroalicyclic. 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 to 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 being C, and having a fully conjugated pi-electron system. Heteroaryl groups may be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halo, hydroxy, cyano, nitro, carbonyl, and heteroalicyclic. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazinyl.

The term "cycloalkyl" as used herein alone or as part of another ingredient refers to a stable monovalent non-aromatic monocyclic or polycyclic hydrocarbon group containing only carbon and hydrogen atoms, and may include fused, spiro or bridged ring systems containing from 3 to 15 ring-forming carbon atoms, preferably from 3 to 10 ring-forming carbon atoms, more preferably from 3 to 8 ring-forming carbon atoms, which may or may not be saturated, attached to the rest of the molecule by single bonds. Non-limiting examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

The terms "heterocyclyl", "heterocycloalkyl", "heterocycle", as used herein alone or as part of another ingredient, 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, the nitrogen, carbon or sulfur of the heterocyclyl group may optionally be oxidized, the nitrogen atom may optionally be quaternized, and the heterocyclyl group may be partially or fully saturated. The heterocyclic group may be attached to the rest of the molecule through a single bond via a carbon or heteroatom in the ring. For purposes of this application, the heterocyclic group is preferably a stable 4-11 membered monovalent non-aromatic mono-or bicyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-8 membered monovalent non-aromatic mono-ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclyl groups include azepanyl, azetidinyl, decahydroisoquinolinyl, dihydrofuranyl, indolinyl, dioxolanyl, 1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piperazinyl, piperidinyl, 4-piperidinonyl, pyranyl, pyrazolidinyl, pyrrolidinyl, quinolizinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl and the like.

The term "polymorph" or "polymorph" as used herein means that the compounds of the present invention have multiple lattice morphologies. Some of the compounds of the present invention may have more than one crystal form, and the present invention encompasses all polymorphic forms or mixtures thereof.

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

Unless otherwise specified, the compounds of the present invention contain olefinic double bonds including E and Z isomers.

It is understood that the compounds of the present invention may contain asymmetric centers. These asymmetric centers may independently be in the R or S configuration. It is to be understood that the compounds of the present invention include their individual geometric and stereoisomers as well as mixtures thereof, including racemic mixtures. These isomers may be separated from their mixtures by carrying out or modifying known methods such as chromatographic techniques and recrystallization techniques, or they may be prepared separately from the appropriate isomers of their intermediates.

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

"pharmaceutically acceptable acid addition salts" refers to those salts formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or organic acids such as, but not limited to, acetic acid, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, capric acid, caproic acid, carbonic acid, cinnamic acid, citric acid, and the like, which retain the biological potency and properties of the free base of the compound, which are not biologically or otherwise undesirable. "pharmaceutically acceptable salt to be added to base" 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 an inorganic base 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.

Salt-forming organic bases 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, caffeine, and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

Crystallization often produces solvates of the compounds of the present invention. The term "solvate" as used herein refers to a combination of one or more molecules of the compound of the present invention and 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. Thus, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate 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 also retain water only by chance or a mixture of water and some other solvent. The compounds of the invention may be reacted in a solvent or precipitated or crystallized in a solvent. Solvates of the compounds of the invention are also included within the scope of the invention.

The term "pharmaceutical composition" as used herein refers to a formulation mixed with a compound of the present invention and a vehicle generally accepted in the art for delivering biologically active compounds to a mammal, such as a human. Such media comprise all pharmaceutically acceptable carriers.

As used herein, the term "acceptable" in reference to a formulation, composition or ingredient means that there is no lasting deleterious effect on the overall health of the subject being treated.

The term "pharmaceutically acceptable" as used herein refers to a substance (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological response or interacting in an adverse manner with any of the components contained in the composition.

"pharmaceutically acceptable carriers" include, but are not limited to, adjuvants, carriers, excipients, adjuvants, deodorants, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the relevant governmental authorities for use in humans and domestic animals.

The terms "subject," "patient," "subject" or "individual" as used herein refer to an individual having a disease, disorder or condition, and the like, including mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class mammalia: humans, non-human primates (e.g., 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, and the like. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment related to the methods and compositions provided herein, the mammal is a human.

The term "treatment" as used herein refers to the treatment of a disease or condition associated with a mammal, particularly a human, and includes

(i) Preventing the development of a disease or condition in a mammal, particularly a mammal that has previously been exposed to the disease or condition but has not been diagnosed as having the 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) relieving symptoms caused by the disease or disorder.

The terms "disease" and "condition" as used herein may be used interchangeably and may have different meanings, as certain specific diseases or conditions have no known causative agent (and therefore the cause of the disease is not yet clear) and therefore are not considered as a disease but can be considered as an unwanted condition or syndrome, with more or less specific symptoms being confirmed by clinical researchers.

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

The terms "administering," "administration," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, via 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 the Compounds of the invention

It will be appreciated that in the following description, combinations of substituents and/or variables of the formula are permitted only in the context of forming stable compounds.

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

Example 1: synthesis of 3- ((7- (2- ((4-aminocyclohexene) 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

Step 1: synthesis of Compound 3

To a solution of compound 1(6.00g), compound 2(6.29g) and triphenylphosphine (11.84g) in THF (150mL) was added dropwise DIAD (9.14g) at 0 deg.C. Subsequently, the reaction solution was warmed to room temperature and stirred at room temperature overnight. The reaction was concentrated in vacuo, and the resulting residue was dissolved in ethyl acetate (500mL) and each 5% Na₂CO₃The aqueous solution (100 mL. times.3) and saturated brine (100 mL. times.3) were washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (dichloromethane: methanol 100: 1-100: 2) to give 3(11.7g) as a pale yellow solid.

Step 2: synthesis of Compound 5

Under the protection of nitrogen, compound 3(1.00g), compound 4(1.62g), Pd (dppf) Cl₂A solution of dioxane (30mL) (234mg) and anhydrous potassium acetate (940mg) was heated to 100 deg.C and stirred at this temperature overnight. The reaction mixture was cooled to room temperature and used in the next reaction without further purification.

And step 3: synthesis of Compound 7

To a mixture of Compound 6(24g) and 3M aqueous sulfuric acid (80mL) was slowly added NaNO dropwise at 0 deg.C₂(8.26g) in water (40 mL). The reaction solution was stirred at 0 ℃ for 30 minutes. Then, at this temperature, an aqueous solution (80mL) of KI (21.7g) was slowly added dropwise. After the addition was completed, the reaction solution was allowed to warm to room temperature and stirred overnight, methylene chloride (100mL) was added to the reaction solution, the organic phase was separated, the aqueous phase was extracted with methylene chloride (100 mL. times.2), and the organic phases were combined. The resulting organic phase was washed with saturated aqueous NaHCO3 (100mL), saturated aqueous sodium thiosulfate (100mL) and saturated brine (100mL), respectively, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gelThe mixture was converted (petroleum ether as mobile phase) to obtain compound 7(28g) as a white solid.

And 4, step 4: synthesis of Compound 10

To a solution of 2, 2, 6, 6-tetramethylpiperidine (400mg) in tetrahydrofuran (10mL) at-78 deg.C was slowly added dropwise a solution of n-butyllithium (1.1mL, 2.82 mmol). The reaction solution was reacted at this temperature for 30 minutes, and then a solution of compound 9(628mg) in tetrahydrofuran (5mL) was added dropwise thereto. The reaction solution was reacted at-78 ℃ for 30 minutes, and a tetrahydrofuran (2mL) solution of Compound 8(500mg) was added thereto, followed by allowing the reaction solution to warm slowly to room temperature and stirring overnight. The reaction was quenched by the addition of saturated aqueous ammonium chloride (20 mL). The organic solvent was removed by concentration under reduced pressure, and ethyl acetate/water (50mL/50mL) was added thereto, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (20 mL. times.2). The organic phases were combined, the resulting 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).

And 5: synthesis of Compound 11

A mixture of compound 10(143mg), compound 7(140mg), tetrakistriphenylphosphine palladium (46mg) and anhydrous sodium carbonate (89mg) in dioxane/water (4mL/1mL) was heated to 80 ℃ under a nitrogen blanket, and stirred overnight, the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the resulting 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

A mixture of compound 11(87mg), compound 5(132mg), tetrakistriphenylphosphine palladium (23mg), and anhydrous sodium carbonate (45mg) in dioxane/water (4mL/1mL) was heated to 80 ℃ under nitrogen and stirred overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting residue was isolated and purified by flash silica gel column chromatography (dichloromethane: ethyl acetate 5: 1) to obtain compound 12(85 mg).

And 7: synthesis of Compound 13

To a solution of Compound 12(85mg) in dichloromethane (2mL) was added dropwise trisFluoroacetic acid (0.2mL) was added, and the reaction mixture 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 a saturated aqueous sodium carbonate solution (10mL × 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to separation and purification by flash silica gel column chromatography (dichloromethane: methanol ═ 20: 1 to 10: 1) to obtain compound 13(65mg).¹H NMR(400MHz，CDCl₃)，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

Borane dimethylsulfide (2M, 64mL) was slowly added dropwise to a solution of compound 14(18.8g) in tetrahydrofuran (200mL) at 0 ℃. The reaction was then warmed to 50 ℃ and heated overnight. The reaction solution was cooled to 0 ℃ and quenched by slowly adding methanol dropwise. The reaction solution was concentrated, and the resulting 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(16.2g) in dichloromethane (200mL) at 0 deg.C was added PBr3(37.2 g). Subsequently, the reaction was allowed to warm to room temperature and stirring was continued at room temperature overnight. The reaction was quenched with saturated aqueous sodium bicarbonate, the organic phase separated and the aqueous phase 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 subjected to separation and purification by flash silica gel column chromatography (petroleum ether: ethyl acetate: 100: 1) to obtain compound 16(21.3 g).

And step 3: synthesis of Compound 17

Triethyl phosphite (15mL) was added to compound 16(4.4g), and the reaction was heated to 160 ℃ with a microwave and reacted overnight. Cooled to room temperature, and the reaction mixture was concentrated under reduced pressure. The resulting residue was isolated and purified by flash silica gel column chromatography (petroleum ether: ethyl acetate 3: 1 to 1: 1) to give compound 17(5.0g) as a colorless oily substance.

And 4, step 4: synthesis of Compound 19

To a solution of compound 17(70mg) in tetrahydrofuran (0.75mL) at 0 deg.C, LiHMDS (1M, 0.26mL) was slowly added dropwise. The resulting reaction solution was stirred at this temperature for further 30 minutes, and then a solution of compound 18(50mg) in tetrahydrofuran (0.25mL) was added dropwise thereto. After the addition was complete, the reaction was allowed to warm slowly to room temperature and stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride (0.1 mL). Concentrated under reduced pressure and ethyl acetate/water (20mL/20mL) was added. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (20 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting 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 mixture of compound 19(30mg), compound 5(41mg), tetrakistriphenylphosphine palladium (8mg), and anhydrous sodium carbonate (14mg) in dioxane/water (2mL/0.5mL) was heated to 80 ℃ under nitrogen blanket and stirred overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting residue was isolated and purified by flash silica gel column chromatography (petroleum ether: ethyl acetate 5: 1 to 2: 1) to obtain compound 20(35 mg).

And 7: synthesis of Compound 21

Trifluoroacetic acid (0.2mL) was added dropwise to a dichloromethane (2mL) solution of compound 20(35mg), and the reaction was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was separated and purified by flash silica gel column chromatography (dichloromethane: methanol 20: 1 to 10: 1),compound 21(21mg) was obtained.¹H NMR(400MHz，CDCl₃)，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-ylenylmethyl) 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 3 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，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-ylenylmethyl) 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 4 is the same as that of example 1.¹H NMR(400MHz，CD₃OD)，8.66(s，1H)，7.70(d，J＝2.0Hz，1H)，7.46-7.50(m，2H)，7.29(d，J＝4.4Hz，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-ylenylmethyl) 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 5 is the same as that of example 1.¹H NMR12(400MHz，CD₃OD)，8.67(d，J＝4.8Hz，1H)，7.49(s，1H)，7.45(dd，J＝10.0Hz，2.0Hz，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-ylidene) 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 6 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，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 synthesis method of example 7 is the same as that of example 1。¹H NMR(400MHz，DMSO-d₆)，8.60(d，J＝4.8Hz，1H)，7.48(s，2H)，7.33(s，1H)，7.06(d，J＝5.2Hz，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-ylene) 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 8 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，8.62(d，J＝5.2Hz，1H)，7.53(s，1H)，7.29(d，J＝2.0Hz，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 synthesis method of example 9 is the same as that of example 2.¹H NMR(400MHz，CDCl₃)，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-ylenylmethyl) 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 1.¹H NMR(400MHz，CDCl₃)，8.69(d，J＝4.8Hz，1H)，7.53(s，1H)，7.42(dd，J＝8.0Hz，2.0Hz，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- (piperidinyl-4-alkenylmethyl) 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 11 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，8.63(d，J＝4.8Hz，1H)，7.52(s，1H)，7.30(d，J＝1.6Hz，1H)，7.18(d，J＝1.6Hz，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-ylenylmethyl) methyl) -3-methylphenyl) thieno [3, 2-b ] pyridin-2-yl) methyl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2, 4-dione

Synthesis of example 12The method is the same as the synthesis method of example 1.¹H NMR(400MHz，CDCl₃)，8.65(d，J＝4.4Hz，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 ] pyridine 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 2.¹H NMR(400MHz，CDCl₃)，8.76-9.50(br，2H)，8.71(d，J＝4.8Hz，1H)，7.62(s，1H)，7.26(d，J＝2.0Hz，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 of example 14 was the same as example 2.¹H NMR(400MHz，CDCl₃)，8.65(d，J＝5.2Hz，1H)，7.53(s，1H)，7.21(d，J＝2.0Hz，1H)，7.18(d，J＝2.0Hz，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 of example 15 was performed in the same manner as in example 2.¹H NMR(400MHz，CDCl₃)，8.68(d，J＝5.2Hz，1H)，7.54(s，1H)，7.25(d，J＝1.6Hz，1H)，7.15(d，J＝1.6Hz，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 of example 16 was performed in the same manner as in example 2.¹H NMR(400MHz，CDCl₃)，8.82-9.44(br，2H)，8.74(d，J＝4.8Hz，1H)，7.68(s，1H)，7.28(d，J＝1.6Hz，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-ylenylmethyl) -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 of example 17 was performed in the same manner as in example 1.¹H NMR(400MHz，DMSO-d₆)，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-ylenemethyl) phenyl) thieno [3, 2-b ] pyridin-2-yl) methyl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2, 4-dione trifluoroacetate

The synthesis of example 18 was performed in the same manner as in example 1.¹H NMR(400MHz，DMSO-d₆)，8.63(d，J＝4.8Hz，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 of example 19 was performed in the same manner as in example 1.¹H NMR(400MHz，CD₃OD)，8.66(d，J＝4.8Hz，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-ene) methyl) phenyl) thieno [3, 2-b ] pyridin-2-yl) methyl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2, 4-dione

The synthesis of example 20 was performed in the same manner as in example 1.¹H NMR(400MHz，CDCl₃)，8.65(d，J＝4.8Hz，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 example 2.¹H NMR(400MHz，DMSO-d₆)，8.65(d，J＝4.8Hz，1H)，7.62-8.42(br，2H)，7.49(d，J＝2.0Hz，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 of example 22 was the same as example 2.¹H NMR(400MHz，DMSO-d₆)，8.63(d，J＝5.2Hz，1H)，7.47(s，1H)，7.43(d，J＝2.0Hz，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-ylenylmethyl) phenyl) thieno [2, 3-b ] pyridin-2-yl) methyl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2, 4-dione trifluoroacetate

The synthesis of example 23 was performed in the same manner as in example 1.¹H NMR(400MHz，DMSO-d₆)，8.54(s，1H)，7.90-8.40(br，2H)，7.48(d，J＝2.0Hz，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-ylenylmethyl) 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 24 is the same as that of example 1.¹H NMR(400MHz，DMSO-d₆)，8.70(d，J＝4.4Hz，1H)，7.55(d，J＝1.6Hz，1H)，7.50(s，1H)，7.40(d，J＝2.0Hz，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(100mg) in tetrahydrofuran (2mL) at 0 deg.C was added sodium hydride (10 mg). The reaction solution was further stirred at 0 ℃ for 30 minutes, and methyl iodide (92mg) was then slowly added dropwise thereto. The reaction solution was then warmed to room temperature and the reaction was continued for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was isolated 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(65mg) in dichloromethane (3mL) at room temperature was added trifluoroacetic acid (0.3 mL). The reaction solution was stirred at room temperature for 2 hours until the reaction was completed. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (dichloromethane: methanol 100: 1 to 10: 1) to obtain compound 23(25 mg).¹H NMR(400MHz，DMSO-d₆)，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-ylenemethyl) phenyl) thieno [3, 2-b ] pyridin-2-yl) methyl) thiazolidine-2, 4-dione trifluoroacetate salt

Step 1: synthesis of Compound 25

TBSCl (11.32g) was added to a dichloromethane solution (100mL) of Compound 24(5.0g) and imidazole (10.23g) at room temperature. The reaction solution was reacted at room temperature for 2 hours, followed by concentrating the reaction solution under reduced pressure, and the resulting 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, compound 25(1.00g), compound 4(1.62g), Pd (dppf) Cl₂A solution of dioxane (30mL) (234mg) and anhydrous potassium acetate (940mg) was heated to 100 deg.C and stirred at this temperature overnight. The reaction mixture was cooled to room temperature and used in the next reaction without further purification.

And step 3: synthesis of Compound 28

A mixture of compound 26(300mg), compound 27(320mg), tetrakistriphenylphosphine palladium (90mg), and anhydrous sodium carbonate (190mg) in dioxane/water (8mL/2mL) was heated to 80 deg.C under nitrogen blanket and stirred overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography (dichloromethane: methanol 100: 1 to 100: 3) to obtain compound 28(200 mg).

And 4, step 4: synthesis of Compound 29

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

And 5: synthesis of Compound 31

To a solution of compound 29(124mg), compound 30(60mg), and triphenylphosphine (134mg) in anhydrous tetrahydrofuran (2mL) was added dropwise DIAD (103mg) at 0 ℃. The reaction was then warmed to room temperature and stirred overnight. After the reaction was completed, the reaction solution was concentrated. The resulting residue was isolated 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(110mg) in dichloromethane (5mL) at room temperature was added trifluoroacetic acid (0.5 mL). The reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction liquid was concentrated under reduced pressure, and the residue was isolated and purified by flash silica gel column chromatography (dichloromethane: methanol 100: 1 to 10: 1) to obtain compound 32(43mg).¹H NMR(400MHz，DMSO-d₆)，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 2.¹H NMR(400MHz，CD₃OD)，8.62(d，J＝4.4Hz，1H)，7.47(s，1H)，7.39(d，J＝1.6Hz，1H)，7.27(d，J＝4.8Hz，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-ylenemethyl) 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(1g) and cesium carbonate (3.1g) in DMF (5mL) at room temperature was added SEMCl (1.7 g). The reaction was stirred at room temperature overnight until the reaction was complete. Subsequently, the reaction solution was poured into water (30 mL). The aqueous phase was extracted with ethyl acetate (50 mL. times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to separation and purification 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(1g) in anhydrous tetrahydrofuran (30mL) was added dropwise a 2.5M solution of n-butyllithium in hexane (1.75mL) at-78 ℃. After completion of the dropwise addition, the reaction solution was stirred for further 30 minutes at that temperature, and then anhydrous DMF (0.9mL) was added dropwise to the reaction solution to slowly raise the temperature of the reaction solution to-20 ℃ and the reaction was continued at that temperature for 4 hours, after completion of the reaction, a saturated ammonium chloride solution (50mL) was added to quench the reaction. Concentrating under reduced pressure to remove tetrahydrofuran. The resulting solution was extracted with ethyl acetate (50 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel column chromatography (petroleum ether: ethyl acetate 5: 1) to obtain compound 35(670 mg).

And step 3: synthesis of Compound 36

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

And 4, step 4: synthesis of Compound 37

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

And 5: synthesis of Compound 38

TBAF (480mg) was added to a tetrahydrofuran (10mL) solution of Compound 37(510mg) at room temperature, and the reaction mixture was heated to 45 ℃ for overnight reaction. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was subjected to separation and purification 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(230mg), triethylamine (0.4mL) in dichloromethane (5mL) was added trifluoromethanesulfonic anhydride (0.2mL) at 0 ℃. The reaction mixture was allowed to react at room temperature for 6 hours. After completion of the reaction, the reaction mixture was poured into ice water (30mL) and extracted with dichloromethane (30 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (petroleum ether: ethyl acetate 5: 1) to obtain compound 39(110 mg).

And 7: synthesis of Compound 40

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

And 8: synthesis of Compound 41

To a solution of compound 40(80mg) in methanol (2mL) at 0 ℃ was added sodium borohydride (11mg) in portions, followed by warming the reaction solution to room temperature. The reaction solution was further stirred at room temperature for 4 hours. After the reaction, the reaction mixture was concentrated under reduced pressure. Water (10mL) was added to the resulting residue, and extracted with ethyl acetate (10 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel column chromatography (petroleum ether: ethyl acetate 2: 1) to obtain compound 36(43 mg).

And step 9: synthesis of Compound 42

A mixture of compound 41(43mg), compound 42(50mg), tetrakistriphenylphosphine palladium (11mg), and anhydrous sodium carbonate (20mg) in dioxane/water (1mL/0.2mL) was heated to 80 ℃ under nitrogen blanket and stirred overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting residue was isolated and purified by flash silica gel column chromatography (dichloromethane: methanol 20: 1 to 5: 1) to obtain compound 42(5.3 mg).¹H NMR(400MHz，CDCl₃)，8.13(d，J＝4.4Hz，1H)，7.29(s，1H)，7.17(s，1H)，6.33(d，J＝4.4Hz，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] hex-6-yl) 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 trifluoroacetate

The synthesis method of example 29 is the same as that of example 2.¹H NMR(400MHz，CDCl₃)，8.84-10.28(br，2H)，8.62(d，J＝4.4Hz，1H)，7.50(s，1H)，7.24(d，J＝2.0Hz，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＝16.0Hz，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-ylenylmethyl) 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 30 is the same as that of example 1.¹H NMR(400MHz，DMSO-d₆)，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-ylenylmethyl) 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 1.¹H NMR(400MHz，DMSO-d₆)，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-ylenylmethyl) 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 1.¹H NMR(400MHz，DMSO-d₆)，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] hex-3-yl) methyl) thieno [3, 2-b ] pyridin-7-yl) -5-methyl-4- (piperidin-4-ylalkenylmethyl) benzamide

The synthesis method of example 33 is the same as that of example 1.¹H NMR(400MHz，DMSO-d₆)，8.66(d，J＝4.8Hz，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 1.¹H NMR(400MHz，CDCl₃)，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] hex-3-yl) methyl) thieno [3, 2-b ] pyridin-7-yl) -5-methyl-4- (piperidin-4-ylethenylmethyl) benzonitrile

The synthesis method of example 35 is the same as that of example 1.¹H NMR(400MHz，DMSO-d₆)，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 salt

To a solution of the compound of example 11 (100mg) and potassium carbonate (82mg) in tetrahydrofuran (1mL) was added methyl bromide (65mg). The reaction mixture was reacted at room temperature overnight, followed by concentration of the reaction mixture under reduced pressure, and the resulting 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).¹H NMR(400MHz，CDCl₃)，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-ylalkenylmethyl) phenyl) pyrrolo [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

A mixture of compound 44(150mg), compound 45(447mg), tetrakistriphenylphosphine palladium (77mg) and anhydrous sodium carbonate (141mg) in dioxane/water (4mL/1mL) was heated to 80 ℃ under nitrogen and stirred overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting residue was isolated 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(110mg) in tetrahydrofuran (5mL) was added DIBAL-H in toluene (0.75mL, 1M) dropwise at 0 deg.C under nitrogen. The reaction was then allowed to warm to room temperature and stirring was continued at room temperature for 2 hours. After completion of the reaction, the reaction solution was quenched with a saturated sodium sulfate solution, the resulting mixture was filtered through celite, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography (dichloromethane: methanol ═ 100: 1 to 100: 3) to obtain compound 47(42 mg).

And step 3: synthesis of Compound 48

To a solution of compound 47(42mg), compound 2(25mg) and PPh3(47mg) in tetrahydrofuran (1mL) was added dropwise DIAD (36mg) at 0 ℃ overnight. After completion of the reaction, the reaction mixture 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 48(21 mg).

And 4, step 4: synthesis of Compound 49

To a solution of compound 48(21mg) in dichloromethane (1mL) at room temperature was added trifluoroacetic acid (0.1 mL). The reaction solution was stirred at room temperature for 2 hours until the reaction was completed. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate (5mL) and the aqueous phase was extracted with dichloromethane (5 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by flash column chromatography on silica gel (dichloromethane: methanol ═ 20: 1 to 5: 1) to obtain compound 23(7.4 mg).¹H NMR(400MHz，CD₃OD)，8.45(s，1H)，7.95(s，1H)，7.49(s，1H)，7.40(s，1H)，6.58(s，1H)，6.32(s，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-ylenemethyl) phenyl) thieno [3, 2-b ] pyridin-2-yl) methyl) pyrrolidine-2, 5-dione

The synthesis method of example 38 was the same as that of example 26.¹H NMR(400MHz，CD₃OD)，8.63(d，J＝4.4Hz，1H)，7.49(s，1H)，7.43(d，J＝2.0Hz，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-ylenylmethyl) phenyl) thieno [3, 2-b ] pyridin-2-yl) methyl) -1- (2, 2, 2-trifluoroethyl) pyrimidine-2, 4(1H, 3H) -dione trifluoroacetate

ExamplesThe synthesis method of 39 is the same as that of example 26.¹H NMR(400MHz，DMSO-d₆)，8.63(d，J＝4.8Hz，1H)，7.75(d，J＝8.0Hz，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) 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 40 is the same as that of example 2. LC-MS (ESI): [ M + H ] 492.3.

Example 41: 3- ((7- (5-chloro-2- ((hexahydrocyclopenta [ c ] pyrrol-5 (1H) -ylidene) methyl) -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 41 is the same as that of example 1.¹H NMR(400MHz，DMSO-d₆)，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-ylenylmethyl) phenyl) thieno [3, 2-b ] pyridin-2-yl) methyl) isoindole-1, 3-dione trifluoroacetate

The synthesis method of example 42 was the same as that of example 26.¹H NMR(400MHz，CD₃OD)，8.63(d，J＝4.4Hz，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 was the same as that of example 36.¹H NMR(400MHz，DMSO-d₆)，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-ylenemethyl) phenyl) thieno [3, 2-b ] pyridin-2-yl) methyl) tetrahydrocyclopenta [ c ] pyrrole-1, 3(2H, 3aH) -dione trifluoroacetate

The synthesis method of example 44 was the same as that of example 26.¹H NMR(400MHz，DMSO-d₆)，8.64(d，J＝4.8Hz，1H)，8.38-8.58(br，1H)，8.12-8.29(br，1H)，7.50(d，J＝2.0Hz，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-ylenylmethyl) phenyl) thieno [3, 2-b ] pyridin-2-yl) methyl) hexahydro-1H-isoindole-1, 3(2H) -dione trifluoroacetate

The synthesis method of example 45 was the same as that of example 26.¹H NMR(400MHz，DMSO-d₆)，8.64(d，J＝4.8Hz，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-ylenylmethyl) 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 was the same as that of example 26.¹H NMR(400MHz，CDCl₃)，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-ylenemethyl) 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 26.¹H NMR(400MHz，CD₃OD)，8.60(d，J＝4.8Hz，1H)，7.86(s，1H)，7.53(s，1H)，7.40(d，J＝2.0Hz，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-ylenylmethyl) phenyl) thieno [3, 2-b ] pyridin-2-yl) methyl) -3, 3-dimethylpyrrolidine-2, 5-dione trifluoroacetate

The synthesis method of example 48 was the same as that of example 26.¹H NMR(400MHz，CDCl₃)，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-ylenylenemethyl) phenyl) thieno [3, 2-b ] pyridin-2-yl) methyl) -3a, 4, 7, 7 a-tetrahydro-1H-4, 7-methylideneisoindole-1, 3(2H) -dione trifluoroacetate

The synthesis method of example 49 was the same as that of example 26.¹H NMR(400MHz，CDCl₃)，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

BrCN (40mg) was added to a solution of the compound of example 11 (100mg) and DIEA (62. mu.L) in methylene chloride (5 mL). The reaction solution was reacted at room temperature overnight, followed by concentrating the reaction solution under reduced pressure, and the resulting 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).¹H NMR(400MHz，CD₃OD)，8.57-8.67(m，1H)，7.50(s，1H)，7.41(s，1H)，7.30(s，1H)，7.24(d，J＝4.8Hz，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-ylene) 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 was the same as that of example 36.¹H NMR(400MHz，CD₃OD)，8.61-8.68(m，1H)，7.50(s，1H)，7.44(d，J＝1.6Hz，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-ylene) 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 1.¹H NMR(400MHz，CD₃OD)，8.62(d，J＝4.4Hz，1H)，7.47(s，1H)，7.39(d，J＝2.0Hz，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-ylenylmethyl) phenyl) thieno [3, 2-b ] pyridin-2-yl) methyl) -3a, 7 a-dimethylhexahydro-1H-4, 7-oxisoindole-1, 3(2H) -dione trifluoroacetate

The synthesis method of example 53 was the same as that of example 26.¹H NMR(400MHz，CDCl₃)，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-ylenemethyl) phenyl) thieno [3, 2-b ] pyridin-2-yl) methyl) -3-azabicyclo [3.2.0] hepta-2, 4-dione trifluoroacetate

The synthesis method of example 54 was the same as that of example 26.¹H NMR(400MHz，CDCl₃)，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-ethylazacyclobutyl-3-ylidene) 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 was the same as that of example 36.¹H NMR(400MHz，CDCl₃)，8.73(d，J＝4.8Hz，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 was the same as that of example 36.¹H NMR(400MHz，CDCl₃)，8.62(d，J＝4.4Hz，1H)，7.48(s，1H)，7.28(s，1H)，7.24(s，1H)，7.04(d，J＝4.0Hz，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 was the same as that of example 36.¹H NMR(400MHz，CDCl₃)，8.62(d，J＝4.8Hz，1H)，7.50(s，1H)，7.30(d，J＝1.6Hz，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 2.¹H NMR(400MHz，CDCl₃)，8.67-8.75(m，1H)，7.61(s，1H)，7.29(d，J＝2.0Hz，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-ylidene) 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 59 was the same as that of example 36.¹H NMR(400MHz，CDCl₃)，8.68(d，J＝4.8Hz，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 was the same as that of example 36.¹H NMR(400MHz，DMSO-d₆)，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] hept 2-ylene) 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 was the same as that of example 1.¹H NMR(400MHz，CD₃OD)，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 was the same as that of example 36.¹H NMR(400MHz，CD₃OD)，8.60(d，J＝5.2Hz，1H)，7.47(s，1H)，7.41(d，J＝2.0Hz，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-ylenemethyl) phenyl) thieno [3, 2-b ] pyridin-2-yl) methyl) oxazoline-2, 4-dione trifluoroacetate

The synthesis method of example 63 was the same as that of example 26.¹H NMR(400MHz，CDCl₃)，8.67-9.68(br，2H)，8.66(s，1H)，7.61(s，1H)，7.32(d，J＝2.0Hz，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-ylene) 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 was the same as that of example 36.¹H NMR(400MHz，CDCl₃)，8.70(d，J＝4.4Hz，1H)，7.55(s，1H)，7.31(d，J＝1.6Hz，1H)，7.21(d，J＝1.6Hz，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-ylenemethyl) 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 was the same as that of example 1.¹H NMR(400MHz，DMSO-d₆)，8.69(d，J＝5.2Hz，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-ylenylmethyl) -5- (trifluoromethyl) phenyl) thieno [3, 2-b ] pyridin-2-yl) methyl) -3-azabicyclo [3.1.0] hexane-2, 4-dione

The synthesis method of example 66 was the same as that of example 1.¹H NMR(400MHz，CDCl₃)，8.65(d，J＝4.8Hz，1H)，7.56(s，1H)，7.54(s，1H)，7.44(s，1H)，7.01(d，J＝4.8Hz，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-ylenemethyl) phenyl) thieno [3, 2-b ] pyridin-2-yl) methyl) -1-methylimidazoline-2, 4-dione trifluoroacetate salt

The synthesis method of example 67 was the same as that of example 26.¹H NMR(400MHz，CDCl₃)，8.74-9.76(br，2H)，8.63(d，J＝4.8Hz，1H)，7.54(s，1H)，7.31(d，J＝1.6Hz，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-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 68 was the same as that of example 36.¹H NMR(400MHz，CDCl₃)，8.69(d，J＝4.0Hz，1H)，7.55(s，1H)，7.27(s，1H)，7.18(s，1H)，7.06(d，J＝4.0Hz，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] undecan-9-ylene) 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 was the same as that of example 1.¹H 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-ylene) 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 1.¹H NMR(400MHz，CD₃OD)，8.56(d，J＝5.2Hz，1H)，7.44(s，1H)，7.40(d，J＝2.0Hz，1H)，7.29(d，J＝2.0Hz，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] hexan-3-yl) methyl) thieno [3, 2-b ] pyridin-7-yl) -5-methyl-4- ((1-methylpiperidin-4-ylene) methyl) benzonitrile

The synthesis method of example 71 was the same as that of example 36.¹H NMR(400MHz，CD₃OD)，8.65(d，J＝5.2Hz，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] hex-3-yl) methyl) thieno [3, 2-b ] pyridin-7-yl) -5-methyl-4- ((8-methyl-8-azabicyclo [3.2.1] oct-3-ylene) methyl) benzonitrile

The synthesis method of example 72 was the same as that of example 36.¹H NMR(400MHz，CDCl₃)，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- (azetidin-3-ylenemethyl) -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

Example 73 the same synthetic method as example 1The same is true.¹H NMR(400MHz，CDCl₃)，8.69(d，J＝4.8Hz，1H)，7.56(s，1H)，7.55(s，1H)，7.49(s，1H)，7.04(d，J＝4.8Hz，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] hex-3-yl) methyl) thieno [3, 2-b ] pyridin-7-yl) -5-methylbenzonitrile

The synthesis method of example 74 was the same as that of example 36.¹H NMR(400MHz，CD₃OD)，8.64(d，J＝4.4Hz，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-ylenylmethyl) 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 was the same as that of example 26.¹H NMR(400MHz，CDCl₃)，8.90-9.66(br，2H)，8.66(s，1H)，7.57(s，1H)，7.32(d，J＝2.0Hz，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 was the same as that of example 36.¹H NMR(400MHz，DMSO-d₆)，8.66(d，J＝4.8Hz，1H)，7.46-7.51(m，2H)，7.32(d，J＝1.6Hz，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] hex-3-yl) methyl) thieno [3, 2-b ] pyridin-7-yl) -4- ((1-isopropylazetidin-3-ylene) methyl) -5-methylbenzonitrile

The synthesis method of example 77 was the same as that of example 36.¹H NMR(400MHz，CDCl₃)，8.74(d，J＝2.8Hz，1H)，7.61(s，1H)，7.57(s，1H)，7.51(s，1H)，7.09(d，J＝2.8Hz，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] hex-3-yl) methyl) thieno [3, 2-b ] pyridin-7-yl) -4- ((1-ethylazacyclobutyl-3-ylen) methyl) -5-methylbenzonitrile hydrochloride

Example 78 Synthesis procedureThe synthesis method of example 36 was the same.¹H NMR(400MHz，DMSO-d₆)，10.41-10.97(br，1H)，8.71(d，J＝4.8Hz，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 was the same as that of example 1.¹H NMR(400MHz，CDCl₃)，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] hex-3-yl) methyl) thieno [3, 2-b ] pyridin-7-yl) -4- ((4- (dimethylamino) cyclohexylene) methyl) -5-methylbenzonitrile

The synthesis method of example 80 was the same as that of example 36.¹H NMR(400MHz，CDCl₃)，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-ylenemethyl) benzonitrile

The synthesis method of example 81 was the same as that of example 26.¹HNMR(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-ylenylmethyl) phenyl) thieno [3, 2-b ] pyridin-2-yl) methyl) -3, 3, 4, 4-tetramethylpyrrolidine-2, 5-dione trifluoroacetate

The synthesis method of example 82 was the same as that of example 26.¹H NMR(400MHz，DMSO-d₆)，8.64(d，J＝4.8Hz，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 for Compound inhibition of USP7

The enzymatic activity detection of USP7 in the patent is carried out by a rapid fluorescence method, and the rapid fluorescence method uses Ubiquitin-Rhodamine 110 as a substitute substrate to carry out reaction and optimize to establish a high-flux screening platform. The detection of inhibitory activity of compounds against USP7 was performed on this platform. The specific method comprises the following steps: compounds were diluted in 5-fold gradients starting at 1mM with 100% DMSO (7 concentrations), and 2. mu.L of each compound was added to 48. mu.L of reaction buffer (20mM Tris, pH 8.0, 2mM CaCl2, 1mM reduced glutamone, 0.01% (v/v) Triton X-100, 0.01% (w/v) BSA) for dilution and mixing. mu.L of the final diluted compound was added to a black 384 well plate (OptiPlate-384, cat # 6007270, from Perkinelmer) followed by 10. mu.L of His-USP7 (final concentration 0.05 nM). After the 384-well plate was placed in an incubator at 23 ℃ for 30 minutes, 5. mu.L of the substitute 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 for 1.5 hours in the incubator at 23 ℃. The reaction was stopped by adding 5. mu.L of citric acid per well (cat. No. 77-92-9, from national pharmaceutical Co., Ltd., final concentration 10mM) and the fluorescence was read using a BMG ClariostarMicroplate Reader (excitation485nm/emission 535 nm). IC50 values for inhibition of USP7 enzymatic activity by this compound were calculated using GraphPad Prism software.

TABLE 1 inhibition of USP7 by the example compounds

2. Compounds inhibit RS 4; 11 Activity assay for cell proliferation

Human acute lymphoblastic leukemia cell line RS 4; 11 cells were cultured in RPMI-1640 medium plus 10% fetal bovine serum (FBS, available from Biological Industries, BI) and 1% penicillin/streptomycin (P/S, available from Thermo Fisher Scientific) at 37 deg.C, 5% CO₂. RS 4; 11 cells were plated at a concentration of 4000 cells/195 μ L/well in 96-well plates (cat #3917, purchased from CORNING). After 24 hours, compounds were diluted from 10mM in 100% DMSO using a 3-fold gradient (10 concentrations) and 4. mu.L of each compound was added to 96. mu.L of RPMI-1640 medium. Adding 5 μ L of diluted compound into the cell suspension, placing the compound and cells in a cell culture boxThe cells were incubated for 72 hours (3 days). Then 35. mu.L of Cell-Titer was added

(product No. G7570, from Promega) for 5-10 minutes at room temperature in a shaker. Chemiluminescence values were read on a BMG clariostar microplate Reader, and the data were processed using GraphPad Prism software to calculate the IC50 value of the compound for inhibition of cell proliferation.

Table 2 compound pair RS 4; inhibition of 11 cell lines

Claims (11)

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

wherein the content of the first and second substances,

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 content of the first and second substances,

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.