USP7 inhibitors

Abstract

This application relates to a USP7 inhibitor represented by formula (I), its preparation method, and its therapeutic use in tumor diseases. During the preparation process, a series of reactions such as substitution, coupling, reduction, and deprotection are performed to obtain the compound of the present invention. #imgabs0#

Description

[0001] Cross-references

[0002] This application claims priority to Chinese patent application No. 202010908542.4 filed on September 2, 2020, with the patent name “USP7 inhibitors”, Chinese patent application No. 202011334132.X filed on November 24, 2020, Chinese patent application No. 202011541873.5 filed on December 23, 2020, Chinese patent application No. 202110181139.0 filed on February 9, 2021, with the patent name “USP7 inhibitors”, and Chinese patent application No. 202110429367.5 filed on April 21, 2021, with the patent name “USP7 inhibitors”, and all disclosures of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present application relates to a USP7 inhibitor, a preparation method thereof and its therapeutic use in tumor diseases. Background Art

[0004] Post-translational modifications (PTMs) are generally enzymatic modifications of proteins after their biosynthesis. PTMs include methylation, acetylation, phosphorylation, glycosylation, ubiquitination, and S-nitrosylation. As one of the most studied PTMs, ubiquitination is involved in the intracellular proteolytic machinery and regulates many physical activities within the cell. The process of adding ubiquitin to substrate proteins is called ubiquitination, which facilitates protein degradation. A cascade reaction consisting of ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligases (E3) catalyzes the ubiquitination of target proteins. First, ubiquitin is activated by E1 in the presence of ATP and transferred to E2 via a transsulfuration reaction. Then, in the presence of E3, it is conjugated to a lysine or α-amino group on the substrate protein. Ultimately, proteins marked with four or more ubiquitin molecules are recognized and subjected to the 26S proteasome, where they are degraded to produce small polypeptides.

[0005] Deubiquitinating enzymes (DUBS) are responsible for removing ubiquitin and maintaining substrate stability by degrading it. To date, approximately 100 DUBs have been identified, which can be divided into five subclasses based on their Ub protease domains: ubiquitin-specific proteases (USPSs), ubiquitin C-terminal hydrolases (UCHs), ovarian tumor proteases (OTUSs), cysteine-dependent proteases such as Machado-Joseph disease proteases (MJDSs), and zinc metalloproteases such as JAB1 / MPN / Mov34 (JAMMSs).

[0006] The USPS family, with nearly 50 members, is the largest of all DUB subfamilies. These members contain three major functional domains: Cys, His, and Asp / Asn boxes, which are conserved and responsible for the reorganization of ubiquitin-binding molecules.

[0007] Among the USP family members, the ubiquitin-specific protease USP7, also known as herpes-associated ubiquitin-specific protease (HAUSP), is a unique deubiquitinase discovered in 1997. It is a new member of the ubiquitin-specific protease family that interacts with the herpes simplex virus type 1 immediate-early protein (Vmw110). USP7 was later found to interact with other viral proteins, such as Epstein-Barr nuclear antigen 1 (EBNA1) of Epstein-Barr virus (EBV) and vIRF1 (viral interferon regulatory factor 1) protein of Kaposi's sarcoma-associated herpesvirus (KSHV), thus indicating that it is a universal target of herpes viruses and leading to its designation as herpes-associated ubiquitin-specific protease. To date, USP7 is the most extensively studied deubiquitinase and is considered an oncogene that promotes tumor growth and affects patients' immune responses to tumors.

[0008] 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 carcinogenesis in non-small cell lung cancer (NSCLC) through a p53-dependent pathway. Studies have shown that in vivo, changes in USP7 regulate the growth and apoptosis sensitivity of colon cancer. USP7 maintains the DNA damage response and promotes cervical cancer and is positively correlated with the low survival rate of cervical cancer patients. USP7 regulates human erythroid terminal differentiation by stabilizing GATA1, providing certain treatment for leukemia. In short, USP7 plays an important role in multiple pathological processes and is a good target from a therapeutic perspective.

[0009] USP7 not only plays a role in regulating cellular pathways such as viral proteins, immune responses, oncogenes, and DNA damage, but is also aberrantly expressed in various cancers, making it a promising target. However, due to the lack of a co-crystal structure between USP7 and a small molecule inhibitor, effective and selective USP7 inhibitors remained elusive. Over the past few years, crystal structures of several USP7 small molecule inhibitors and their complexes with USP7 have been published, providing guidance for the development of structure-based small molecule inhibitors. Although several USP7 small molecule inhibitors have been reported in recent years, these inhibitors have not yet entered clinical trials due to unsatisfactory in vivo efficacy data. Therefore, the development of USP7 inhibitors with robust in vivo activity is urgently needed for the early treatment of patients with tumors harboring aberrant USP7 expression.

[0010] The compound of the present invention is a USP7 deubiquitinase inhibitor, which can highly selectively inhibit USP7 deubiquitinase, thereby safely and effectively treating tumor patients with abnormal USP7 expression. Summary of the Invention

[0011] In one aspect, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof,

[0012]

[0013] in,

[0014] The C ring is a 5-membered or 6-membered aromatic ring or non-aromatic ring containing 1-2 N atoms, and the carbon atoms on the C ring may be optionally oxidized (=O) or sulfided (=S).

[0015] or,

[0016] The C ring is a 5-membered or 6-membered aromatic ring or non-aromatic ring containing O or S, and the carbon atoms on the C ring can be optionally oxidized (=O) or sulfidized (=S).

[0017] One of Y1, Y2, Y3 and Y4 is CR 30 , the remaining three are each independently selected from N and CR3,

[0018] R 30 for

[0019] Ring A and Ring B are aromatic rings.

[0020] X1 and X2 are each independently selected from CR4 and N,

[0021] X3 and X4 are each independently selected from C and N,

[0022] X5 and X6 are each independently selected from N, NR5, O, S and CR6, and X5 and X6 are not CR6 at the same time,

[0023] L1 and L2 are each independently selected from -(CR 12 R 13 ) n -、-O-、-S-、-NR 10 -、-(CO)-、-(CO)NR 10 -, -(CO)O-, -S(O)2- and -S(O)2NR 10 -,

[0024] n is 0, 1, 2, 3, or 4,

[0025] R1 and R3 are each independently selected from H, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR 10 、-NR 10 R 11 、C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl may be optionally substituted with halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR 10 、-NR 10 R 11 、C 3-8 Cycloalkyl, or 3-8 membered heterocycloalkyl substituted,

[0026] R4 is selected from H, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR 10 、-NR 10 R 11 、C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl may be optionally substituted with halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR 10 、-NR 10 R 11 、C 3-8 Cycloalkyl, or 3-8 membered heterocycloalkyl substituted,

[0027] R5 is selected from H, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl may be optionally substituted with halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR 10 、-NR 10 R 11 、C 3-8 Cycloalkyl, or 3-8 membered heterocycloalkyl substituted,

[0028] R6 is selected from H, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR 10 、-NR 10 R 11 、C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl may be optionally substituted with halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR 10 、-NR 10 R 11 、C 3-8 Cycloalkyl, or 3-8 membered heterocycloalkyl substituted,

[0029] R2 is a 3-12 membered cycloalkyl or a 3-12 membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl may be optionally substituted by (=O), halogen, -CN, -OR 10 、-NR 10 R 11 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR 10 、-NR 10 R 11 、C 3-8 The alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl optionally substituted on the cycloalkyl and heterocycloalkyl groups may be optionally substituted with halogen, -CN, -OR 10 、-NR 10 R 11 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR 10 、-NR 10 R 11 、C 3-8Cycloalkyl, or 3-8 membered heterocycloalkyl substituted,

[0030] R7 is a 5-12 membered heteroaryl, a 3-12 membered cycloalkyl or a 3-12 membered heterocycloalkyl, and may be optionally replaced by R 40 The cycloalkyl and heterocycloalkyl groups may be optionally fused with 5-10 membered aryl or 5-12 membered heteroaryl groups, and the aryl or heteroaryl groups fused with the cycloalkyl or heterocycloalkyl groups may be optionally fused with R 40 replace,

[0031] R 40 Selected from (=O), halogen, -CN, -OR 10 、-NR 10 R 11 、-NR 10 (COR 11 ), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 6-10 membered aryl, 5-12 membered heteroaryl, C 3-8 Cycloalkyl, or 3-8 membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl may be optionally substituted with (=O), halogen, -CN, -OR 10 、-NH-(CO)-C 1-6 Alkyl, -NH-Cbz, -NR 10 R 11 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR 10 、-NR 10 R 11 、C 3-8 Cycloalkyl, or 3-8 membered heterocycloalkyl substituted,

[0032] R 10 and R 11 Each independently selected from H, C 1-6 Alkyl and C 3-8 Cycloalkyl,

[0033] R 12 and R 13 are each independently selected from H, halogen and C 1-6 alkyl,

[0034] p is 0, 1, or 2.

[0035] In some embodiments, R 40 Selected from (=O), halogen, -CN, -OR 10 、-NR 10 (COR 11), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 6-10 membered aryl, 5-12 membered heteroaryl, C 3-8 Cycloalkyl, or 3-8 membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl may be optionally substituted with (=O), halogen, -CN, -OR 10 、-NH-(CO)-C 1-6 Alkyl, -NH-Cbz, -NR 10 R 11 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR 10 、-NR 10 R 11 、C 3-8 Cycloalkyl, or 3-8 membered heterocycloalkyl substituted,

[0036] In some embodiments, R 40 Selected from (=O), halogen, -CN, -OR 10 、-NR 10 R 11 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, or 3-8 membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl may be optionally substituted by halogen, -CN, -OR 10 、-NR 10 R 11 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR 10 、-NR 10 R 11 、C 3-8 Cycloalkyl, or 3-8 membered heterocycloalkyl substituted,

[0037] In some embodiments, the C ring is a 5-membered or 6-membered aromatic ring or a non-aromatic ring containing 1 N;

[0038] In some embodiments, the C ring is a 5-membered or 6-membered aromatic ring or a non-aromatic ring containing 2 N;

[0039] In some embodiments, the C ring is a 5-membered or 6-membered aromatic ring or a non-aromatic ring containing 1 O;

[0040] In some embodiments, L1 and L2 are each independently selected from -(CR 12R 13 ) n -;

[0041] In some embodiments, R1 and R3 are each independently selected from H, halogen, -CN, C 1-6 Alkyl, -OR 10 、-NR 10 R 11 、C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl;

[0042] In some embodiments, R4 is independently selected from H, halogen and C 1-6 alkyl;

[0043] In some embodiments, R5 is independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl;

[0044] In some embodiments, R6 is selected from H, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl;

[0045] In some embodiments, R2 is a 3-12 membered cycloalkyl or a 3-12 membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl may be optionally substituted with (=O), halogen, -CN, -OR 10 、-NR 10 R 11 , or C 1-6 Alkyl substituted, said alkyl group may be optionally substituted with halogen, -CN, -OR 10 , or -NR 10 R 11 replace;

[0046] In some embodiments, R7 is a 3-12 membered cycloalkyl or a 3-12 membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl may be optionally substituted by (=O), halogen, or C 1-6 Alkyl substituted, said alkyl group may be optionally substituted with halogen, -CN, -OR 10 , or -NR 10 R 11 replace;

[0047] In another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof,

[0048]

[0049] in,

[0050] Ring A and Ring B are aromatic rings.

[0051] The C ring is a 5-membered or 6-membered aromatic ring or non-aromatic ring containing 1-2 N atoms, and the carbon atoms on the C ring may be optionally oxidized (=O) or sulfided (=S).

[0052] X1 and X2 are each independently selected from CR4 and N,

[0053] X3 and X4 are each independently selected from C or N,

[0054] X5 and X6 are each independently selected from N, NR5, O, S and CR6, and X5 and X6 are not CR6 at the same time,

[0055] Y2, Y3 and Y4 are each independently selected from N and CR3,

[0056] L1 and L2 are each independently selected from -(CR 12 R 13 ) n -,

[0057] n is 0, 1, 2, 3, or 4,

[0058] R1 and R3 are each independently selected from H, halogen, -CN, C 1-6 Alkyl, -OR 10 、-NR 10 R 11 、C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl,

[0059] R4 is selected from H, halogen and C 1-6 alkyl,

[0060] R5 is selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl,

[0061] R6 is selected from H, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl,

[0062] R2 is a 3-12 membered cycloalkyl or a 3-12 membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl may be optionally substituted by (=O), halogen, -CN, -OR 10 、-NR 10 R 11 , or C 1-6 Alkyl substituted, said alkyl group may be optionally substituted with halogen, -CN, -OR 10 , or -NR 10 R 11 replace,

[0063] R7 is a 3-12 membered cycloalkyl or a 3-12 membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl may be optionally substituted by (=O), halogen, or C 1-6 Alkyl substituted, said alkyl group may be optionally substituted with halogen, -CN, -OR 10 , or -NR 10 R 11 replace,

[0064] R 10 and R 11 Each independently selected from H, C 1-6 Alkyl and C 3-8 Cycloalkyl,

[0065] R 12 and R 13 are each independently selected from H, halogen and C 1-6 alkyl,

[0066] p is 0, 1, or 2;

[0067] In some embodiments, n is each independently 0, 1 or 2, preferably 1 or 2, more preferably 1;

[0068] In some embodiments, p is 0 or 1;

[0069] In some embodiments, X5 is CR6, X6 is S, and R6 is selected from H, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl, preferably selected from H, halogen and C 1-6 alkyl;

[0070] In some embodiments, X1 and X2 are each independently CR4, X3 and X4 are each independently C, X5 is CR6, X6 is S, and R4 is selected from H, halogen, and C 1-6 Alkyl, R6 is selected from H, halogen and C 1-6 Alkyl; in some embodiments, R4 is H;

[0071] In some embodiments, R2 is a 3-12 membered heterocycloalkyl group, which may be optionally substituted with halogen, -OR 10 、-NR 10 R 11 , or C 1-6 Alkyl substitution,

[0072] R 10 and R 11 Each independently selected from H and C 1-6 alkyl;

[0073] In some embodiments, R7 is a 3-12 membered heterocycloalkyl group, which may be optionally substituted with (=O), or C 1-6 Alkyl substitution;

[0074] In some embodiments, R7 is

[0075] In some embodiments, Y2, Y3 and Y4 are each independently selected from CR3, and R3 is each independently selected from H, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl;

[0076] In some embodiments, Y2, Y3 and Y4 are each independently selected from CR3, and R3 is each independently selected from H, halogen and C 1-6 alkyl;

[0077] In some embodiments, R 10 and R 11 Each independently selected from H and C 1-6 alkyl;

[0078] In some embodiments, R 12 and R 13 is hydrogen;

[0079] In some embodiments, the compound of formula (I) is the following compound or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof,

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087] 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 comprising a pharmaceutically acceptable carrier;

[0088] In another aspect, the present invention provides a method for treating a disease associated with USP7 activity, 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, kidney cancer, melanoma, liver cancer, colon cancer, sarcoma, brain cancer, prostate cancer, leukemia, lymphoma, or multiple myeloma;

[0089] In some embodiments of the present invention, the subject of the present invention is a mammal including a human;

[0090] In another aspect, the present invention provides 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 preparation of a medicament for treating a disease associated with USP7 activity; in some embodiments, the disease associated with USP7 activity is ovarian cancer, breast cancer, lung cancer, pancreatic cancer, kidney cancer, melanoma, liver cancer, colon cancer, sarcoma, brain cancer, prostate cancer, leukemia, lymphoma, or multiple myeloma. Detailed Description of the Invention

[0092] 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 of the invention.

[0093] It should be understood that the scope of protection of various aspects of the present invention is determined by the claims, and methods and structures within the scope of the claims and their equivalents are all within the scope of the claims.

[0094] Unless otherwise defined, all technical and scientific terms herein have the same meanings as commonly understood by those skilled in the art to which the subject matter of the claims pertains. Unless otherwise indicated, all patents, patent applications, and publications cited herein are incorporated herein by reference in their entirety.

[0095] It should be understood that the foregoing brief description and the following detailed description are exemplary and explanatory, rather than limiting, of any subject matter of the present invention. Unless otherwise specifically stated, the use of the singular also includes the plural. Unless otherwise specified, the use of "or" and "alternatively" means "and / or." In addition, the use of the term "include," as well as other forms such as "comprises," "includes," and "comprising" are not limiting.

[0096] Some chemical terms

[0097] The terms "optional," "optional," or "optionally" mean that the subsequently described event or circumstance may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, "optionally substituted alkyl" means "unsubstituted alkyl" or "substituted alkyl." Furthermore, an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or any hierarchy between monosubstituted and fully substituted (e.g., -CH2CHF2, -CF2CH3, -CFHCHF2, etc.). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that would be sterically impossible and / or incomposable to synthesize will be introduced.

[0098] Unless otherwise indicated, conventional methods within the technical scope of the art, such as mass spectrometry, nuclear magnetic resonance, high performance liquid chromatography, infrared and ultraviolet / visible spectroscopy and pharmacological methods, are adopted. Unless specifically defined, the relevant terms and experimental procedures and techniques of analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry herein are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and in the treatment of patients. For example, the manufacturer's instructions for use of the test kit can be utilized, or reactions and purification can be carried out according to methods well known in the art or the description of the present invention. Conventionally, the above-mentioned techniques and methods can be implemented according to conventional methods well known in the art, based on the description in the multiple summaries and more specific documents cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0099] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0100] As used herein, the terms "group" and "chemical group" refer to a specific part or functional group of a molecule. A chemical group is often considered to be a chemical entity embedded in or attached to a molecule.

[0101] Some chemical groups named herein may be abbreviated to indicate the total number of carbon atoms. For example, C1-C6 alkyl describes an alkyl group, as defined below, having a total of 1 to 6 carbon atoms. The total number of carbon atoms indicated in the abbreviated notation does not include carbon atoms in possible substituents.

[0102] The compounds of the present 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, including1 H. 2 H (D or deuterium) and 3 H (T or tritium); C can be any isotopic form, including 12 C. 13 C and 14 C; O can be in any isotopic form, including 16 O and 18 O etc.

[0103] The term "halogen," "halo," or "halide" refers to bromine, chlorine, fluorine, or iodine.

[0104] As used herein, the terms "aromatic," "aromatic ring," "aromatic," "aromatic," and "aromatic ring" refer to a planar ring or ring moiety having a delocalized electron conjugate system containing 4n+2 electrons, where n is an integer. Aromatic rings can be formed by 5, 6, 7, 8, 9, or more atoms. Aromatic compounds can be optionally substituted and can be monocyclic or polycyclic with fused rings. The term aromatic compound includes all carbon rings (e.g., benzene rings) and rings containing one or more heteroatoms (e.g., pyridine).

[0105] As used herein, the term "heteroatom" or "hetero" refers to atoms other than carbon and hydrogen, either alone or as part of another component. Heteroatoms are independently selected from the group consisting of 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 one another, or some or all of the two or more heteroatoms may be different from one another.

[0106]

[0046] The term "fused" or "fused ring," as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more bonds.

[0107]

[00146] The term "spiro" or "spirocycle," as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.

[0108] The term "alkyl" as used herein alone or as part of another component (e.g., monoalkylamino) refers to an optionally substituted straight-chain or optionally substituted branched monovalent saturated hydrocarbon having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, connected to the rest of the molecule by a single bond, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, n-nonyl, n-decyl, and the like.

[0109] The term "alkenyl" as used herein, alone or in combination, refers to an optionally substituted straight-chain or optionally substituted branched monovalent hydrocarbon group having one or more C=C double bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. The double bonds in these groups can be in cis or trans configurations and should be understood to include both isomers. Examples include, but are not limited to, vinyl (CH=CH2), 1-propenyl (CH2CH=CH2), isopropenyl (C(CH3)=CH2), butenyl and 1,3-butadienyl, etc. When a numerical range appears for an alkenyl group as defined herein, for example, "C2-C6 alkenyl" or "C2-6 alkenyl" refers to an alkenyl group that can 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 encompasses situations where no numerical range is specified.

[0110] The term "alkynyl" as used herein, alone or in combination, refers to an optionally substituted, straight or branched, monovalent hydrocarbon radical having one or more C≡C triple bonds and 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1,3-butadiynyl. When a numerical range appears for an alkynyl group as defined herein, for example, "C2-C6 alkynyl" or "C2-6 alkynyl" 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. The alkynyl groups herein also encompass situations where no numerical range is specified.

[0111] The term "aryl" refers to an all-carbon monocyclic or fused ring having a completely conjugated π electron system having 6-14 carbon atoms, preferably 6-12 carbon atoms, and most preferably 6 carbon atoms. Aryl can be unsubstituted or substituted with one or more substituents, examples of which include but are not limited to alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxyl, sulfonyl, sulfinyl, phosphoryl, and heteroalicyclic groups. Non-limiting examples of unsubstituted aryl include but are not limited to phenyl, naphthyl, and anthracenyl.

[0112] The term "heteroaryl" refers to a monocyclic or fused ring of 5-12 ring atoms, having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, of which 1, 2, 3 or 4 are selected from N, O, S, with the remaining ring atoms being C, and having a completely conjugated π-electron system. Heteroaryl groups may be unsubstituted or substituted, with substituents including, but not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxy, cyano, nitro, carbonyl and heteroalicyclic groups. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl and triazinyl.

[0113] The term "cycloalkyl," as used herein, alone or in combination, refers to a stable, monovalent, non-aromatic, monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, which may include fused, spiro, or bridged ring systems, containing 3-15 carbon atoms, preferably 3-10 carbon atoms, more preferably 3-8 carbon atoms, which may be saturated or unsaturated, and which is attached to the rest of the molecule by a single bond. Non-limiting examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0114] The terms "heterocyclyl," "heterocycloalkyl," and "heterocycle," as used herein, alone or as part of another component, refer to a stable 3-18 membered monovalent non-aromatic ring comprising 2-12 carbon atoms and 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, spirocyclic, or bridged ring systems. The nitrogen, carbon, or sulfur atoms in the heterocyclyl group may be optionally oxidized, the nitrogen atom may be optionally quaternized, and the heterocyclyl group may be partially or fully saturated. The heterocyclyl group may be attached to the rest of the molecule via a single bond through a carbon atom or heteroatom in the ring. A heterocyclyl group containing a fused ring may contain one or more aromatic or heteroaromatic rings, as long as the atoms attached to the rest of the molecule are non-aromatic ring atoms. For the purposes of the present application, the heterocyclic group is preferably a stable 4-11 membered monovalent non-aromatic monocyclic or bicyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-8 membered monovalent non-aromatic monocyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclic groups include azepanyl, azetidinyl, decahydroisoquinolinyl, dihydrofuranyl, dihydroindolinyl, dioxolane, 1,1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piperazinyl, piperidinyl, 4-piperidonyl, pyranyl, pyrazolidinyl, pyrrolidinyl, quinolizinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, and the like.

[0115] The term "polymorph" or "polymorphism" as used herein refers to compounds of the present invention having multiple crystal lattice morphologies. Some compounds of the present invention may have more than one crystal form, and the present invention encompasses all polymorphic forms or mixtures thereof.

[0116] Intermediate compounds of the compounds of the present invention and polymorphs thereof are also within the scope of the present invention.

[0117] Unless otherwise specified, compounds of the present invention containing olefinic double bonds include both E and Z isomers.

[0118] It should be understood that the compounds of the present invention may contain asymmetric centers. These asymmetric centers can independently be in the R or S configuration. Some compounds of the present invention may also exhibit cis-trans isomerism, which is apparent to those skilled in the art. It should be understood that the compounds of the present invention include their individual geometric isomers and stereoisomers and mixtures thereof, including racemic mixtures. These isomers can be separated from their mixtures by implementing or modifying known methods, such as chromatography and recrystallization techniques, or they can be prepared separately from the appropriate isomers of their intermediates.

[0119] As used herein, the term "pharmaceutically acceptable salt" includes both acid-addition salts and base-addition salts.

[0120] "Pharmaceutically acceptable salts" refer to salts formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, capric acid, hexanoic acid, carbonic acid, cinnamic acid, and citric acid, which retain the biological efficacy and properties of the free acid and are not biologically or otherwise undesirable. "Pharmaceutically acceptable base-added salts" refer to salts that retain the biological efficacy and properties of the free acid and are not biologically or otherwise undesirable. These salts are prepared by reacting the free acid with an inorganic or organic base. Salts formed by reaction with inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and manganese salts.

[0121] Organic bases for forming salts include, but are not limited to, primary amines, secondary amines, tertiary amines, cyclic amines, and the like, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purine, piperazine, piperidine, choline, and caffeine. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0122] Crystallization often produces solvates of the compounds of the invention. The term "solvate" as used herein refers to an association of one or more molecules of the compound of the invention with one or more solvent molecules.

[0123] The solvent may be water, in which case the solvate is a hydrate. Alternatively, it may be an organic solvent. Thus, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms. The compounds of the present invention may be true solvates, but in other cases, the compounds of the present invention may simply accidentally retain water or a mixture of water and some other solvent. The compounds of the present invention may be reacted in a solvent or precipitated or crystallized in a solvent. Solvates of the compounds of the present invention are also encompassed within the scope of the present invention.

[0124] The term "pharmaceutical composition" as used herein refers to a preparation containing a compound of the present invention and a medium generally accepted in the art for delivering biologically active compounds to mammals (such as humans), including all pharmaceutically acceptable carriers.

[0125] The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0126] As used herein, the term "pharmaceutically acceptable" refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, that is, the substance can be administered to a subject without causing an adverse biological response or interacting in an adverse manner with any components contained in the composition.

[0127] "Pharmaceutically acceptable carrier" includes, but is not limited to, adjuvants, carriers, excipients, auxiliary agents, 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 relevant government administrative departments for use in humans and domesticated animals.

[0128] As used herein, the terms "subject," "patient," "subject," or "individual" refer to individuals suffering from a disease, disorder, or condition, and include 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. Examples of non-human mammals include, but are not limited to, birds and fish. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0129] The term "treatment" as used herein refers to the treatment of a disease or condition in a mammal, especially a human, including

[0130] (i) preventing the development of a disease or condition in a mammal, particularly a mammal that has been previously exposed to the disease or condition but has not yet been diagnosed with the disease or condition;

[0131] (ii) inhibiting the disease or condition, i.e., controlling its development;

[0132] (iii) alleviate the disease or condition, i.e., cause the disease or condition to regress;

[0133] (iv) Alleviate symptoms caused by a disease or condition.

[0134] As used herein, the terms "disease" and "disorder" are used interchangeably or may have different meanings because certain diseases or disorders do not yet have a known causative agent (and therefore the cause of the disease is unknown) and therefore cannot be considered diseases but rather are considered to be undesirable conditions or syndromes with more or less specific symptoms that have been confirmed by clinical researchers.

[0135] As used herein, the terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" refer to an amount of at least one agent or compound sufficient to provide some relief to some degree from one or more symptoms of the disease or condition being treated. This can result in a reduction and / or alleviation of signs, symptoms, or causes of disease, or any other desired change in a biological system. For example, a therapeutically effective amount is the amount of a composition comprising a compound disclosed herein that provides a clinically significant alleviation of symptoms. Techniques such as dose escalation studies can be used to determine the effective amount appropriate for any individual case.

[0136] As used herein, the terms "administer," "administer," "dosing," and the like refer to methods that enable a compound or composition to be delivered to the desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, 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.

[0137] Preparation of the compounds of the present invention

[0138] It is understood that in the following description, combinations of substituent groups and / or variables of the described formulas are permissible only if such combinations result in stable compounds.

[0139] Those skilled in the art will also appreciate that the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. Protecting groups can be added or removed by standard techniques known to those skilled in the art.

[0140] Example 1: 3-((7-(5-chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0141]

[0142]

[0143] Step 1: Synthesis of compound 3

[0144] At 0 ° C, DIAD (9.14 g) was added dropwise to a solution of compound 1 (6.00 g), compound 2 (6.29 g) and triphenylphosphine (11.84 g) in THF (150 mL). Subsequently, the reaction solution was warmed to room temperature and stirred at room temperature overnight. The reaction solution was concentrated in vacuo, and the resulting residue was dissolved in ethyl acetate (500 mL) and washed with 5% Na2CO3 aqueous solution (100 mL×3) and saturated brine (100 mL×3), respectively, then 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 = 100:1–100:2) to obtain a light yellow solid 3 (11.7 g).

[0145] Step 2: Synthesis of compound 5

[0146] Under nitrogen, a solution of compound 3 (1.00 g), compound 4 (1.62 g), Pd(dppf)Cl2 (234 mg), and anhydrous potassium acetate (940 mg) in dioxane (30 mL) was heated to 100°C and stirred overnight at this temperature. After cooling to room temperature, the reaction solution was used directly in the next reaction without further purification.

[0147] Step 3: Synthesis of compound 7

[0148] At -40 ° C, under nitrogen protection, 1M vinyl magnesium bromide tetrahydrofuran solution (14 mL) was added to a solution of compound 6 (1.0 g) in tetrahydrofuran (200 mL). The reaction solution continued to react at -40 ° C for 1 hour. Subsequently, saturated aqueous ammonium chloride solution (20 mL) was added to quench the reaction. The reaction solution was concentrated under reduced pressure, and ethyl acetate / water (80 mL / 80 mL) was added. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (80 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 7 (1.1 g).

[0149] Step 4: Synthesis of compound 9

[0150] Sodium hydride (0.27 g) was added to a solution of compound 7 (1.0 g) and compound 8 (1.2 g) in DMF (20 mL) at room temperature. The reaction mixture was heated to 70°C and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain the target compound 9 (1.6 g).

[0151] Step 5: Synthesis of compound 10

[0152] To a solution of compound 9 (1.6 g) in dichloromethane (50 mL) was slowly added dropwise DAST (0.9 mL) at 0°C. The reaction mixture was stirred at this temperature for 1 hour. Saturated aqueous NaHCO₃ (30 mL) was then added to quench the reaction. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by flash silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain compound 10 (0.82 g).

[0153] Step 6: Synthesis of compound 11

[0154] Under nitrogen, a mixture of compound 10 (820 mg), compound 5 (1.52 g), tetrakistriphenylphosphine palladium (212 mg), and anhydrous sodium carbonate (390 mg) in dioxane / water (20 mL / 5 mL) was heated to 80°C and stirred overnight. The mixture was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The resulting residue was separated and purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1) to obtain compound 20 (410 mg).

[0155] Step 7: Synthesis of compound 12

[0156] To a solution of compound 11 (410 mg) in dichloromethane (10 mL) was added trifluoroacetic acid (1 mL) dropwise, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture 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) to obtain compound 12 (215 mg). 1H NMR (400MHz, CDCl3), 8.82 (d, J = 4.8Hz, 1H), 7.69 (d, J = 2.4Hz, 1H), 7.58 (s, 1H), 7.34 (d, J = 4. 8Hz,1H),7.11-7.14(m,1H),7.05(d,J=2.0Hz,1H),6.61(d,J=3.6Hz,1H),4.73-4.81(m,2H),3 .76(dd,J=21.6Hz,15.6Hz,1H),3.49(dd,J=24.4Hz,15.6Hz,1H),3.08-3.17(m,2H),2.80-2. 92(m,2H),2.34-2.37(m,2H),1.32-1.48(m,3H),1.21(s,3H),1.08(s,3H),0.98-1.06(m,1H).

[0157] Example 2: 3-((7-(5-chloro-1-((4-hydroxypiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0158]

[0159] The method for synthesizing the compound in Example 2 is the same as Step 6 and Step 7 in Example 1. 1 H NMR(400MHz, CDCl3),8.88-9.09(br,1H),8.80(d,J=4.8Hz,1H),7.70(d,J=2.0Hz,1H),7 .56(s,1H),7.39-7.49(m,1H),7.37(d,J=4.8Hz,1H),7.02(d,J=2.0Hz,1H),6.62(d,J=3. 6Hz,1H),4.74-4.82(m,2H),3.64(d,J=15.2Hz,1H),3.33(d,J=15.2Hz,1H),2.76-3.06(m ,4H),2.33-2.37(m,2H),1.23-1.39(m,3H),1.21(s,3H),1.09(s,3H),0.84-0.94(m,1H).

[0160] Example 3: 3-((7-(5-chloro-1-((4-hydroxypiperidin-4-yl)methyl)-1H-indol-7-yl)thienyl[3,2-b]pyridin-2-yl)methyl)-1-(2,2,2-trifluoroethyl)pyrimidine-2,4(1H,3H)-dione

[0161]

[0162] The synthesis method of Example 3 is the same as that of Example 2. 1 H NMR(400MHz, DMSO-d6),8.75(d,J=4.8Hz,1H),7.77(d,J=2.4Hz,1H),7.71(d,J=8.0Hz,1H),7.53(s, 1H),7.47(d,J=3.2Hz,1H),7.44(d,J=4.4Hz,1H),7.03(d,J=1.6Hz,1H),6.63(d,J=3.2Hz,1H),5.84( d,J=8.0Hz,1H),5.26(d,J=14.8Hz,1H),5.17(d,J=14.8Hz,1H),4.94(s,1H),4.61-4.68(m,2H),3.6 5(d,J=14.8Hz,1H),3.28(d,J=14.8Hz,1H),2.65-2.87(m,4H),0.74-0.83(m,3H),0.59-0.67(m,1H).

[0163] Example 4: 3-((7-(6-chloro-2-((4-hydroxypiperidin-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0164]

[0165]

[0166] Step 1: Preparation of compound 17

[0167] A toluene solution (50 mL) of compound 15 (5.0 g) and compound 16 (2.4 g) was heated to 120°C, and the generated water was removed using a water separator. The reaction mixture was allowed to react at this temperature for 4 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to obtain a crude product of compound 17 (7.5 g). This crude product was used directly in the next reaction without further purification.

[0168] Step 2: Preparation of compound 18

[0169] At 0 ° C, sodium borohydride solid (1.4 g) was added in batches to a solution of crude compound 17 (7.5 g) in methanol (100 mL). After the addition was completed, the reaction solution temperature was raised to room temperature and stirring was continued at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and water (200 mL) was added thereto. The aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude compound 18 (7.5 g). The crude product was used directly in the next reaction without further purification.

[0170] Step 3: Synthesis of compound 19

[0171] To a solution of compound 18 (7.5 g), DMAP (0.15 g), and triethylamine (6.75 g) in dichloromethane (150 mL) was added TsCl (4.6 g) at 0°C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The resulting residue was separated and purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 20:1) to obtain compound 19 (8.5 g).

[0172] Step 4: Synthesis of compound 20

[0173] To a solution of compound 19 (4.76 g) in dichloromethane (100 mL) was added anhydrous aluminum chloride (6.6 g) at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 to 5:1) to obtain compound 20 (1.2 g).

[0174] Step 5: Synthesis of compound 21

[0175] At 0 ° C, sodium cyanoborocyanide (1.56 g) was added to a methanol (50 mL) solution of compound 20 (1.2 g). The reaction solution was stirred at this temperature for 20 minutes, and then boron trifluoride etherate (3 mL) was added dropwise to the solution at this temperature. The resulting solution was stirred at this temperature for 1 hour, and then the reaction solution was heated to reflux and stirred for 4 hours. After cooling to room temperature, a saturated aqueous sodium carbonate solution (50 mL) was added to the reaction solution. The organic solvent was removed by concentration under reduced pressure. The aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by rapid silica gel column chromatography (dichloromethane: methanol = 100: 1 to 20: 1) to obtain compound 21 (1.2 g).

[0176] Step 6: Synthesis of compound 22

[0177] To a solution of compound 21 (1.2 g) in dichloromethane (50 mL) were added triethylamine (1.5 g) and Boc2O (1.1 g), and the reaction mixture was stirred at room temperature overnight. 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 = 100:1 to 30:1) to obtain compound 22 (1.1 g).

[0178] Step 7: Synthesis of compound 23

[0179] Under nitrogen, a solution of compound 22 (1.1 g), compound 4 (1.2 g), Pd(dppf)Cl2 (231 mg), and anhydrous potassium acetate (780 mg) in dioxane (20 mL) was heated to 100°C and stirred overnight. The resulting solution was cooled to room temperature and used directly in the next reaction without further purification.

[0180] Step 8: Synthesis of compound 24

[0181] Under nitrogen, a solution of compound 23 (354 mg), compound 3 (282 mg), tetrakis(triphenylphosphine)palladium (86 mg), and anhydrous sodium carbonate (158 mg) in dioxane / water (8 mL / 2 mL) was heated to 100° C. and stirred overnight. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was separated and purified by flash silica gel column chromatography (dichloromethane:methanol = 200:1 to 50:1) to obtain compound 24 (180 mg).

[0182] Step 9: Synthesis of compound 25

[0183] To compound 24 (180 mg) was added a 4N HCl solution in dioxane (5 mL), and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain compound 25 (95 mg).

[0184] Step 10: Synthesis of compound 26

[0185] A solution of compound 25 (75 mg), compound 8 (90 mg), and anhydrous potassium carbonate (50 mg) in ethanol (5 mL) was heated to 80° C. and stirred overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by flash vacuum column chromatography (dichloromethane:methanol=200:1 to 50:1) to obtain compound 26 (52 mg).

[0186] Step 11: Synthesis of compound 27

[0187] 4N HCl in dioxane (2 mL) was added to compound 26 (52 mg), and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain compound 27 (23 mg). 1H NMR(400MHz, CD3OD),8.89(d,J=4.8Hz,1H),7.71(s,1H),7.65(d,J=4.8Hz,1H),7.60(s,1H),7.47(s,1H),4.90 -4.94(m,2H),3.58-3.74(m,3H),3.14-3.47(m,9H),2.50(s,2H),1.76-1.98(m,4H),1.24(s,3H),1.12(s,3H).

[0188] Example 5: 3-((7-(5-chloro-1-((4-hydroxypiperidin-4-yl)methyl)-1H-benzo[d]imidazol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0189]

[0190] Step 1: Synthesis of compound 29

[0191] Compound 28 (3.00 g) and 28% aqueous ammonia (30.0 mL) were added to a 100 mL sealed tube and heated to 70°C for 3 hours. The reaction solution was cooled to room temperature and concentrated to obtain crude compound 29 (3.2 g), which was used directly in the next reaction.

[0192] Step 2: Synthesis of compound 30

[0193] Compound 29 (0.99 g) was dissolved in dichloromethane (50 mL), and 5-chloro-2-fluoronitrobenzene (1.20 g) and triethylamine (0.16 mL) were added sequentially, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 to 1:1) to obtain compound 30 (0.90 g).

[0194] Step 3: Synthesis of compound 31

[0195] Compound 30 (0.90 g) was dissolved in acetic acid (20 mL), and NBS (0.50 g) was added, followed by stirring at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 to 1:1) to afford compound 31 (0.80 g).

[0196] Step 4: Synthesis of compound 32

[0197] Compound 31 (0.80 g) was dissolved in acetic acid (20 mL), iron powder (0.46 g) was added, and the mixture was stirred at room temperature overnight. The reaction solution was poured into ethyl acetate (50 mL), diluted, and filtered. The filtrate was washed sequentially with water (50 mL) and saturated aqueous sodium bicarbonate solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 3:1 to 1:1) to obtain compound 32 (0.60 g).

[0198] Step 5: Synthesis of compound 34

[0199] Compound 32 (0.60 g) was dissolved in trimethyl orthoformate (20 mL), p-toluenesulfonic acid (5 mg) was added, and the temperature was raised to 80°C with stirring for 2 hours. After cooling to room temperature, the reaction solution was poured into ethyl acetate (100 mL) and diluted, then washed with water (50 mL) and saturated sodium bicarbonate solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1 to 3:1) to obtain compound 33 (0.50 g). Compound 34 was then prepared using the synthetic methods of steps 6 and 7 of the compound synthesis method of Example 1. 1 H NMR (400MHz, DMSO-d6)8.84-8.93(m,2H),8.76(s,1H),8.37-8.50(m,1H),8.01(d,J=2.0H z,1H),7.63(s,1H),7.61(d,J=4.8Hz,1H),7.43(d,J=2.0Hz,1H),4.78(s,2H),3.86(d,J= 14.8Hz,1H),3.52(d,J=14.8Hz,1H),2.74-2.869(m,2H),2.59-2.73(m,2H),2.54-2.57(m ,2H),1.16-1.25(m,1H),1.13(s,3H),1.02-1.09(m,1H),0.99(s,3H),0.82-0.98(m,2H).

[0200] Example 6: 3-((7-(5-chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-benzo[d]imidazol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0201]

[0202] The compound in Example 6 was prepared using compound 33 as a raw material through the methods of steps 5, 6 and 7 in Example 1. 1H NMR(400MHz,DMSO-d6),8.92-9.01(br,1H),8.72-8.88(m,2H),8.47(s,1H),7.96( d,J=1.2Hz,1H),7.60(s,1H),7.53(d,J=4.8Hz,1H),7.36(d,J=1.6Hz,1H),4.76(s ,2H),4.13-4.21(m,1H),3.71-3.80(m,1H),2.92-3.05(m,2H),2.36-2.66(m,5H), 1.30-1.62(m,2H),1.15-1.24(m,1H),1.13(s,3H),1.02-1.10(m,1H),0.97(s,1H).

[0203] Example 7: 3-((7-(5-chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indazol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0204]

[0205] Step 1: Synthesis of compounds 37a and 37b

[0206] A solution of compound 35 (123 mg), compound 36 (200 mg), and cesium carbonate (253 mg) in dioxane (3 mL) was heated to 90° C. and stirred under these conditions for 60 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was separated and purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 to 1:1) to obtain compound 37a (70 mg) and compound 37b (53 mg).

[0207] Step 2: Synthesis of compound 38

[0208] Compound 38 can be prepared using compound 37a as a raw material by the synthesis method of steps 6 and 7 in the synthesis method of the compound in Example 1. 1H NMR(400MHz, CDCl3),8.77(d,J=4.8Hz,1H),8.06(s,1H),7.80(d,J=2.0Hz,1H),7.57(s,1H) ,7.28(d,J=2.0Hz,1H),7.23-7.26(m,1H),4.80(d,J=15.2Hz,1H),4.74(d,J=15.2Hz,1H),4 .09(dd,J=21.6Hz,15.6Hz,1H),3.72(t,J=15.6Hz,1H),3.06-3.17(m,2H),2.66-2.84(m,2H ),2.33-2.36(m,2H),1.71-1.92(m,2H),1.37-1.47(m,1H),1.20(s,3H),1.02-1.14(m,4H).

[0209] Example 8: 3-((7-(5-chloro-2-((4-fluoropiperidin-4-yl)methyl)-2H-indazol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0210]

[0211] Using compound 37b as a raw material, the compound in Example 8 can be prepared by the synthesis method of steps 6 and 7 in the synthesis method of the compound in Example 1. 1 H NMR(400MHz, CD3OD),8.68(d,J=4.8Hz,1H),8.41(d,J=1.2Hz,1H),7.93(d,J=1.6Hz,1H),7. 70(d,J=5.2Hz,1H),7.57(d,J=2.0Hz,1H),7.53(s,1H),4.84(s,2H),4.76(d,J=20.8Hz,2H), 3.38-3.45(m,2H),3.15-3.23(m,2H),2.46(s,2H),1.93-2.13(m,4H),1.20(s,3H),1.04(s,3H).

[0212] Example 9: 3-((7-(5-chloro-1-(piperidin-4-ylmethyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0213]

[0214] Step 1: Synthesis of compound 40

[0215] A solution of compound 7 (200 mg), compound 39 (640 mg), potassium iodide (14 mg) and cesium carbonate (850 mg) in dioxane (5 mL) was heated to 80 ° C, and the reaction solution was stirred at this temperature for 36 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate (50 mL). The resulting organic solution was washed with water (20 mL), saturated sodium thiosulfate solution (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 3:1 to 2:1) to obtain compound 40 (153 mg). 1 HNMR(400MHz, CDCl3),8.68-8.92(m,3H),7.70(d,J=2.4Hz,1H),7.62(s,1H),7.27(d,J=4.4Hz,1H),7. 08(d,J=2.0Hz,1H),6.98(d,J=3.2Hz,1H),6.51(d,J=3.2Hz,1H),4.79(s,2H),3.51(dd,J=14.4Hz,5.6 Hz,1H),3.30(dd,J=14.4Hz,8.4Hz,1H),3.17-3.25(m,1H),3.07-3.15(m,1H),2.30-2.44(m,3H),1.96 -2.10(m,1H),1.13-1.32(m,5H),1.12(s,3H),0.96-1.09(m,1H),0.83-0.92(m,1H),0.49-0.58(m,1H).

[0216] Example 10: 3-((7-(5-chloro-1-((3-fluoro-8-azabicyclo[3.2.1]octan-3-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

[0217]

[0218] The synthesis method of Example 10 is the same as that of Example 1. 1H NMR(400MHz, DMSO-d6),8.75(d,J=4.8Hz,1H),8.45-8.72(br,2H),7.78(d,J=2. 0Hz,1H),7.53(s,1H),7.38-7.42(m,2H),7.06(d,J=2.0Hz,1H),6.66(d,J=3.2H z,1H),4.72(s,2H),3.73-3.81(m,2H),3.21-3.43(m,2H),2.51-2.53(m,2H),1. 59-1.85(m,5H),1.44-1.54(m,1H),1.12(s,3H),1.01-1.08(m,2H),0.98(s,3H).

[0219] Example 11: 3-((7-(5-chloro-1-(((R)-morpholin-2-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0220]

[0221] The synthesis method of Example 11 is the same as that of Example 9. 1 H NMR(400MHz, CDCl3),8.72-8.76(m,1H),7.67(d,J=2.0Hz,1H),7.56(d,J=5.6Hz,1H),7.24-7.28(m,1H),7.10- 7.12(m,1H),7.01-7.03(m,1H),6.51-6.53(m,1H),4.74-4.82(m,2H),3.57-3.65(m,1H),3.47-3.53(m,0.5H), 3.35-3.45(m,1H),3.08-3.23(m,2H),2.99-3.06(m,0.5H),2.54-2.64(m,2H),2.32-2.36(m,2H),1.82-2.01(m ,1H),1.79-1.84(m,0.5H),1.62-1.66(m,0.5H),1.22(s,1.5H),1.21(s,1.5H),1.13(s,1.5H),1.08(s,1.5H).

[0222] Example 12: 3-((7-(5-chloro-1-((4-methylpiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

[0223]

[0224] The synthesis method of Example 12 is the same as that of Example 9. 1 H NMR(400MHz, DMSO-d6),8.77(d,J=4.4Hz,1H),8.15-8.26(br,1H),7.81-7.95(br,1H),7.80(d,J =2.0Hz,1H),7.55(s,1H),7.50(d,J=4.4Hz,1H),7.44(d,J=3.2Hz,1H),7.10(d,J=2.0Hz,1H),6.6 7(d,J=3.2Hz,1H),4.73(s,2H),3.62(d,J=14.8Hz,1H),3.29(d,J=14.8Hz,1H),2.65-2.92(m,4H) ,2.53(s,2H),1.13(s,3H),1.06-1.11(m,1H),0.92-1.03(m,5H),0.59-0.67(m,1H),0.31(s,3H).

[0225] Example 13: 3-((7-(5-chloro-1-((1-ethyl-4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0226]

[0227] To a solution of compound 12 (30 mg) and anhydrous potassium carbonate (38 mg) in DMF (1 mL) was added bromoethane (12 μL) dropwise. The reaction mixture was allowed to react overnight at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (dichloromethane:methanol = 30:1 to 10:1) to obtain compound 41 (15 mg). 1H NMR (400MHz, CDCl3), 8.79 (d, J = 4.8 Hz, 1H), 7.68 (d, J =2.0Hz,1H),7.55(s,1H),7.31(d,J=4.8Hz,1H),7.11(s,1H),7.05(d,J=2 .0Hz,1H),6.60(d,J=3.2Hz,1H),4.71-4.82(m,2H),3.78(dd,J=21.2Hz,1 5.6Hz,1H),3.49(dd,J=23.6Hz,16.0Hz,1H),2.60-3.26(m,4H),2.35-2.5 9(m,2H),2.33(s,2H),1.38-1.72(m,4H),1.20-1.27(m,6H),1.08(s,3H).

[0228] Example 14: 3-((7-(6-chloro-3-(piperidin-4-ylenmethyl)benzofuran-4-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0229]

[0230] Step 1: To a solution of compound 42 (2.0 g) in acetone (100 mL) at 0°C were added potassium carbonate (2.64 g) and bromoacetone (2.64 g) in sequence. The reaction mixture was stirred at room temperature for 10 minutes and then heated to 60°C overnight. After the reaction, the reaction mixture was filtered to obtain a filtrate. The filtrate was concentrated under reduced pressure and purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 50:1) to obtain compound 44 (2.6 g).

[0231] Step 2: Polyphosphoric acid (10 mL) was added to compound 44, and the reaction mixture was heated to 150°C for 30 min. After completion of the reaction, the reaction mixture was diluted with water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 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 to obtain compounds 45a and 45b (1.3 g total, approximately 1:1 ratio).

[0232] Step 3: Under nitrogen, to a solution of a mixture of 45a and 45b (1.3 g) in carbon tetrachloride (100 mL) were added NBS (2.0 g) and BPO (50 mg). The reaction mixture was heated to 70°C overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 30:1) to obtain the desired products 46a and 46b (800 mg).

[0233] Step 4: To a solution of a mixture of compounds 46a and 46b (800 mg) in tetrahydrofuran (5 mL) was added 1N HCl (5 mL). The reaction mixture was then heated to 70°C for 1 h. After cooling to room temperature, the mixture was diluted with water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL x 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 (petroleum ether:ethyl acetate = 20:1 to 5:1) to obtain a mixture of the desired products 47a and 47b (500 mg total).

[0234] Step 5: At -78°C, under nitrogen, n-butyllithium (2 mL, 2.5 M) was added dropwise to a solution of methyltriphenylphosphonium bromide (826 mg) in anhydrous tetrahydrofuran (10 mL). After the addition was complete, the reaction mixture was heated to 0°C and the reaction continued for 30 min. The reaction mixture was then cooled to -78°C and a solution of a mixture of compounds 47a and 47b (500 mg) in THF (5 mL) was added dropwise. The reaction mixture was then warmed to room temperature and allowed to react overnight. After the reaction was completed, saturated ammonium chloride solution (100 mL) was added to quench the reaction mixture, and the aqueous phase was extracted with ethyl acetate (50 mL x 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 (petroleum ether:ethyl acetate = 50:1 to 20:1) to obtain a mixture of compounds 48a and 48b (300 mg).

[0235] Step 6: Under nitrogen, compound 49 (919 mg) and Hoveyda-Grubbs second-generation catalyst (109 mg) were added to a dichloromethane solution (10 mL) of a mixture of compounds 48a and 48b (300 mg). The reaction mixture was then heated to 40°C and stirred overnight. After the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (ethyl acetate:petroleum ether = 10:1 to 2:1) to obtain a mixture of 50a and 50b (150 mg).

[0236] Step 7: Under nitrogen, a mixture of compounds 50a and 50b (150 mg), compound 5 (100 mg), sodium carbonate (80 mg), and tetrakistriphenylphosphine palladium (30 mg) were dissolved in 1,4-dioxane and water (5 mL, v / v 4:1). The reaction solution was heated to 80°C overnight. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography (dichloromethane:methanol = 200:1 to 100:1) to obtain a mixture of 51a and 51b (100 mg).

[0237] Step 8: To a solution of a mixture of 51a and 51b (100 mg) in dichloromethane (5 mL) was added trifluoroacetic acid (0.5 mL) at room temperature and stirred for 1 h until the reaction was complete. Saturated aqueous sodium bicarbonate solution (10 mL) was added to quench the reaction, and the aqueous phase was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by preparative thin layer chromatography (dichloromethane: methanol = 15: 1) to give Example 14 compound 52a (20 mg) and by-product 52b (10 mg), respectively. Compound 52a: 1 H NMR(400MHz, CD3OD),8.66(d,J=4.4Hz,1H),7.91(s,1H),7.85(d,J=3.6Hz,1H),7.61(d,J=3.6Hz,1H),7.53(s,1H),7.44-7.48(m,1 H),6.70-6.74(m,1H),4.86(s,2H),3.31-3.34(m,2H),3.23-3.26(m,2H),2.71-2.76(m,4H),2.48(s,2H),1.21(s,3H),1.05(s,3H).

[0238] Example 15: 3-((7-(6-chloro-3-((4-fluoropiperidin-4-yl)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione hydrochloride

[0239]

[0240] Step 1: Synthesis of compound 54

[0241] Compound 53 (0.99 g) was dissolved in dichloromethane (50 mL), and 5-chloro-2-fluoronitrobenzene (1.20 g) and triethylamine (0.16 mL) were added sequentially. The reaction was allowed to react at room temperature overnight. The reaction was completed as monitored by LC-MS. The reaction solution was directly concentrated, and the residue was separated and purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 3:1) to give compound 54 (1.1 g).

[0242] Step 2: Synthesis of compound 55

[0243] Compound 30 (1.1 g) was dissolved in acetic acid (20 mL), and NBS (0.60 g) was added. The reaction was allowed to react at room temperature overnight. The reaction was completed as monitored by LC-MS. The reaction solution was directly concentrated, and the residue was separated and purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 3:1) to give compound 55 (0.75 g).

[0244] Step 3: Synthesis of compound 56

[0245] Compound 55 (0.75 g) was dissolved in acetic acid (20 mL), and iron powder (0.46 g) was added. The reaction was allowed to react at room temperature overnight. The reaction was completed as monitored by LC-MS. The reaction solution was poured into ethyl acetate (50 mL) and filtered. The filtrate was washed with water (50 mL) and saturated sodium bicarbonate (50 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1) to give compound 56 (0.53 g).

[0246] Step 4: Synthesis of compound 58

[0247] Compound 56 (0.53 g) was dissolved in anhydrous tetrahydrofuran (10 mL) at 0°C, and triphosgene (0.18 g) was added. The mixture was allowed to react overnight at room temperature. LC-MS confirmed the completion of the reaction. The reaction solution was poured into ethyl acetate (100 mL), washed sequentially with water (50 mL) and saturated sodium bicarbonate (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1) to obtain compound 57 (0.23 g). Compound 58 was then prepared using the synthetic methods of steps 6 and 7 of Example 1. 1 H NMR(400MHz, DMSO-d6),11.67(s,1H),8.79-8.88(br,1H),8.73(d,J=4.4Hz,1H),8.42-8.55(br,1H),7.54(s,1H),7.41(d,J=4.4Hz,1H),7.20(s,1H) ,7.02(s,1H),4.76(s,2H),3.62-3.76(m,2H),3.28-3.40(m,2H),2.94-3. 05(m,2H),2.42-2.64(m,4H),1.44-1.64(m,2H),1.13(s,3H),0.96(s,3H).

[0248] Example 16: 3-((7-(6-chloro-3-((4-fluoropiperidin-4-yl)methyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0249]

[0250] At 0 ° C, sodium hydride (13 mg) was added to a solution of compound 57 (100 mg) in tetrahydrofuran (2 mL). The reaction solution was stirred at this temperature for 30 min, and then iodomethane (40 μL) was added dropwise thereto. The reaction solution temperature was raised to room temperature and the reaction was allowed to proceed overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was separated and purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 to 2:1) to obtain compound 59 (55 mg). Subsequently, the synthetic method of steps 6 and 7 in the synthetic method of Example 1 was used to prepare compound 60. 1 H NMR(400MHz, DMSO-d6),8.70-8.85(m,2H),8.34-8.50(br,1H),7.52-7.56(m,2H),7.40(d,J=4.4Hz,1H),7.07(d,J=1.6Hz,1H),4.7 6(s,2H),3.68-3.80(m,2H),3.35-3.47(m,5H),2.95-3.05(m,2H),2.42-2.64(m,4H),1.42-1.65(m,2H),1.07(s,3H),0.96(s,3H).

[0251] Example 17: 3-((7-(4-chloro-3-(piperidin-4-ylenmethyl)benzofuran-6-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0252]

[0253] Compound 51b was obtained by the preparation method of Example 14, which is the compound of Example 16. 1 H NMR(400MHz, CD3OD),8.66(d,J=4.4Hz,1H),7.91(s,1H),7.85(d,J=3.6Hz,1H),7.61(d,J=3.2Hz,1H),7.53(s,1H),7.45-7.47(m ,1H),6.72(s,1H),4.85(s,2H),3.31-3.34(m,2H),3.23-3.26(m,2H),2.71-2.76(m,4H),2.48(s,2H),1.21(s,3H),1.05(s,3H).

[0254] Example 18: 3-((7-(5-chloro-3-fluoro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0255]

[0256]

[0257] Step 1: Synthesis of compound 62

[0258] To a solution of compound 61 (5 g) in ethanol (80 mL) was added dropwise bromine (4.2 mL) at 70°C. The reaction mixture was stirred at 70°C for 1 h, then cooled to room temperature and concentrated hydrochloric acid (80 mL) was added. The reaction mixture was stirred at room temperature for 30 min and filtered. The resulting filter cake was washed with water (20 mL x 3) and dried under vacuum to obtain compound 62 (5.9 g).

[0259] Step 2: Synthesis of compound 63

[0260] To a solution of compound 62 (1 g) in dichloromethane (30 mL) was slowly added dropwise DAST (2.5 mL) at room temperature. The reaction mixture was allowed to react at room temperature for 4 h. After completion of the reaction, methanol (3 mL) was added to the reaction mixture to quench the reaction. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 63 (580 mg).

[0261] Step 3: Synthesis of compound 65

[0262] To a solution of compound 63 (500 mg) in tetrahydrofuran (5 mL) was added dropwise a 2 M borane dimethyl sulfide solution (4.4 mL). The reaction mixture was allowed to react overnight at room temperature. After completion of the reaction, the reaction mixture was quenched with methanol (5 mL) and then concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 100:1) to obtain compound 64 (360 mg).

[0263] Compound 65 was obtained using compound 64 as raw material and the synthetic method of Example 7. 1H NMR(400MHz, CDCl3),8.77(d,J=4.8Hz,1H),7.69(d,J=1.6Hz,1H),7.57(s,1H),7.2 7(d,J=4.8Hz,1H),7.06(d,J=1.6Hz,1H),6.98(s,1H),4.81(d,J=14.8Hz,1H),4.75( d,J=14.8Hz,1H),3.54(dd,J=21.2Hz,15.6Hz,1H),3.36(dd,J=24.0Hz,15.6Hz,1H) ,2.58-2.65(m,4H),2.34(s,2H),1.16-1.26(m,4H),1.08(s,3H),0.75-0.98(m,3H).

[0264] Example 19: 3-((7-(5-chloro-1-(((S)-morpholin-2-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0265]

[0266] The synthesis method of Example 19 is the same as that of Example 9. 1 H NMR(400MHz, CDCl3),8.72-8.75(m,1H),7.67(d,J=2.4Hz,1H),7.56(d,J=5.6Hz,1H),7.24-7.28(m,1H),7.10-7.12(m,1H),7.01- 7.03(m,1H),6.51-6.52(m,1H),4.74-4.82(m,2H),3.57-3.64(m,1H),3.47-3.53(m,0.5H),3.35-3.45(m,1H),3.08-3.24(m,2H), 0.97-3.05(m,0.5H),2.53-2.63(m,2H),2.32-2.35(m,2H),1.82-2.01(m,1H),1.79-1.84(m ,0.5H),1.62-1.66(m,0.5H),1.22(s,1.5H),1.21(s,1.5H),1.13(s,1.5H),1.08(s,1.5H).

[0267] Example 20: 3-((7-(5-chloro-1-(pyrrolidin-3-ylmethyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione hydrochloride

[0268]

[0269] The synthesis method of Example 20 is the same as that of Example 9. 1 H NMR(400MHz, DMSO-d6),8.48-8.90(m,3H),7.80(d,J=2.0Hz,1H),7.57(s,1H),7.51-7.5 2(m,2H),7.08-7.10(m,1H),6.61-6.62(m,1H),4.70-4.79(m,2H),3.88-4.01(m,1H),3.5 5-3.71(m,1H),3.21-3.36(m,1H),2.72-3.12(m,3H),2.44-2.54(m,3.5H),2.24-2.34(m ,0.5H),1.86-1.98(m,1H),1.13(s,1.5H),1.12(s,1.5H),0.97(s,1.5H),0.95(s,1.5H).

[0270] Example 21: 1-((7-(5-chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)pyrrolidine-2,5-dione

[0271]

[0272] Step 1: Synthesis of compound 66

[0273] A solution of compound 7 (200 mg), compound 36 (504 mg), potassium iodide (14 mg), and cesium carbonate (565 mg) in dioxane (5 mL) was heated to 80°C, and the reaction mixture was stirred at this temperature for 36 h until the reaction was complete. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was diluted with ethyl acetate (50 mL). The resulting organic solution was washed with water (20 mL), saturated sodium thiosulfate solution (20 mL), and saturated brine (20 mL). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 to 2:1) to obtain compound 66 (210 mg).

[0274] Step 2: Synthesis of compound 68

[0275] Under nitrogen, a mixture of compound 66 (210 mg), compound 67 (286 mg), tetrakistriphenylphosphine palladium (54 mg), and anhydrous sodium carbonate (100 mg) in dioxane / water (8 mL / 2 mL) was heated to 80°C and stirred overnight. The mixture was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The resulting residue was separated and purified by flash silica gel column chromatography (dichloromethane:methanol = 100:1 to 100:3) to obtain compound 68 (204 mg).

[0276] Step 3: Synthesis of compound 69

[0277] To a solution of compound 68 (204 mg) in tetrahydrofuran (3 mL) was added TBAF (100 mg) at room temperature. The reaction mixture was stirred at room temperature overnight until the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the resulting residue was separated and purified by flash silica gel column chromatography (dichloromethane:methanol = 100:1 to 100:3) to obtain compound 69 (115 mg).

[0278] Step 4: Synthesis of compound 71

[0279] To a solution of compound 69 (110 mg), compound 70 (41 mg) and triphenylphosphine (108 mg) in anhydrous tetrahydrofuran (2 mL) was added DIAD (84 mg) dropwise at 0°C. The reaction solution was then warmed to room temperature and stirred overnight. After completion of the reaction, the reaction solution was concentrated. The resulting residue was separated and purified by rapid silica gel column chromatography (dichloromethane:methanol=200:1 to 100:1) to obtain compound 71 (65 mg).

[0280] Step 5: Synthesis of compound 72

[0281] To a solution of compound 71 (65 mg) in dichloromethane (2 mL) was added trifluoroacetic acid (0.2 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h until the reaction was complete. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and separated and purified by flash silica gel column chromatography (dichloromethane:methanol = 100:1 to 10:1) to obtain compound 72 (26 mg). 1H NMR(400MHz,CD3OD),8.54-8.99(m,1H),7.71(s,1H),7.42-7.62(m,2H),7.31(s,1H),7.08(s,1H),6.65(d,J=2.8Hz,1H),4.85-4.95(m,2H),3 .99(dd,J=20.8Hz,16.0Hz,1H),3.62(dd,J=22.0Hz,15.2Hz,1H),3.24-3.39(m,4H),3.07-3.14(m,2H),2.80-2.92(m,2H),1.11-1.43(m,4H).

[0282] Example 22: 3-((7-(5-chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-1-(2,2,2-trifluoroethyl)pyrimidine-2,4(1H,3H)-dione trifluoroacetate

[0283]

[0284] The synthesis method of Example 22 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.75(d,J=4.8Hz,1H),8.31-8.71(br,2H),7.79(d,J=2.0Hz,1H),7. 71(d,J=8.0Hz,1H),7.54(s,1H),7.40-7.43(m,2H),7.06(d,J=2.4Hz,1H),6.67(d,J=3.2Hz, 1H),5.84(d,J=8.0Hz,1H),5.27(d,J=15.2Hz,1H),5.15(d,J=15.2Hz,1H),4.61-4.68(m,2H), 3.96-4.05(m,1H),3.39-3.50(m,1H),2.97-3.05(m,2H),2.58-2.70(m,2H),0.85-1.34(m,4H).

[0285] Example 23: 3-((7-(1-(2-(azetidin-3-yl)ethyl)-5-chloro-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

[0286]

[0287] The synthesis method of Example 23 is the same as that of Example 9.1 H NMR(400MHz, DMSO-d6),8.77(d,J=4.4Hz,1H),8.42-8.67(br,2H),7.78(d,J=2. 0Hz, 1H), 7.56 (s, 1H), 7.54 (d, J = 4.8Hz, 1H), 7.44 (d, J = 3.2Hz, 1H), 7.07 (d, J = 1. 6Hz,1H),6.60(d,J=2.4Hz,1H),4.74(s,2H),3.46-3.61(m,3H),2.98-3.19(m,3 H),2.54(s,2H),1.92-2.04(m,1H),1.33-1.39(m,2H),1.12(s,3H),0.96(s,3H).

[0288] Example 24: 3-((7-(1-((3-azabicyclo[3.1.0]hexan-6-yl)methyl)-5-chloro-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0289]

[0290] The synthesis method of Example 24 is the same as that of Example 9. 1 H NMR(400MHz, DMSO-d6),8.73(d,J=4.4Hz,1H),7.76(d,J=2.0Hz,1H),7.55(s, 1H),7.52(d,J=4.8Hz,1H),7.47(d,J=3.2Hz,1H),7.04(d,J=2.4Hz,1H),6.58 (d,J=3.6Hz,1H),4.73(s,2H),3.23(d,J=6.8Hz,2H),2.52(s,2H),2.38-2.48 (m,4H),1.12(s,3H),0.93-0.99(s,4H),0.88-0.92(m,1H),0.46-0.52(m,1H).

[0291] Example 25: 4-((5-chloro-7-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0292]

[0293] The synthesis method of Example 25 is the same as that of Example 9. 1H NMR (400 MHz, DMSO-d6), 8.81 (d,J=4.4Hz,1H),7.81(d,J=2.0Hz,1H),7.56(s,1H),7.50-7.53(m,2H),7.09(d ,J=2.0Hz,1H),6.70(d,J=3.2Hz,1H),4.68-4.769m,2H),3.89(d,J=15.2Hz,1H) ,3.40(d,J=15.2Hz,1H),2.60-2.66(m,2H),2.52(s,2H),2.22-2.32(m,2H),2.0 1-2.18(br,1H),1.24-1.31(m,1H),1.12(s,3H),0.96(s,3H),0.69-0.84(m,3H).

[0294] Example 26: 3-((7-(5-chloro-3-fluoro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

[0295]

[0296] To a solution of compound 35 (1.2 g) and glacial acetic acid (1 mL) in acetonitrile (100 mL) at room temperature was added a selective fluorine reagent (3.5 g). The reaction mixture was heated to 80°C for 24 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 to 10:1) to obtain compound 73 (705 mg).

[0297] Compound 74 was synthesized using the synthesis method of Example 7 using compound 73 as raw material. 1 H NMR(400MHz, CDCl3),9.10-9.60(br,2H),8.78(d,J=3.6Hz,1H),7.76(d,J=2.0Hz,1H) ,7.59(s,1H),7.33(d,J=2.0Hz,1H),7.25-7.26(m,1H),4.74-4.84(m,2H),3.84-3.94 (m,1H),3.57(t,J=16.0Hz,1H),3.01-3.22(m,2H),2.67-2.91(m,2H),2.35-2.38(m,2 H),1.71-1.95(m,2H),1.44-1.52(m,1H),1.21(s,3H),1.11-1.18(m,1H),1.08(s,3H).

[0298] Example 27: 3-((7-(5-chloro-1-(2-(piperidin-2-yl)ethyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

[0299]

[0300] The synthesis method of Example 27 is the same as that of Example 9. 1 H NMR(400MHz, CDCl3),8.97-9.47(br,1.5H),8.67-8.92(m,1.5H),7.61-7.71(m,2H),7.43-7.58(m,1H), 7.33(d,J=3.2Hz,0.5H),7.20(d,J=3.2Hz,0.5H),7.06(d,J=2.0Hz,0.5H),7.03(d,J=2.0Hz,0.5H),6.4 9(d,J=2.0Hz,1H),4.75-4.87(m,2H),3.51-3.78(m,2H),3.10-3.22(m,1H),2.48-2.69(m,1.5H),2.14- 2.43(m,4.5H),1.96-2.12(m,1H),1.37-1.88(m,5H),1.20-1.24(m,3H),1.13(s,1.5H),1.11(s,1.5H).

[0301] Example 28: 3-((7-(5-chloro-1-((4-fluoropiperidin-4-yl)methyl)indolin-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

[0302]

[0303] At room temperature, sodium cyanoborohydride (45 mg) was added to a solution of compound 10 (200 mg) in trifluoroacetic acid (5 mL). The reaction solution was then heated to 70 ° C and reacted for 1 h until the reaction was completed. Cooled to room temperature, the reaction solution was concentrated under reduced pressure, and a saturated sodium bicarbonate solution (20 mL) was added thereto. The aqueous phase was extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (5 mL), and DMAP (5 mg), triethylamine (0.2 mL) and Boc anhydride (150 mg) were added sequentially. The reaction solution was reacted at room temperature overnight and concentrated under reduced pressure. The resulting residue was purified by rapid silica gel column chromatography to obtain compound 75 (110 mg).

[0304] Compound 75 was used as the starting material and the synthesis method of steps 6 and 7 in the synthesis method of the compound in Example 1 was adopted to prepare compound 76. 1 H NMR(400MHz, CDCl3),9.63-9.82(br,1H),9.13-9.23(m,1H),8.10-8.33(br,1H),7.89-7.97(m,1H),7.53-7.62(m,1H),7.16(s,1H),6.96(s ,1H),4.88(s,2H),3.38-3.61(m,4H),2.98-3.15(m,4H),2.66(d,J=2 3.2Hz,2H),2.43(s,2H),1.90-1.98(m,4H),1.24(s,3H),1.14(s,3H).

[0305] Example 29: 1-((7-(5-chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-3,3-dimethylpyrrolidine-2,5-dione trifluoroacetate

[0306]

[0307] The synthesis method of Example 29 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),9.01-9.42(br,2H),8.70-8.80(m,1H),7.67(d,J=2.0Hz,1H),7.54(s,1H) ,7.35(d,J=4.4Hz,1H),7.08-7.12(m,1H),7.05(d,J=2.0Hz,1H),6.60(d,J=3.2Hz,1H),4.80-4. 92(m,2H),3.80(dd,J=20.8Hz,16.0Hz,1H),3.46(dd,J=24.8Hz,16.0Hz,1H),2.98-3.12(m,2H), 2.72-2.88(m,2H),2.54(s,2H),1.30-1.60(m,3H),1.26(s,3H),1.24(s,3H),0.92-1.12(m,1H).

[0308] Example 30: 7-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1-((4-fluoropiperidin-4-yl)methyl)-1H-indole-5-carbonitrile

[0309]

[0310] The synthesis method of Example 30 is the same as that of Example 9. 1 H NMR(400MHz,DMSO-d6),8.77(d,J=4.8Hz,1H),8.28(d,J=1.2Hz,1H),7.55(s,1H) ,7.52(d,J=3.2Hz,1H),7.43-7.47(m,2H),6.81(d,J=3.2Hz,1H),4.73(s,2H),3.8 7(dd,J=21.6Hz,15.2Hz,1H),3.43(dd,J=20.0Hz,15.6Hz,1H),2.52(s,2H),2.39- 2.47(m,2H),2.20-2.33(m,2H),1.12(s,3H),0.81-1.1(m,6H),0.62-0.71(m,1H).

[0311] Example 31: 3-((7-(7-chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-5-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0312]

[0313] The synthesis method of Example 31 is the same as that of Example 9. 1 H NMR(400MHz, CDCl3),8.67(d,J=4.8Hz,1H),7.89(d,J=1.2Hz,1H),7.57(s,1H),7.47(d,J=1.6Hz,1H),7.26-7.28(m,2H),6.65(d ,J=3.2Hz,1H),4.83(s,2H),4.81(d,J=23.2Hz,2H),2.83-2.97(m,4H),2.34(s,2H),1.54-1.74(m,4H),1.20(s,3H),1.08(s,3H).

[0314] Example 32: 3-((7-(6-chloro-3-(piperidin-4-ylenmethyl)benzo[b]thiophen-4-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0315]

[0316] The synthesis method of Example 32 is the same as that of Example 14.1 H NMR(400MHz,CD3OD),8.68-8.77(m,1H),8.13(d,J=1.2Hz,1H),7.50(s,1H),7 .38-7.41(m,2H),7.36(d,J=2.0Hz,1H),5.30(s,1H),4.77-4.88(m,2H),3.07 -3.13(m,1H),2.95-3.01(m,1H),2.59-2.65(m,1H),2.47-2.50(m,2H),2.31- 2.44(m,3H),1.93-2.01(m,1H),1.63-1.70(m,1H),1.21(s,3H),1.07(s,3H).

[0317] Example 33: 3-((7-(4-chloro-3-(piperidin-4-ylenmethyl)benzo[b]thiophen-6-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0318]

[0319] The synthesis method of Example 33 is the same as that of Example 17. 1 H NMR(400MHz,CD3OD), 8.62-8.70(m,1H),8.23(d,J=1.6Hz,1H),7.72(d,J=1.2Hz,1H),7.58(s,1H),7.52(s,1H),7.47(d,J=5.2Hz,1H),6.90(s,1H),4 .85(s,2H),3.32-3.35(m,2H),3.20-3.23(m,2H),2.71-2.74(m,2H),2.65-2.68(m,2H),2.47(s,2H),1.21(s,3H),1.05(s,3H).

[0320] Example 34: 3-((7-(5-chloro-1-((1,2,3,6-tetrahydropyridin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0321]

[0322] The synthesis method of Example 34 is the same as that of Example 9. 1H NMR(400MHz,DMSO-d6),8.74(d,J=4.4Hz,1H),8.38-8.52(br,2H),7.80(d,J=2.0Hz,1H),7 .56(s,1H),7.41-7.44(m,2H),7.08(d,J=2.4Hz,1H),6.64(d,J=2.8Hz,1H),4.70-4.80(m,2 H),4.24-4.32(m,1H),4.11(s,1H),3.84-3.90(m,1H),3.14(s,2H),2.80-2.88(m,1H),2.57 -2.66(m,1H),2.56(s,2H),1.32-1.42(m,1H),1.19-1.28(m,1H),1.14(s,3H),1.00(s,3H).

[0323] Example 35: 3-((7-(5-chloro-3-fluoro-1-(pyrrolidin-3-ylmethyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

[0324]

[0325] The synthesis method of Example 35 is the same as that of Example 18. 1 H NMR(400MHz,DMSO-d6),8.76-8.79(m,1H),8.30-8.54(br,2H),7.80-7.82(m,1H) ,7.55-7.59(m,2H),7.53(d,J=4.8Hz,1H),7.20-7.21(m,1H),4.70-4.79(m,2H),3 .42-3.55(m,1H),3.02-3.24(m,2H),2.75-2.98(m,2H),2.51-2.60(m,3H),2.23- 2.31(m,1H),1.89-2.01(m,2H),1.10-1.16(m,3H),0.98(s,1.5H),0.95(s,1.5H).

[0326] Example 36: 3-((7-(5-chloro-3-fluoro-1-(((S)-morpholin-2-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

[0327]

[0328] The synthesis method of Example 36 is the same as that of Example 18. 1 H NMR(400MHz,DMSO-d6),8.74-8.78(m,1H),7.80-8.30(br,2H),7.78-7.79(m,1H),7.55- 7.57(m,1H),7.43-7.50(m,2H),7.17-7.19(m,1H),4.70-4.79(m,2H),3.48-3.62(m,2H), 3.07-3.28(m,3H),2.85-2.92(m,1H),2.47-2.66(m,3H),2.34-2.42(m,0.5H),2.06-2.17(m,1.5H),1.11-1.15(m,3H),0.96-1.11(m,3H).

[0329] Example 37: 1-((4-cyanopiperidin-4-yl)methyl)-7-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indole-5-carbonitrile

[0330]

[0331] The synthesis method of Example 37 is the same as that of Example 9. 1 H NMR(400MHz, DMSO-d6),8.84(d,J=4.8Hz,1H),8.33(d,J=1.6Hz,1H),7.68(d,J=3.6Hz,1H),7.58(s, 1H),7.55(d,J=4.8Hz,1H),7.51(d,J=1.6Hz,1H),6.91(d,J=2.8Hz,1H),4.75(d,J=15.6Hz,1H),4.70 (d,J=15.6Hz,1H),4.13(d,J=14.8Hz,1H),3.44(d,J=14.8Hz,1H),3.04-3.15(m,2H),2.56-2.66(m, 2H),2.53(s,2H),1.63-1.70(m,1H),1.14-1.26(m,2H),1.13(s,3H),0.98-1.06(m,1H),0.96(s,3H).

[0332] Example 38: 4-((5-chloro-7-(2-((2,5-oxo-3-(2,2,2-trifluoroethyl)imidazolin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate

[0333]

[0334] The synthesis method of Example 38 is the same as that of Example 9. 1 H NMR(400MHz, CDCl3),9.34-9.85(br,2H),8.82(d,J=5.2Hz,1H),7.71(d,J=2.0Hz,1H),7.61(s,1H),7.4 8(d,J=4.8Hz,1H),7.28(d,J=3.6Hz,1H),7.09(d,J=2.0Hz,1H),6.70(d,J=3.6Hz,1H),4.94(d,J=15.6Hz ,1H),4.90(d,J=15.6Hz,1H),4.04(s,2H),3.92-3.99(m,2H),3.83(d,J=15.2Hz,1H),3.54(d,J=15.2Hz, 1H), 3.21 (t, J = 14.8Hz, 2H), 2.83-2.92 (m, 2H), 1.62-1.70 (m, 1H), 1.34-1.50 (m, 2H), 1.02-1.09 (m, 1H).

[0335] Example 39: 4-((5-chloro-7-(2-((2,5-dioxopyrrolidin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0336]

[0337] The synthesis method of Example 39 is the same as that of Example 9. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=4.4Hz,1H),7.80(s,1H),7.57(s,1H),7.46-7.55(m,2H),7.09(s,1H), 6.68-6.73(m,1H),4.84(d,J=16.0Hz,1H),4.74(d,J=16.0Hz,1H),3.95(d,J=14.8Hz,1H),3.86 (d,J=14.8Hz,1H),2.51-2.54(m,6H),2.05-2.08(m,2H),1.25-1.35(m,2H),0.74-0.85(m,2H).

[0338] Example 40: 3-((7-(5-chloro-1-(((R)-morpholin-2-yl)methyl)-1H-benzo[d]imidazol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

[0339]

[0340] The synthesis method of Example 40 is the same as that of Example 5. 1 H NMR(400MHz, CDCl3),8.94-11.06(br,2H),8.66-8.81(m,1H),8.06(s,0.33H),7.96(s,0.67H),7.91(s,1H),7 .57(s,0.67H),7.54(s,0.33H),7.35(d,J=4.8Hz,0.67H),7.38(d,J=4.8Hz,0.33H),7.22(d,J=1.6Hz,0.33H) ,7.20(d,J=1.6Hz,0.67H),4.74-4.84(m,2H),3.82-3.92(m,1H),3.42-3.74(m,3H),3.25-3.34(m,0.67H),3. 08-3.21(m,1H),2.81-2.97(m,1.33H),2.18-2.44(m,4H),1.23(s,1H),1.21(s,2H),1.14(s,1H),1.10(s,2H).

[0341] Example 41: 3-((7-(5-chloro-1-(((R)-morpholin-2-yl)methyl)-1H-indazol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0342]

[0343] The synthesis method of Example 41 is the same as that of Example 7. 1H NMR(400MHz, CDCl3),8.72-8.79(m,1H),8.05(s,1H),7.81(d,J=2.0Hz,0.5H),7.80( d,J=2.0Hz,0.5H),7.58(s,0.5H),7.56(s,0.5H),7.25-7.28(m,2H),4.73-4.82(m,2H ),3.87-3.92(m,1H),3.35-3.74(m,4H),2.93-2.99(m,1H),2.85(d,J=12.8Hz,0.5H) ,2.61-2.76(m,1.5H),2.28-2.37(m,3H),1.20(s,3H),1.10(s,1.5H),1.09(s,1.5H).

[0344] Example 42: 3-((7-(6-chloro-3-(((R)-morpholin-2-yl)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

[0345]

[0346] The synthesis method of Example 42 is the same as that of Example 15. 1 H NMR(400MHz, CDCl3),11.27(s, 0.5H),11.21(s,0.5H),9.36-10.02(br,2H),8.79(d,J=5.2Hz,0.5H),8.77(d,J=5.2Hz,0.5H),7.63(s,0.5H),7.59(s, 0.5H),7.32(d,J=4.8Hz,0.5H),7.27(d,J=4.8Hz,0.5H),7.20(d,J=2.0Hz,0.5H),7.18(d,J=2.0Hz,0.5H),6.97(d,J=2 .0Hz,0.5H),6.94(d,J=2.0Hz,0.5H),4.73-4.88(m,2H),3.41-3.63(m,3H),3.22-3.32(m,1H),2.95-3.19(m,3H),2.76 -2.90(m,0.5H),2.58-2.72(m,0.5H),2.34-2.54(m,3H),1.23(s,1.5H),1.22(s,1.5H),1.14(s,1.5H),1.10(s,1.5H).

[0347] Example 43: 3-((7-(4-chloro-3-(piperidin-4-ylmethyl)benzo[b]thiophen-6-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0348]

[0349] The synthesis method of Example 43 is the same as that of Example 17. 1 H NMR(400MHz,CD3OD),8.67(d,J=5.2Hz,1H),7.86(s,1H),7.83(s,1H),7.64(s,1H),7.54(s,1H),7.47(d,J=4.8Hz,1H),4.86(s,2H),3 .37-3.43(m,2H),2.90-3.02(m,4H),2.47(s,2H),2.21-2.31(m,1H),1.98-2.06(m,2H),1.48-1.57(m,2H),1.21(s,3H),1.05(s,3H).

[0350] Example 44: 3-((7-(6-chloro-3-(piperidin-4-ylmethyl)benzofuran-4-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0351]

[0352] The synthesis method of Example 44 is the same as that of Example 14. 1 H NMR(400MHz,CD3OD),8.75(d,J=4.8Hz,1H),7.74(d,J=2.4Hz,1H),7.70(s,1H),7.57(d,J=2.0Hz, 1H),7.43(d,J=5.2Hz,1H),7.30(s,1H),4.85(s,2H),3.04-3.17(m,2H),2.39-2.51(m,3H),2.19-2 .28(m,1H),2.09(dd,J=14.4Hz,6.0Hz,1H),1.92(dd,J=14.4Hz,7.2Hz,1H),1.28-1.32(m,1H),1.2 2(s,3H),1.10(s,3H),1.11-1.17(m,1H),0.93-0.98(m,1H),0.82-0.87(m,1H),0.62-0.74(m,1H).

[0353] Example 45: 3-((7-(5-chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)oxazoline-2,4-dione

[0354]

[0355] The synthesis method of Example 45 is the same as that of Example 21. 1 H NMR(400MHz,CD3OD),8.76(d,J=4.8Hz,1H),7.72(d,J=2.4Hz,1H),7.60(s,1H),7.47(d,J=4.8Hz,1H), 7.30-7.32(m,1H),7.12(d,J=2.0Hz,1H),6.67(d,J=2.4Hz,1H),4.93-5.01(m,2H),4.82(s,2H),4.01(dd,J=2 0.0Hz, 15.6Hz, 1H), 3.64 (dd, J = 22.0Hz, 16.0Hz, 1H), 3.08-3.14 (m, 2H), 2.82-2.91 (m, 2H), 1.12-1.53 ​​(m, 4H).

[0356] Example 46: 3-((7-(5-chloro-3-fluoro-1-(((R)-morpholin-2-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0357]

[0358] The synthesis method of Example 46 is the same as that of Example 18. 1 H NMR(400MHz, DMSO-d6),8.77(d,J=4.8Hz,0.4H),8.75(d,J=4.8Hz,0.6H),7. 77-7.78(m,1H),7.55-7.57(m,1H),7.42-7.49(m,2H),7.17-7.18(m,1H),4.7 4(s,2H),3.46-3.59(m,2H),3.02-3.22(m,3H),2.74-2.81(m,1H),2.39-2.58 (m,3H),1.92-2.04(m,2H),1.11-1.15(m,3H),0.99(s,1.8H),0.97(s,1.2H).

[0359] Example 47: 4-((5-chloro-7-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)-3-fluoro-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0360]

[0361] The synthesis method of Example 47 is the same as that of Example 18. 1 H NMR(400MHz,DMSO-d6),8.82(d,J=4.4Hz,1H),7.81(d,J=2.0Hz,1H),7.55-7.5 8(m,2H),7.53(d,J=4.4Hz,1H),7.20(d,J=2.0Hz,1H),4.69-4.77(m,2H),3.78 (d,J=15.2Hz,1H),3.33(d,J=15.2Hz,1H),2.60-2.68(m,2H),2.53(s,2H),2.2 3-2.32(m,2H),1.27-1.34(m,1H),1.13(s,3H),0.96(s,3H),0.70-0.86(m,3H).

[0362] Example 48: 3-((7-(5-chloro-1-(((S)-morpholin-2-yl)methyl)-1H-indazol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0363]

[0364] The synthesis method of Example 48 is the same as that of Example 7. 1 H NMR(400MHz, CDCl3),8.76(d,J=4.8Hz,1H),8.05(s,1H),7.81(d,J=1.6Hz,0.5H), 7.80(d,J=1.6Hz,0.5H),7.58(s,0.5H),7.56(s,0.5H),7.26-7.28(m,2H),4.73-4. 83(m,2H),3.78-3.96(m,1.5H),3.60-3.74(m,2.5H),3.34-3.58(m,1.5H),2.59-2 .98(m,2.5H),2.28-2.36(m,3H),1.22-1.25(m,3H),1.10(s,1.5H),1.09(s,1.5H).

[0365] Example 49: 3-((7-(5-chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-1-methylimidazoline-2,4-dione trifluoroacetate

[0366]

[0367] The synthesis method of Example 49 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),9.73-9.98(br,1H),8.89-9.09(br,1H),8.82-8.89(m,1H),7.71(d ,J=2.0Hz,1H),7.67(s,1H),7.40-7.44(m,1H),7.13-7.17(m,1H),7.08(d,J=2.0Hz,1H), 6.63(d,J=3.2Hz,1H),4.88-4.97(m,2H),3.91(s,2H),3.72-3.82(m,1H),3.56(dd,J=23 .6Hz,16.0Hz,1H),3.04-3.14(m,2H),2.97(s,3H),2.76-2.93(m,2H),1.05-1.56(m,4H).

[0368] Example 50: 3-((7-(5-chloro-1-(((S)-morpholin-2-yl)methyl)-1H-benzo[d]imidazol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

[0369]

[0370] The synthesis method of Example 50 is the same as that of Example 5. 1H NMR(400MHz,DMSO-d6),9.32-9.52(br,1H),8.98-9.18(br,1H),8.79-8.81(m,1H),8.41(s,0 .4H),8.31(s,0.6H),7.93(s,1H),7.51-7.60(m,2H),7.33(s,1H),4.71-4.80(m,2H),3.97-4 .03(m,0.6H),3.75-3.82(m,1H),3.26-3.60(m,4H),2.92-3.02(m,1.4H),2.63-2.71(m,1H), 2.55(s,1.2H),2.4(s,0.8H),2.19-2.32(m,1H),1.13(s,3H),1.00(s,1.8H),0.98(s,1.2H).

[0371] Example 51: 2-((7-(5-chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)cyclopentane-1,3-dione

[0372]

[0373] The synthesis method of Example 51 is the same as that of Example 21. 1 H NMR(400MHz, CD3OD),8.58(d,J=4.4Hz,1H),7.68-7.70(m,1H),7.35(s,1H),7.31(s,1H),7.20(d,J=4.8Hz,1H),7.08(s,1H),6.64 (d,J=2.8Hz,1H),3.93(t,J=16.0Hz,1H),3.29-3.80(m,3H),2.79-3.11(m,4H),2.29(s,4H),1.48-1.57(m,1H),0.92-1.33(m,4H).

[0374] Example 52: 3-((7-(1-(azetidin-3-ylmethyl)-5-chloro-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

[0375]

[0376] The synthesis method of Example 52 is the same as that of Example 7. 1H NMR(400MHz,DMSO-d6),8.75(d,J=5.2Hz,1H),8.21-8.53(br,2H),7.80(d,J=2.0Hz ,1H),7.56(s,1H),7.50(d,J=4.8Hz,1H),7.48(d,J=3.2Hz,1H),7.08(d,J=2.0Hz,1H ),6.63(d,J=3.6Hz,1H),4.78(d,J=15.6Hz,1H),4.72(d,J=15.6Hz,1H),3.82(dd,J= 14.8Hz,8.0Hz,1H),3.31-3.50(m,5H),2.53-2.61(m,3H),1.13(s,3H),0.98(s,3H).

[0377] Example 53: 3-((5-chloro-7-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)azetidinyl-3-carbonitrile

[0378]

[0379] The synthesis method of Example 53 is the same as that of Example 7. 1 H NMR(400MHz, DMSO-d6),8.77(d,J=4.4Hz,1H),7.81(d,J=2.0Hz,1H),7.55(s,1H),7.51(d, J=3.6Hz,1H),7.47(d,J=4.8Hz,1H),7.09(d,J=2.0Hz,1H),6.70(d,J=3.2Hz,1H),4.73(s, 2H),4.16(d,J=15.6Hz,1H),3.67(d,J=15.6Hz,1H),3.25(d,J=8.0Hz,1H),3.15(d,J=8.0H z, 1H), 3.12 (d, J = 8.0Hz, 1H), 2.99 (d, J = 8.0Hz, 1H), 2.53 (s, 2H), 1.12 (s, 3H), 0.95 (s, 3H).

[0380] Example 54: 3-((7-(5-chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-1-(2,2,2-trifluoroethyl)imidazoline-2,4-dione trifluoroacetate

[0381]

[0382] The synthesis method of Example 54 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),9.43-9.78(br,1H),8.98-9.33(br,1H),8.68-8.86(m,1H),7.69(d,J=1.6H z,1H),7.57-7.62(m,1H),7.33(s,1H),7.11(s,1H),7.07(d,J=2.0Hz,1H),6.62(d,J=3.2Hz,1H), 4.89-4.97(m,2H),4.05(s,2H),3.93-4.01(m,2H),3.80(dd,J=21.6Hz,16.0Hz,1H),3.53(dd,J= 24.0Hz,16.0Hz,1H),2.98-3.10(m,2H),2.75-2.90(m,2H),1.22-1.58(m,3H),0.99-1.08(m,1H).

[0383] Example 55: 4-((5-chloro-7-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-benzo[d]imidazol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate

[0384]

[0385] The synthesis method of Example 55 is the same as that of Example 5. 1 H NMR(400MHz,DMSO-d6),8.82(d,J=5.2Hz,1H),8.38-8.56(m,2H),8.14-8.33(br,1H ),7.98(d,J=2.0Hz,1H),7.58(s,1H),7.54(d,J=4.8Hz,1H),7.36(d,J=2.0Hz,1H),4 .70-4.79(m,2H),4.24(d,J=15.2Hz,1H),3.70(d,J=15.2Hz,1H),3.07-3.16(m,2H) ,2.60-2.72(m,2H),2.54(s,2H),1.64-1.71(m,1H),1.10-1.26(m,6H),0.99(s,3H).

[0386] Example 56: 3-((7-(5-chloro-1-((3-fluoroazetidin-3-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0387]

[0388] The synthesis method of Example 56 is the same as that of Example 9. 1 H NMR(400MHz, DMSO-d6),8.72(d,J=4.8Hz,1H),7.78(d,J=2.0Hz,1H),7.53(s, 1H),7.49(d,J=3.2Hz,1H),7.41(d,J=4.8Hz,1H),7.07(d,J=2.4Hz,1H),6.65 (d,J=3.2Hz,1H),4.73(s,2H),4.09(dd,J=22.0Hz,15.6Hz,1H),3.77(dd,J=2 1.2Hz,15.6Hz,1H),3.05-3.23(m,4H),2.53(s,2H),1.12(s,3H),0.95(s,3H).

[0389] Example 57: 3-((7-(6-chloro-3-((4-cyclopropylpiperazin-1-yl)methyl)benzofuran-4-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0390]

[0391] The synthesis method of Example 57 is the same as that of Example 14. 1 H NMR(400MHz, CD3OD),8.68-8.76(m,1H),7.82(s,1H),7.74(d,J=1.6Hz,1H),7.56(s,1H),7.37(d,J=5.2Hz,1H),7.35(d,J=1.6Hz,1H),4.85( s,2H),3.28-3.35(m,1H),2.91-3.01(m,1H),2.49(s,2H),1.65-2.08( m,8H),1.51-1.63(m,1H),1.23(s,3H),1.14(s,3H),0.50-0.72(m,4H).

[0392] Example 58: 3-((7-(6-chloro-3-((4-isopropylpiperazin-1-yl)methyl)benzofuran-4-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0393]

[0394] The synthesis method of Example 58 is the same as that of Example 14. 1 H NMR(400MHz,CD3OD),8.73(d, J=5.2Hz,1H),7.85(s,1H),7.76(d,J=2.0Hz,1H),7.56(s,1H),7.39(d,J=4.8Hz,1H),7.37(d,J=1.6Hz,1H),4.84(s,2H),3.29 (s,2H),2.88-3.19(m,4H),2.51(s,2H),2.14-2.30(m,1H),1.78-2.10(m,4H),1.24(s,3H),1.16(d,J=6.8Hz,6H),1.13(s,3H).

[0395] Example 59: 3-((7-(6-chloro-3-(((R)-morpholin-2-yl)methyl)-2-thioxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

[0396]

[0397] The synthesis method of Example 59 is the same as that of Example 15. 1 H NMR(400MHz, CDCl3),12.40-12.59(br,1H),9.08-9.99(br,2H),8.76-8.85(m,1H),7.63(s ,0.5H),7.61(s,0.5H),7.38-7.46(m,1H),7.34(s,0.5H),7.28(d,J=4.8Hz,0.5H),7.10(s ,0.5H),7.03(s,0.5H),4.75-4.91(m,2H),4.19-4.34(m,1H),3.22-3.82(m,4H),2.51-3.1 8(m,4H),2.35-2.44(m,2H),1.23(s,1.5H),1.21(s,1.5H),1.17(s,1.5H),1.09(s,1.5H).

[0398] Example 60: 3-((7-(6-chloro-3-(((S)-morpholin-2-yl)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

[0399]

[0400] The synthesis method of Example 60 is the same as that of Example 15. 1 H NMR(400MHz, CDCl3),11.27(s,0.5H),11.21(s,0.5H),9.36-10.02(br,2H),8.79(d,J=5.2Hz,0.5H),8.77(d,J=5.2Hz,0.5H), 7.63(s,0.5H),7.59(s,0.5H),7.32(d,J=4.8Hz,0.5H),7.27(d,J=4.8Hz,0.5H),7.20(d,J=2.0Hz,0.5H),7.18(d,J=2.0Hz,0.5 H),6.97(d,J=2.0Hz,0.5H),6.94(d,J=2.0Hz,0.5H),4.73-4.88(m,2H),3.41-3.63(m,3H),3.22-3.32(m,1H),2.95-3.19(m,3 H),2.76-2.90(m,0.5H),2.58-2.72(m,0.5H),2.34-2.54(m,3H),1.23(s,1.5H),1.22(s,1.5H),1.14(s,1.5H),1.10(s,1.5H).

[0401] Example 61: 3-((7-(6-chloro-3-(((S)-morpholin-2-yl)methyl)-2-thioxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

[0402]

[0403] The synthesis method of Example 61 is the same as that of Example 15. 1H NMR(400MHz, CDCl3),12.40-12.59(br,1H),9.08-9.99(br,2H),8.76-8.85(m,1H),7.63(s ,0.5H),7.61(s,0.5H),7.38-7.46(m,1H),7.34(s,0.5H),7.28(d,J=4.8Hz,0.5H),7.10(s ,0.5H),7.03(s,0.5H),4.75-4.91(m,2H),4.19-4.34(m,1H),3.22-3.82(m,4H),2.51-3.1 8(m,4H),2.35-2.44(m,2H),1.23(s,1.5H),1.21(s,1.5H),1.17(s,1.5H),1.09(s,1.5H).

[0404] Example 62: 3-((7-(5-chloro-1-(((3,4-trans)-3-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0405]

[0406] The synthesis method of Example 62 is the same as that of Example 9. 1H NMR(400MHz, DMSO-d6),8.70(d,J=4.8Hz,0.5H),8.67(d,J=4.8Hz,0.5H),7.75-7.77(m,1H),7.53(s,0.5H),7.52(s,0.5H),7.49(d,J=4.8 Hz,0.5H),7.40-7.42(m,1.5H),7.06(d,J=2.0Hz,0.5H),7.02(d,J=2.0Hz,0.5H),6.53-6.55(m,1H),4.69-4.79(m,2H),3.94(dd,J=14.0H z,4.8Hz,0.5H),3.56-3.82(m,1.5H),3.42-3.52(m,1H),2.68-2.84(m,1H),2.46-2.56(m,2.5H),2.38-2.45(m,1H),1.86-2.00(m,1H),1. 63-1.74(m,1H),1.44-1.52(m,0.5H),1.13(s,1.5H),1.12(s,1.5H), 1.03(s,1.5H),0.98(s,1.5H),0.60-0.73(m,1H),0.28-0.38(m,1H).

[0407] Example 63: 3-((7-(5-chloro-1-(((3,4-cis)-3-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0408]

[0409] The synthesis method of Example 63 is the same as that of Example 9. 1H NMR(400MHz, DMSO-d6),8.75(d,J=4.4Hz,0.5H),8.73(d,J=4.4Hz,0.5H),7.79(s,1H),7.57(d,J=4.0Hz,1H), 7.54(d,J=4.4Hz,0.5H),7.49(d,J=4.4Hz,0.5H),7.36-7.39(m,1H),7.10(d,J=2.0Hz,0.5H),7.08(d,J=2.0Hz ,0.5H),6.57(d,J=3.6Hz,1H),4.70-4.80(m,2H),3.60-3.65(m,0.5H),3.48-3.54(m,0.5H),3.38-3.45(m,0.5 H),3.15-3.21(m,0.5H),2.60-2.85(m,2H),2.51-2.54(m,2H),1.80-2.09(m,2.5H),1.50-1.59(m,0.5H),1.13 (s,3H),1.02(s,1.5H),0.98(s,1.5H),0.78-0.94(m,2H),0.09-0.16(m,0.5H),-0.29-0.16(m,0.5H).

[0410] Example 64: 4-((5-chloro-7-(2-((3,3,4,4-tetramethyl-2,5-dioxopyrrolidin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0411]

[0412] The synthesis method of Example 64 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),7.81(d,J=1.6Hz,1H),7.50-7.54(m,3H),7.13(d,J=2.4Hz,1H),6.71(d,J=3.2Hz,1H),4.78-4.86( m,2H),3.95(d,J=15.2Hz,1H),3.45(d,J=15.2Hz,1H),2.66-2.76(m,2H) ,2.28-2.38(m,2H),1.17-1.33(m,3H),1.02(s,12H),0.85-0.94(m,1H).

[0413] Example 65: 4-((5-chloro-7-(2-((4,4-dimethyl-2,6-dioxopiperidin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0414]

[0415] The synthesis method of Example 65 is the same as that of Example 21. 1 H NMR(400MHz,DMSO-d6),8.80(d,J=4.8Hz,1H),7.81(s,1H),7.50-7.52(m,3H), 7.10(s,1H),6.71(d,J=3.6Hz,1H),5.00(d,J=15.2Hz,1H),5.02(d,J=15.2Hz,1 H),3.98(d,J=15.2Hz,1H),3.42(d,J=15.2Hz,1H),2.76-2.85(m,2H),2.52(s,4 H),2.35-2.45(m,2H),1.40-1.46(m,1H),1.21-1.28(m,1H),0.80-1.00(m,8H).

[0416] Example 66: 4-((5-chloro-7-(2-((5,7-dioxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate

[0417]

[0418] The synthesis method of Example 66 is the same as that of Example 21. 1H NMR(400MHz, DMSO-d6),8.94(d,J=4.0Hz,1H),8.81(d,J=4.4Hz,1H),8.50-8.63(br ,1H),8.24-8.39(m,2H),7.81(d,J=1.6Hz,1H),7.76(dd,J=7.6Hz,5.2Hz,1H),7.71( s,1H),7.55(d,J=3.2Hz,1H),7.51(d,J=4.8Hz,1H),7.10(d,J=1.6Hz,1H),6.73(d,J =3.2Hz,1H),5.10(d,J=16.8Hz,1H),5.02(d,J=16.4Hz,1H),4.13(d,J=15.2Hz,1H), 3.50(d,J=15.2Hz,1H),3.09-3.20(m,2H),2.58-2.72(m,2H),1.66-1.75(m,1H),1.03-1.30(m,3H).

[0419] Example 67: 1-((7-(5-chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]piperidin-2-yl)methyl)-4,4-dimethylpiperidine-2,6-dione trifluoroacetate

[0420]

[0421] The synthesis method of Example 67 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),9.44-9.60(br,1H),9.12-9.30(br,1H),8.68-8.86(m,1H),7.68(d,J=1.6Hz,1H), 7.59(s,1H),7.30-7.38(m,1H),7.08-7.11(m,1H),7.05(d,J=2.0Hz,1H),6.61(d,J=3.2Hz,1H),5.21(d, J=15.2Hz,1H),5.13(d,J=15.2Hz,1H),3.78(dd,J=20.8Hz,16.0Hz,1H),3.46(dd,J=24.4Hz,16.0Hz,1H ),2.99-3.11(m,2H),2.74-2.89(m,2H),2.50(s,4H),1.34-1.60(m,3H),1.01(s,6H),0.92-1.00(m,1H).

[0422] Example 68: 6-((7-(5-chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione trifluoroacetate

[0423]

[0424] The synthesis method of Example 68 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),9.52-9.65(br,1H),9.09-9.24(br,1H),8.95(dd,J=4.8Hz,1.6Hz,1H),8.79(d,J=4.8Hz,1H),8.17(d d,J=8.0Hz,1.6Hz,1H),7.67(d,J=2.0Hz,1H),7.66(s,1H),7.62(dd,J=7.6Hz,4.8Hz,1H),7.34(d,J=4.4Hz,1H),7.10-7.1 4(m,1H),7.04(d,J=2.0Hz,1H),6.60(d,J=2.8Hz,1H),5.18(d,J=16.0Hz,1H),5.13(d,J=16.0Hz,1H),3.78(dd,J=21.6Hz, 16.0Hz, 1H), 3.52 (dd, J = 24.0Hz, 16.0Hz, 1H), 3.02-3.12 (m, 2H), 2.77-2.91 (m, 2H), 1.31-1.60 (m, 3H), 0.99-1.08 (m, 1H).

[0425] Example 69: 3-((7-(5-chloro-1-((3-fluoropyrrolidin-3-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0426]

[0427] The synthesis method of Example 69 is the same as that of Example 9. MS (ESI): [M+H] + :537.2.

[0428] Example 70: 4-((5-chloro-7-(2-((4-methyl-2,6-dioxopiperazin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0429]

[0430] The synthesis method of Example 70 is the same as that of Example 21. 1 H NMR(400MHz, CD3OD),8.78(d,J=4.4Hz,1H),7.76(d,J=2.4Hz,1H),7.56(d,J=4.8Hz,1H),7. 53(s,1H),7.47(d,J=3.6Hz,1H),7.13(d,J=2.0Hz,1H),6.74(d,J=3.6Hz,1H),5.19(d,J=15 .2Hz,1H),5.15(d,J=15.2Hz,1H),4.02(d,J=15.2Hz,1H),3.62(d,J=15.2Hz,1H),3.41(s,4 H),3.10-3.19(m,2H),2.77-2.86(m,2H),2.33(s,3H),1.69-1.76(m,1H),1.12-1.32(m,3H).

[0431] Example 71: 3-((7-(5-chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-1-cyclopropylimidazoline-2,4-dione trifluoroacetate

[0432]

[0433] The synthesis method of Example 71 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),9.48-9.84(br,1H),9.02-9.32(br,1H),8.70-8.83(m,1H),7.68(s,1H),7.5 4(s,1H),7.30(d,J=3.6Hz,1H),7.11(s,1H),7.05(s,1H),6.61(d,J=2.4Hz,1H),4.82-4.92(m,2H ),3.84(s,2H),3.76(dd,J=22.0Hz,16.0Hz,1H),3.52(dd,J=24.0Hz,16.0Hz,1H),2.97-3.12(m,2 H),2.76-2.92(m,2H),2.54-2.62(m,1H),1.30-1.55(m,3H),0.96-1.07(m,1H),0.66-0.88(m,4H).

[0434] Example 72: 2-((7-(5-chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione trifluoroacetate

[0435]

[0436] The synthesis method of Example 72 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),9.42-9.55(br,1H),9.12-9.30(m,2H),9.04-9.10(m,1H),8.82-8.90(m,1H),7 .76(d,J=4.8Hz,1H),7.68-7.74(m,2H),7.41-7.47(m,1H),7.11-7.14(m,1H),7.04(d,J=2.0Hz,1H) ,6.63(d,J=3.2Hz,1H),5.15(d,J=16.0Hz,1H),5.10(d,J=16.0Hz,1H),3.76-3.87(m,1H),3.49(dd, J=25.2Hz,15.2Hz,1H),2.95-3.17(m,2H),2.74-2.91(m,2H),1.35-1.68(m,3H),0.95-1.06(m,1H).

[0437] Example 73: 1-((7-(5-chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-3,3-dimethylpiperidine-2,6-dione trifluoroacetate

[0438]

[0439] The synthesis method of Example 73 is the same as that of Example 21. 1H NMR(400MHz, CDCl3),8.86-9.27(br,2H),8.70-8.84(m,1H),7.69(s,1H),7.49-7.62(m, 1H),7.31-7.44(m,1H),7.11(s,1H),7.05(s,1H),6.57-6.64(m,1H),5.19(d,J=14.8Hz, 1H),5.09(d,J=14.8Hz,1H),3.71-3.86(m,1H),3.44(dd,J=24.4Hz,15.2Hz,1H),3.02-3 .22(m,2H),2.63-2.92(m,4H),1.73-1.83(m,2H),1.11-1.60(m,9H),0.90-1.02(m,1H).

[0440] Example 74: 4-((5-chloro-7-(2-((3-cyclopropyl-2,5-dioxoimidazolin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0441]

[0442] The synthesis method of Example 74 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=4.4Hz,1H),7.81(d,J=2.4Hz,1H),7.57(s,1H),7.51-7.53(m, 2H),7.10(d,J=2.0Hz,1H),6.71(d,J=3.6Hz,1H),4.82(d,J=16.0Hz,1H),4.73(d,J=16.0Hz,1H), 3.99(d,J=15.2Hz,1H),3.94(s,2H),3.47(d,J=15.2Hz,1H),2.73-2.81(m,2H),2.54-2.60(m,1H ),2.33-2.43(m,2H),1.37-1.44(m,1H),1.20-1.28(m,1H),0.80-0.98(m,2H),0.60-0.66(m,4H).

[0443] Example 75: 4-((5-chloro-7-(2-((3,3-dimethyl-2,6-dioxopiperidin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0444]

[0445] The synthesis method of Example 75 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.79(d,J=4.8Hz,1H),7.81(d,J=1.6Hz,1H),7.52(d,J=3.6Hz,1H),7.49(d,J=4. 4Hz,1H),7.47(s,1H),7.11(d,J=1.6Hz,1H),6.71(d,J=3.2Hz,1H),5.07(d,J=15.2Hz,1H),4.97(d,J=15. 2Hz,1H),3.99(d,J=14.8Hz,1H),3.45(d,J=14.8Hz,1H),2.73-2.82(m,2H),2.67(t,J=6.4Hz,2H),2.33- 2.43(m,2H),1.71(t,J=6.4Hz,2H),1.34-1.42(m,1H),1.20-1.26(m,1H),1.10(s,6H),0.80-0.95(m,2H).

[0446] Example 76: 4-((5-chloro-7-(2-((3,3-dimethyl-2,5-dioxopyrrolidin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0447]

[0448] The synthesis method of Example 76 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=4.4Hz,1H),7.81(d,J=2.0Hz,1H),7.55(s,1H),7.51-7. 53(m,2H),7.12(d,J=2.0Hz,1H),6.72(d,J=3.2Hz,1H),4.84(d,J=16.0Hz,1H),4.76(d,J= 16.0Hz,1H),4.01(d,J=14.8Hz,1H),3.46(d,J=14.8Hz,1H),2.79-2.86(m,2H),2.59(s,2H ),2.36-2.46(m,2H),1.39-1.45(m,1H),1.20-1.28(m,1H),1.14(s,6H),0.85-1.04(m,2H).

[0449] Example 77: 4-((5-chloro-7-(2-((1,3-dioxohexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0450]

[0451] The synthesis method of Example 77 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),7.81(d,J=2.4Hz,1H),7.51-7.54(m,3H),7.11(d ,J=2.4Hz,1H),6.72(d,J=2.8Hz,1H),4.81(d,J=16.0Hz,1H),4.76(d,J=16.0Hz,1H),4.01(d,J =14.8Hz,1H),3.45(d,J=14.8Hz,1H),3.15-3.22(m,2H),2.88-2.96(m,2H),2.42-2.52(m,2H), 1.68-1.85(m,3H),1.54-1.63(m,1H),1.46-1.52(m,1H),1.20-1.28(m,1H),0.90-1.14(m,4H).

[0452] Example 78: 4-((5-chloro-7-(2-((3-methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate

[0453]

[0454] The synthesis method of Example 78 is the same as that of Example 21. 1H NMR(400MHz, CDCl3),9.36-9.88(br,2H),8.78-8.90(m,1H),7.71(d,J=2.0Hz,1H),7.57(s,1H),7.49-7. 52(m,1H),7.29(d,J=3.2Hz,1H),7.07(d,J=1.6Hz,1H),6.69(d,J=3.2Hz,1H),3.34(d,J=1.6Hz,1H),4.8 8(d,J=16.0Hz,1H),4.86(d,J=16.0Hz,1H),3.84(d,J=15.2Hz,1H),3.50(d,J=15.2Hz,1H),3.16-3.30(m ,2H),2.80-2.95(m,2H),2.05(d,J=2.0Hz,3H),1.66-1.72(m,1H),1.38-1.54(m,2H),0.97-1.05(m,1H).

[0455] Example 79: 1-((7-(5-chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-4-methylpiperazine-2,6-dione

[0456]

[0457] The synthesis method of Example 79 is the same as that of Example 21. 1 H NMR(400MHz, CD3OD),8.74(d,J=4.4Hz,1H),7.73(d,J=1.6Hz,1H),7.51(s,1H),7.45(d,J= 4.4Hz,1H),7.31-7.34(m,1H),7.10(d,J=2.0Hz,1H),6.68(d,J=3.2Hz,1H),5.20(d,J=15. 2Hz,1H),5.15(d,J=15.2Hz1H),4.01(dd,J=20.0Hz,16.0Hz,1H),3.62(dd,J=22.0Hz,16.0 Hz,1H),3.42(s,4H),3.08-3.14(m,2H),2.82-2.92(m,2H),2.34(s,3H),1.01-1.39(m,4H).

[0458] Example 80: 4-((5-chloro-7-(2-((2,4-dioxo-3-azabicyclo[3.2.0]heptane-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate

[0459]

[0460] The synthesis method of Example 80 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.82(d,J=4.4Hz,1H),8.48-8.58(br,1H),8.26-8.39(br,1H),7.82(d,J=2.0Hz,1H), 7.59(s,1H),7.56(d,J=3.6Hz.1H),7.52(d,J=4.8Hz,1H),7.13(d,J=2.0Hz,1H),6.74(d,J=3.6Hz,1H),4.90(d ,J=16.0Hz,1H),4.82(d,J=16.0Hz,1H),4.12(d,J=15.2Hz,1H),3.49(d,J=15.2Hz,1H),3.24-3.30(m,2H),3.0 9-3.18(m,2H),2.58-2.71(m,2H),2.44-2.54(m,2H),1.86-1.92(m,2H),1.64-1.72(m,1H),1.05-1.30(m,3H).

[0461] Example 81: 4-((5-chloro-7-(2-((3-methyl-2,5-dioxoimidazolin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate

[0462]

[0463] The synthesis method of Example 81 is the same as that of Example 21. 1 H NMR(400MHz,DMSO-d6),8.81(d,J=4.4Hz,1H),8.28-8.58(br,2H),7.82(s,1H),7.59(s,1H), 7.56(d,J=3.2Hz,1H),7.52(d,J=4.8Hz,1H),7.11(s,1H),6.74(d,J=3.2Hz,1H),4.84(d,J=1 6.0Hz,1H),4.75(d,J=16.0Hz,1H),4.12(d,J=14.8Hz,1H),3.96(s,2H),3.48(d,J=14.8Hz,1 H),3.08-3.18(m,2H),2.79(s,3H),2.60-2.70(m,2H),1.67-1.73(m,1H),1.01-1.30(m,3H).

[0464] Example 82: 4-((5-chloro-7-(2-((5,7-dioxo-6-azaspiro[2.5]octan-6-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate

[0465]

[0466] The synthesis method of Example 82 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),9.18-9.76(br,2H),8.83(s,1H),7.72(d,J=2.0Hz,1H),7.50-7.65(m,2H) ,7.30(d,J=2.8Hz,1H),7.08(d,J=1.6Hz,1H),6.69(d,J=3.2Hz,1H),5.24(d,J=14.8Hz,1H),5. 13(d,J=14.8Hz,1H),3.86(d,J=14.8Hz,1H),3.48(d,J=14.8Hz,1H),3.17-3.34(m,2H),2.79-2 .95(m,2H),2.51(s,4H),1.64-1.74(m,1H),1.36-1.56(m,2H),0.98-1.07(m,1H),0.49(s,4H).

[0467] Example 83: 6-((7-(5-chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6-azaspiro[2.5]octane-5,7-dione trifluoroacetate

[0468]

[0469] The synthesis method of Example 83 is the same as that of Example 21. 1H NMR(400MHz, CDCl3),9.24-9.46(br,1H),8.95-9.20(br,1H),8.74-8.86(m,1H),7.70(d,J=2.0Hz,1H ),7.60-7.66(m,1H),7.41-7.48(m,1H),7.09-7.15(m,1H),7.06(d,J=2.0Hz,1H),6.62(d,J=3.2Hz,1H ),5.25(d,J=15.2Hz,1H),5.16(d,J=15.2Hz,1H),3.74-3.88(m,1H),3.47(dd,J=24.4Hz,15.6Hz,1H), 3.01-3.17(m,2H),2.74-2.90(m,2H),2.53(s,4H),1.34-1.64(m,3H),0.92-1.03(m,1H),0.50(s,4H).

[0470] Example 84: 4-((5-chloro-7-(2-((3,5-dioxomorpholino)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0471]

[0472] The synthesis method of Example 84 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=4.4Hz,1H),7.81(d,J=2.0Hz,1H),7.57(s,1H),7.54(d ,J=3.2Hz,1H),7.52(d,J=4.8Hz,1H),7.10(d,J=2.0Hz,1H),6.73(d,J=3.2Hz,1H),5.12( d,J=15.2Hz,1H),5.02(d,J=15.2Hz,1H),4.40(s,4H),4.06(d,J=14.8Hz,1H),3.48(d,J= 14.8Hz,1H),2.88-2.99(m,2H),2.46-2.55(m,2H),1.51-1.58(m,1H),0.88-1.16(m,3H).

[0473] Example 85: 3-((7-(5-chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

[0474]

[0475] The synthesis method of Example 85 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),9.62-9.73(br,1H),9.17-9.36(br,1H),8.84-8.90(m,1H),7.70(d,J=2.0Hz,1H) ,7.55(s,1H),7.42(d,J=3.6Hz,1H),7.12-7.14(m,1H),7.07(d,J=1.6Hz,1H),6.62(d,J=3.2Hz,1H),4. 79(d,J=15.2Hz,1H),4.74(d,J=15.2Hz,1H),3.80(dd,J=20.8Hz,15.6Hz,1H),3.50(dd,J=25.2Hz,15.6 Hz,1H),3.07-3.17(m,2H),2.78-2.90(m,2H),2.49-2.52(m,2H),1.18-1.69(m,5H),0.96-1.03(m,1H).

[0476] Example 86: 4-((5-chloro-7-(2-((2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0477]

[0478] The synthesis method of Example 86 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),8.87(d,J=4.4Hz,1H),7.70(s,1H),7.50(s,1H),7.47(d,J=4.8Hz,1H),7.3 1(d,J=2.8Hz,1H),7.08(d,J=1.6Hz,1H),6.68(d,J=3.2Hz,1H),4.74(d,J=16.0Hz,1H),4.71(d,J =16.0Hz,1H),3.80(d,J=15.2Hz,1H),3.50(d,J=15.2Hz,1H),3.08-3.20(m,2H),2.75-2.88(m,2H ),2.47-2.50(m,2H),1.58-1.64(m,1H),1.50-1.56(m,1H),1.17-1.39(m,3H),0.91-0.99(m,1H).

[0479] Example 87: 4-((5-chloro-7-(2-((1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0480]

[0481] The synthesis method of Example 87 is the same as that of Example 21. 1 H NMR(400MHz,CD3OD),8.79(d,J=5.2Hz,1H),7.75(d,J=2.0Hz,1H),7.58(d,J=4.8Hz, 1H),7.50(d,J=1.2Hz,1H),7.48(d,J=3.6Hz,1H),7.13(d,J=2.0Hz,1H),6.74(d,J=3. 6Hz,1H),4.86-4.95(m,2H),4.05(d,J=15.2Hz,1H),3.63(d,J=15.2Hz,1H),3.19-3.2 8(m,2H),2.83-2.92(m,2H),2.24-2.32(m,4H),1.69-1.80(m,5H),1.20-1.40(m,3H).

[0482] Example 88: 4-((7-(2-((4-amino-1,3-dioxoisoindol-2-yl)methyl)thieno[3,2-b]pyridin-7-yl)-5-chloro-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0483]

[0484] The synthesis method of Example 88 is the same as that of Example 21. 1 H NMR(400MHz,CD3OD),8.78(d, J=4.8Hz,1H),7.71-7.73(m,1H),7.53-7.56(m,2H),7.44(d,J=3.2Hz,1H),7.39(t ,J=7.6Hz,1H),7.11(d,J=2.0Hz,1H),6.99(d,J=7.2Hz,1H),6.94(d,J=8.8Hz,1H), 6.70(d,J=3.6Hz,1H),4.99-5.06(m,2H),3.97(d,J=15.2Hz,1H),3.60(d,J=15.2H z,1H),3.03-3.13(m,2H),2.71-2.80(m,2H),1.62-1.69(m,1H),1.08-1.32(m,3H).

[0485] Example 89: 4-((5-chloro-7-(2-((1,3-dioxo-2-azaspiro[4.4]nonan-2-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0486]

[0487] The synthesis method of Example 89 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=4.4Hz,1H),7.82(d,J=2.0Hz,1H),7.52-7.54(m,3H), 7.12(d,J=2.4Hz,1H),6.72(d,J=3.6Hz,1H),4.86(d,J=16.0Hz,1H),4.78(d,J=16.0Hz,1 H),4.04(d,J=14.8Hz,1H),3.46(d,J=14.8Hz,1H),2.87-2.94(m,2H),2.65(s,2H),2.43- 2.53(m,2H),1.76-1.86(m,2H),1.56-1.74(m,6H),1.46-1.53(m,1H),0.89-1.14(m,3H).

[0488] Example 90: 2-((7-(5-chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-2-azaspiro[4.4]nonane-1,3-dione trifluoroacetate

[0489]

[0490] The synthesis method of Example 90 is the same as that of Example 21. 1H NMR(400MHz,CD3OD),8.77(d,J=4.8Hz,1H),7.96-8.56(br,2H),7.79(d,J=2.0Hz,1H),7.52(s,1H),7 .42-7.45(m,2H),7.09(d,J=2.0Hz,1H),6.67(d,J=3.2Hz,1H),4.86(d,J=16.0Hz,1H),4.78(d,J=16. 0Hz, 1H), 4.00 (dd, J=19.2Hz, 16.0Hz, 1H), 3.46 (dd, J=21.2Hz, 15.6Hz, 1H), 2.89-2.96 (m, 2H), 2.66 ( s,2H),2.53-2.62(m,2H),1.75-1.86(m,2H),1.54-1.74(m,6H),1.08-1.46(m,3H),0.84-0.91(m,1H).

[0491] Example 91: 4-((5-chloro-7-(2-((4,6-dioxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate

[0492]

[0493] The synthesis method of Example 91 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),9.20-9.96(br,2H),8.82(d,J=4.0Hz,1H),7.86(s,2H),7.69(d,J= 2.0Hz,1H),7.61(s,1H),7.46(d,J=4.4Hz,1H),7.28(d,J=3.2Hz,1H),7.07(d,J=2.0Hz, 1H), 6.68 (d, J = 3.2Hz, 1H), 5.04 (d, J = 16.0Hz, 1H), 4.98 (d, J = 16.0Hz, 1H), 3.82 (d, J = 15.2Hz, 1H), 3.53 (d, J = 15. 2Hz,1H),3.22(t,J=12.0Hz,2H),2.88(q,J=12.0Hz,2H),1.64-1.72(m,1H),1.34-1.50(m,2H),0.99-1.07(m,1H).

[0494] Example 92: 5-((7-(5-chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione trifluoroacetate

[0495]

[0496] The synthesis method of Example 92 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),9.59-9.76(br,1H),9.01-9.20(br,1H),8.78(d,J=3.6Hz,1H),7.88(s,2H),7.67 (d,J=2.0Hz,1H),7.61(s,1H),7.32(d,J=4.4Hz,1H),7.09-7.11(m,1H),7.05(d,J=2.0Hz,1H),6.60(d ,J=2.8Hz,1H),5.05(d,J=16.0Hz,1H),4.99(d,J=16.0Hz,1H),3.78(dd,J=21.2Hz,16.0Hz,1H),3.51( dd,J=24.8Hz,16.0Hz,1H),2.98-3.10(m,2H),2.74-2.91(m,2H),1.30-1.58(m,3H),0.98-1.07(m,1H).

[0497] Example 93: 4-((5-chloro-7-(2-((3-methoxy-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate

[0498]

[0499] The synthesis method of Example 93 is the same as that of Example 21. 1H NMR(400MHz, DMSO-d6),8.81(d,J=4.4Hz,1H),8.46-8.56(br,1H),8.23-8.37(br,1H),7.82(d,J=2.4H z,1H),7.57(s,1H),7.55(d,J=3.6Hz,1H),7.51(d,J=4.8Hz,1H),7.12(d,J=2.0Hz,1H),6.74(d,J=3.6 Hz,1H),5.87(s,1H),4.87(d,J=16.8Hz,1H),4.80(d,J=16.8Hz,1H),4.13(d,J=14.8Hz,1H),3.85(s,3 H), 3.48 (d, J = 14.8Hz, 1H), 3.10-3.19 (m, 2H), 2.59-2.73 (m, 2H), 1.67-1.74 (m, 1H), 1.04-1.30 (m, 3H).

[0500] Example 94: 1-((7-(5-chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-3-methoxypyrrolidine-2,5-dione trifluoroacetate

[0501]

[0502] The synthesis method of Example 94 is the same as that of Example 21. 1 H NMR(400MHz,DMSO-d6),7.76(d,J=5.2Hz,1H),8.44-8.56(br,1H),8.20-8.36(br,1H), 7.80(d,J=2.0Hz,1H),7.56(s,1H),7.43-7.45(m,2H),7.09(d,J=2.0Hz,1H),6.68(d,J= 2.8Hz,1H),4.87(dd,J=16.0Hz,7.6Hz,1H),4.77(dd,J=16.0Hz,7.6Hz,1H),4.34-4.38( m,1H),3.98-4.07(m,1H),3.42-3.52(m,1H),3.37(s,3H),2.93-3.06(m,3H),2.54-2.72 (m,3H),1.08-1.45(m,3H),0.86-0.96(m,1H).

[0503] Example 95: 4-((7-(5-chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)morpholine-3,5-dione trifluoroacetate

[0504]

[0505] The synthesis method of Example 95 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.77(d,J=4.4Hz,1H),8.34-8.72(br,2H),7.79(d,J=2.0Hz,1H),7. 55(s,1H),7.41-7.47(m,2H),7.07(d,J=2.0Hz,1H),6.67(d,J=3.6Hz,1H),5.12(d,J=15.6Hz ,1H),5.02(d,J=15.6Hz,1H),4.41(s,4H),4.02(dd,J=20.4Hz,15.6Hz,1H),3.46(dd,J=20.8 Hz,15.6Hz,1H),2.92-3.02(m,2H),2.55-2.66(m,2H),1.09-1.48(m,3H),0.84-0.92(m,1H).

[0506] Example 96: 1-((7-(5-chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-3-methylpyrrolidine-2,5-dione

[0507]

[0508] The synthesis method of Example 96 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),8.78(d,J=4.4Hz,1H),7.68(d,J=2.0Hz,1H),7.55(s,1H),7.30(d,J=4.8Hz,1H),7 .17-7.18(m,1H),7.05(d,J=2.0Hz,1H),6.59(d,J=3.6Hz,1H),4.93(d,J=15.2Hz,1H),4.86(d,J=15.2Hz ,1H),3.70(dd,J=22.0Hz,15.6Hz,1H),3.48(ddd,J=23.6Hz,15.6Hz,2.0Hz,1H),2.84-2.97(m,2H),2.5 8-2.65(m,4H),2.33(dd,J=17.6Hz,4.0Hz,1H),1.30-1.32(m,3H),1.16-1.23(m,1H),0.81-1.06(m,3H).

[0509] Example 97: 1-((7-(5-chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-4-cyclopropylpiperazine-2,6-dione trifluoroacetate

[0510]

[0511] The synthesis method of Example 97 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.76(d,J=4.8Hz,1H),8.33-8.61(br,2H),7.79(d,J=2.0Hz,1H),7.52(s,1H), 7.42-7.43(m,2H),7.07(d,J=1.6Hz,1H),6.68(d,J=3.2Hz,1H),5.11(d,J =15.6Hz,1H),4.98(d,J=15.6Hz,1H),3.97-4.06(m,1H),3.59(s,4H),3.3 9-3.48(m,1H),2.97-3.03(m,2H),2.57-2.68(m,2H),1.80-1.84(m,1H),1 .09-1.47(m,3H),0.82-0.91(m,1H),0.37-0.42(m,2H),0.31-0.36(m,2H).

[0512] Example 98: 1-((7-(5-chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-4-ethylpiperazine-2,6-dione trifluoroacetate

[0513]

[0514] The synthesis method of Example 98 is the same as that of Example 21. 1H NMR(400MHz,DMSO-d6),8.76(d,J=4.8Hz,1H),8.41-8.71(br,2H),7.79(d,J=2.0Hz,1H),7 .51(s,1H),7.43-7.44(m,2H),7.08(d,J=2.4Hz,1H),6.68(d,J=3.2Hz,1H),5.11(d,J=15.2 Hz,1H),4.99(d,J=15.2Hz,1H),4.02(dd,J=20.0Hz,15.6Hz,1H),3.40-3.49(m,5H),2.96-3 .03(m,2H),2.56-2.68(m,2H),2.42(q,J=7.2Hz,2H),1.13-1.48(m,3H),0.86-0.94(m,4H).

[0515] Example 99: 4-((5-chloro-7-(2-((4-cyclopropyl-2,6-dioxopiperazin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0516]

[0517] The synthesis method of Example 99 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),7.81(d,J=2.0Hz,1H),7.51-7.53(m,3H),7.09 (d,J=2.0Hz,1H),6.72(d,J=3.2Hz,1H),5.11(d,J=15.2Hz,1H),4.99(d,J=15.2Hz,1H),4.03( d,J=15.2Hz,1H),3.58(s,4H),3.45(d,J=15.2Hz,1H),2.85-2.94(m,2H),2.42-2.50(m,2H),1 .78-1.84(m,1H),1.46-1.53(m,1H),0.89-1.16(m,3H),0.37-0.41(m,2H),0.31-0.35(m,2H).

[0518] Example 100: 4-((5-chloro-7-(2-((4-ethyl-2,6-dioxopiperazin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0519]

[0520] The synthesis method of Example 100 is the same as that of Example 21. 1 H NMR(400MHz,DMSO-d6),8.81(d,J=4.4Hz,1H),7.82(d,J=2.0Hz,1H),7.51-7.5 4(m,3H),7.11(d,J=1.6Hz,1H),6.73(d,J=3.2Hz,1H),5.11(d,J=15.2Hz,1H),4 .99(d,J=15.2Hz,1H),4.05(d,J=14.8Hz,1H),3.46(d,J=14.8Hz,1H),3.43(s,4 H),2.89-2.98(m,2H),2.39-2.53(m,4H),1.50-1.57(m,1H),0.90-1.11(m,6H).

[0521] Example 101: 4-((5-chloro-7-(2-((3-methyl-2,5-dioxopyrrolidin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0522]

[0523] The synthesis method of Example 101 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),8.80(d,J=5.2Hz,1H),7.68(d,J=2.0Hz,1H),7.55(s,1H),7.37(d,J=4.8Hz,1H) ,7.35(d,J=3.2Hz,1H),7.07(d,J=2.0Hz,1H),6.64(d,J=2.8Hz,1H),4.91(d,J=15.6Hz,1H),4.84(d,J =15.6Hz,1H),3.73(d,J=14.8Hz,1H),3.53(dd,J=14.8Hz,2.4Hz,1H),2.76-2.95(m,4H),2.58-2.68( m,2H),2.29-2.34(m,1H),1.36-1.42(m,1H),1.29-1.31(m,3H),0.92-0.96(m,1H),0.74-0.84(m,2H).

[0524] Example 102: 1-((7-(5-chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)piperazine-2,6-dione

[0525]

[0526] The synthesis method of Example 102 is the same as that of Example 21. 1 H NMR(400MHz,CD3OD),8.81(s,1H),7.75(d,J=2.0Hz,1H),7.64(s,1H),7.60(d,J=5.2Hz,1H),7.35(s,1H),7.13(d,J=2.0Hz,1H),6.69(d,J=2.8Hz,1H ),5.20-5.29(m,2H),3.99-4.05(m,5H),3.66(dd,J=21.2Hz,16.0Hz,1H),3 .08-3.16(m,2H),2.82-2.93(m,2H),1.16-1.48(m,3H),0.84-0.89(m,1H).

[0527] Example 103: 1-((7-(5-chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-3-phenyl-1H-pyrrole-2,5-dione trifluoroacetate

[0528]

[0529] The synthesis method of Example 103 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),9.39-9.59(br,1H),8.89(s,1H),8.42-8.68(br,1H),7.85-7.88(m,2H),7.6 7-7.71(m,2H),7.38-7.46(m,4H),7.14(s,1H),7.04(d,J=2.0Hz,1H),6.75(s,1H),6.60(d,J=3.6H z,1H),5.00(d,J=15.6Hz,1H),4.96(d,J=15.6Hz,1H),3.82(dd,J=20.4Hz,16.0Hz,1H),3.50(dd,J =25.2Hz,15.6Hz,1H),3.16-3.27(m,2H),2.80-2.96(m,2H),1.38-1.72(m,3H),0.97-1.06(m,1H).

[0530] Example 104: 4-((5-chloro-7-(2-((2,5-dioxo-3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0531]

[0532] The synthesis method of Example 104 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),8.88(d,J=4.8Hz,1H),7.85-7.87(m,2H),7.67(d,J=2.4Hz,1H),7.61(s,1H),7.5 0(d,J=4.8Hz,1H),7.38-7.44(m,3H),7.31(d,J=3.6Hz,1H),7.06(d,J=2.0Hz,1H),6.74(s,1H),6.66(d ,J=3.2Hz,1H),4.98(d,J=12.0Hz,1H),4.94(d,J=12.0Hz,1H),3.85(d,J=15.2Hz,1H),3.50(d,J=15.2 Hz,1H),3.27-3.35(m,2H),2.81-2.92(m,2H),1.66-1.69(m,1H),1.34-1.51(m,2H),0.97-1.01(m,1H).

[0533] Example 105: 1-((7-(5-chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-4-isopropylpiperazine-2,6-dione hydrochloride

[0534]

[0535] The synthesis method of Example 105 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),9.11-9.35(br,2H),8.89(d,J=4.8Hz,1H),7.83(d,J=2.0Hz,1H),7.77(s,1H), 7.66(d,J=5.2Hz,1H),7.47(d,J=2.4Hz,1H),7.11(d,J=2.0Hz,1H),6.69(d,J=3.2Hz,1H),5.14(d,J=15.6Hz,1H),5.09(d,J=15.6Hz,1H),4 .21(s,4H),4.07(dd,J=21.2Hz,15.6Hz,1H),3.48-3.64(m,2H),2.92-3.03(m,2H),2.53-2.69(m,2H),1.19-1.60(m,9H),0.89-0.98(m,1H).

[0536] Example 106: 4-((5-chloro-7-(2-((4-isopropyl-2,6-dioxopiperazin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate

[0537]

[0538] The synthesis method of Example 106 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),9.73-10.06(br,1H),9.33-9.70(br,1H),8.91(s,1H),7.70(d ,J=1.6Hz,1H),7.61(s,1H),7.50-7.54(m,1H),7.32(d,J=3.2Hz,1H),7.09(d,J=1.6 Hz,1H),6.69(d,J=3.2Hz,1H),5.09-5.17(m,2H),3.86(d,J=15.2Hz,1H),3.44-3.57 (m,5H),3.26-3.35(m,2H),2.77-2.97(m,3H),1.26-1.65(m,4H),1.04-1.06(m,6H).

[0539] Example 107: 4-((5-chloro-7-(2-((2,6-dioxopiperidin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0540]

[0541] The synthesis method of Example 96 is the same as that of Example 21. 1H NMR(400MHz, CD3OD),8.77(d,J=4.8Hz,1H),7.75(d,J=2.0Hz,1H),7.55(d,J=4.8Hz,1H),7.47-7.49( m,2H),7.15(d,J=2.0Hz,1H),6.73(d,J=3.6Hz,1H),4.67(d,J=16.0Hz,1H),4.58(d,J=16.0Hz,1H),4. 03(d,J=15.2Hz,1H),3.66(d,J=15.2Hz,1H),3.13-3.22(m,2H),2.79-2.87(m,2H),2.30(t,J=7.2Hz,2 H), 2.25 (t, J = 7.2Hz, 2H), 1.81-1.88 (m, 2H), 1.69-1.73 (m, 1H), 1.15-1.23 (m, 2H), 0.84-0.88 (m, 1H).

[0542] Example 108: 4-((5-chloro-7-(2-((3-methoxy-2,5-dioxopyrrolidin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate

[0543]

[0544] The synthesis method of Example 96 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.82(d,J=4.4Hz,1H),8.54-8.69(br,1H),8.30-8.46(br,1H),7.83(d,J=1.6Hz,1H),7.58( s,1H),7.56(d,J=3.2Hz,1H),7.52(d,J=4.8Hz,1H),7.12(s,1H),6.74(d,J=3.6Hz,1H),4.86(dd,J=16.0Hz,5.6Hz,1 H),4.77(dd,J=15.6Hz,7.2Hz,1H),4.34-4.37(m,1H),4.13(d,J=14.8Hz,1H),3.49(dd,J=15.2Hz,4.4Hz,1H),3.38 (s,3H),3.10-3.20(m,2H),3.01(dd,J=17.6Hz,8.0Hz,1H),2.58-2.72(m,3H),1.69-1.73(m,1H),1.05-1.30(m,3H).

[0545] Example 109: 1-((7-(5-chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)pyrrolidin-2-one trifluoroacetate

[0546]

[0547] Step 1: Synthesis of compound 77

[0548] To a solution of compound 69 (100 mg) in dichloromethane (2 mL) at 0°C, triphenylphosphine (59 mg) and carbon tetrabromide (81 mg) were added sequentially. The reaction solution was warmed to room temperature and stirred overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was separated and purified by flash column chromatography (dichloromethane: methanol = 200: 1 to 50: 1). Compound 69 (14 mg) was obtained.

[0549] Step 2: Synthesis of compound 78

[0550] At 0 ° C, sodium hydride (170 mg) was added to a solution of 2-pyrrolidone (280 mg) in tetrahydrofuran (2 mL), and the reaction solution was stirred for 30 minutes at this temperature. Subsequently, a solution of compound 77 (14 mg) in tetrahydrofuran (0.2 mL) was added dropwise to the reaction solution. The reaction solution temperature was raised to room temperature and stirred overnight. After the reaction was completed, saturated aqueous ammonium chloride solution (1 mL) was added to the reaction solution to quench the reaction. The resulting solution was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was separated and purified by rapid silica gel column chromatography (dichloromethane: methanol = 200: 1 to 50: 1). Compound 78 (7.3 mg) was obtained.

[0551] Step 3: Synthesis of compound 79

[0552] To a solution of compound 78 (7.3 mg) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was separated and purified by flash silica gel column chromatography (dichloromethane:methanol = 30:1 to 10:1). Compound 79 (2.4 mg) was obtained. 1H NMR(400MHz, CD3OD),8.83(d,J=4.4Hz,1H),7.73(d,J=1.6Hz,1H),7.67(s,1H),7.52(d,J=4.8Hz,1H),7 .33-7.34(m,1H),7.13(d,J=2.0Hz,1H),6.67(d,J=3.6Hz,1H),4.82(d,J=16.0Hz,1H),4.69(d,J=15.6Hz ,1H),4.03(dd,J=20.8Hz,16.0Hz,1H),3.62(dd,J=21.6Hz,16.0Hz,1H),3.44-3.50(m,2H),3.10-3.16(m ,2H),2.81-2.91(m,2H),2.38(t,J=8.0Hz,2H),2.00-2.08(m,2H),1.13-1.56(m,3H),0.84-0.88(m,1H).

[0553] Example 110: 3-((7-(5-chloro-1-((4-fluoropyrrol-3-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0554]

[0555] The synthesis method of Example 110 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),8.77(d,J=4.8Hz,0.5H),8.73(d,J=4.8Hz,0.5H),7.68(d,J=2.0Hz,1H),7.56(s,1H),7.28(d,J=4.8Hz, 0.5H),7.24(d,J=4.8Hz,0.5H),7.11(d,J=2.4Hz,1H),7.06(d,J=2.0Hz,0.5H),7.02(d,J=2.0Hz,0.5H),6.54(d,J=3.2Hz,1H) ,4.72-4.82(m,2H),4.22-4.44(m,1H),3.74-3.83(m,1H),3.57(dd,J=14.8Hz,5.2Hz,0.5H),3.28(dd,J=14.8Hz,5.2Hz,0.5H ),2.78-3.13(m,3H),2.22-2.35(m,3.5H),1.65-2.00(m,1.5H),1.21(s,1.5H),1.20(s,1.5H),1.11(s,1.5H),1.07(s,1.5H).

[0556] Example 111: 4-((5-chloro-7-(2-((2,6-dioxopiperazin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0557]

[0558] The synthesis method of Example 111 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=5.2Hz,1H),8.18-8.59(br,2H),7.82(d,J=2.0Hz,1H),7.5 5-7.56(m,2H),7.51(d,J=4.8Hz,1H),7.10(d,J=2.0Hz,1H),6.74(d,J=3.6Hz,1H),5.10(d,J =15.6Hz,1H),4.96(d,J=15.6Hz,1H),4.16(d,J=14.8Hz,1H),3.52(s,4H),3.47(d,J=1 5.2Hz,1H),3.11-3.17(m,2H),2.63-2.67(m,2H),1.70-1.75(m,1H),1.04-1.30(m,3H).

[0559] Example 112: 4-((7-(2-((4-acetyl-2,6-dioxopiperazin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-5-chloro-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0560]

[0561] The synthesis method of Example 112 is the same as that of Example 21. 1H NMR(400MHz,DMSO-d6),8.81(d,J=4.4Hz,1H),7.82(s,1H),7.51-7.57(m,3H),7.09(d,J =1.6Hz,1H),6.74(d,J=3.2Hz,1H),5.09(d,J=15.2Hz,1H),4.96(d,J=15.2Hz,1H),4.46 (s,2H),4.36(s,2H),4.10(d,J=15.6Hz,1H),3.45(d,J=15.6Hz,1H),3.00-3.10(m,2H), 2.52-2.64(m,2H),2.01(s,3H),1.61-1.65(m,1H),1.06-1.17(m,2H),0.97-1.01(m,1H).

[0562] Example 113: 3-((5-chloro-7-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)pyrrolidine-3-carbonitrile

[0563]

[0564] The synthesis method of Example 113 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),8.78(d,J=4.0Hz,1H),7.70-7.71(m,1H),7.57(s,1H),7.73(d,J=3.2Hz ,0.5H),7.34-7.36(m,1.5H),7.07-7.08(m,1H),6.67-6.69(m,1H),4.81(d,J=15.2Hz,1H),4 .74(d,J=15.2Hz,1H),3.75-3.83(m,1H),3.63-3.66(m,1H),2.77-3.03(m,2H),2.11-2.63(m ,5H),1.83-1.92(m,0.5H),1.72-1.81(m,0.5H),1.22(s,1.5H),1.21(s,1.5H),1.10(s,3H).

[0565] Example 114: 4-((5-chloro-7-(2-((3,4-dimethyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0566]

[0567] The synthesis method of Example 114 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),8.78(d,J=4.4Hz,1H),7.67(s,1H),7.51(s,1H),7.34-7.36 (m,2H),7.06(s,1H),6.64(d,J=2.4Hz,1H),4.91(d,J=15.6Hz,1H),4.84(d,J=15. 6Hz,1H),3.72(d,J=7.2Hz,1H),3.54(d,J=7.2Hz,1H),2.73-2.81(m,2H),2.57-2 .65(m,2H),1.92(s,6H),1.35-1.39(m,1H),0.92-0.96(m,1H),0.70-0.80(m,2H).

[0568] Example 115: 4-((5-chloro-7-(2-((3,4-dimethyl-2,5-dioxopyrrol-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0569]

[0570] The synthesis method of Example 115 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),8.79(d,J=4.8Hz,1H),7.67(d,J=2.0Hz,1H),7.52(s,1H),7.38(d,J=4.4H z,1H),7.33(d,J=3.2Hz,1H),7.06(d,J=2.0Hz,1H),6.64(d,J=3.6Hz,1H),4.79-4.91(m,2H),3. 73(d,J=14.8Hz,1H),3.48-3.53(m,1H),2.90-2.96(m,1H),2.77-2.85(m,2H),2.58-2.68(m,2H) ,2.32-2.48(m,2H),1.38-1.43(m,1H),1.27-1.29(m,3H),1.15-1.18(m,3H),0.77-0.94(m,3H).

[0571] Example 116: 4-((5-chloro-7-(2-((3,5-dioxothiomorpholino)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate

[0572]

[0573] The synthesis method of Example 116 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),9.22-9.72(br,2H),8.82(d,J=4.0Hz,1H),7.71(d,J=2.0Hz,1 H),7.60(s,1H),7.51(d,J=4.8Hz,1H),7.30(d,J=3.2Hz,1H),7.08(d,J=1.6Hz,1H), 6.69(d,J=3.6Hz,1H),5.23(d,J=15.2Hz,1H),5.14(d,J=15.2Hz,1H),3.85(d,J=14. 8Hz,1H),3.50(d,J=14.8Hz,1H),3.52(s,4H),3.18-3.31(m,2H),2.80-2.94(m,2H), 1.69-1.72(m,1H),1.36-1.52(m,2H),1.01-1.04(m,1H).

[0574] Example 117: 4-((5-chloro-7-(2-((3,4-dimethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0575]

[0576] The synthesis method of Example 117 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),8.80(d,J=4.8Hz,1H),7.80(d,J=2.0Hz,1H),7.55(s,1H),7.52(d,J=3.2H z,1H),7.50(d,J=4.8Hz,1H),7.08(d,J=2.4Hz,1H),6.71(d,J=3.2Hz,1H),5.61(s,1H),5.24(d ,J=14.8Hz,1H),5.14(d,J=14.8Hz,1H),4.00(d,J=14.8Hz,1H),3.16(d,J=14.8Hz,1H),3.23(s ,3H),2.76-2.82(m,2H),2.37-2.43(m,2H),2.17(s,3H),1.42-1.46(m,1H),0.80-1.01(m,3H).

[0577] Example 118: (S)-4-((5-chloro-7-(2-((1,3-dioxotetrahydro-1H-pyrrolo[1,2-c]imidazol-2(3H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0578]

[0579] The synthesis method of Example 118 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),8.80(d,J=5.2Hz,1H),7.68(d,J=2.4Hz,1H),7.55(s,1H),7.35-7.38(m,2H),7.08 (d,J=2.0Hz,1H),6.64(d,J=2.8Hz,1H),4.80-4.93(m,2H),4.06-4.11(m,1H),3.69-3.76(m,1H),3.60- 3.68(m,1H),3.53(d,J=14.8Hz,1H),3.19-3.25(m,1H),2.76-2.83(m,2H),2.59-2.66(m,2H),2.18-2.2 6(m,1H),1.94-2.11(m,3H),1.61-1.69(m,1H),1.35-1.42(m,1H),0.92-0.98(m,1H),0.72-0.85(m,2H).

[0580] Example 119: 4-((5-chloro-7-(2-((1-oxo-3,5-dioxothiomorpholino)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate

[0581]

[0582] The synthesis method of Example 119 is the same as that of Example 21. 1H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),8.20-8.80(br,2H),7.82(d,J=2.0Hz,1H),7.52- 7.55(m,3H),7.11(d,J=2.0Hz,1H),6.73(d,J=3.2Hz,1H),5.23(d,J=15.6Hz,1H),5.14(d,J=15 .6Hz,1H),4.33-4.38(m,2H),4.22-4.26(m,2H),4.13(d,J=15.2Hz,1H),3.43(d,J=15.6Hz,1H) ,3.02-3.13(m,2H),2.50-2.61(m,2H),1.64-1.68(m,1H),1.19-1.28(m,2H),0.91-0.96(m,1H).

[0583] Example 120: (R)-4-((5-chloro-7-(2-((3-methyl-2,5-dioxopyrrolidin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0584]

[0585] The synthesis method of Example 120 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.80(d,J=4.8Hz,1H),7.80(d,J=1.6Hz,1H),7.56(s,1H),7.51-7 .52(m,2H),7.10(s,1H),6.70(d,J=3.2Hz,1H),4.83(d,J=16.0Hz,1H),4.74(d,J=16.0Hz ,1H),3.94(d,J=14.8Hz,1H),3.47(dd,J=14.8Hz,5.2Hz,1H),2.81-2.91(m,2H),2.61-2. 68(m,2H),2.22-2.35(m,3H),1.26-1.31(m,1H),1.13(d,J=6.0Hz,3H),0.73-0.85(m,3H).

[0586] Example 121: 4-((7-(2-((3-allyl-2,5-dioxopyrrolidin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-5-chloro-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0587]

[0588] The synthesis method of Example 121 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),7.80(d,J=2.0Hz,1H),7.56(s,1H),7.51-7.52(m,2H) ,7.09(s,1H),6.70(d,J=3.2Hz,1H),5.59-5.70(m,1H),5.03(d,J=17.2Hz,1H),4.93(d,J=9.6Hz,1H) ,4.84(d,J=16.0Hz,1H),4.76(d,J=16.0Hz,1H),3.92-3.96(m,1H),3.43-3.48(m,1H),2.94-3.01(m ,1H),2.75-2.82(m,1H),2.62-2.66(m,2H),2.20-2.44(m,5H),1.27-1.31(m,1H),0.74-0.86(m,3H).

[0589] Example 122: 4-((5-chloro-7-(2-((4,6-dioxo-5-azaspiro[2.4]hept-5-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0590]

[0591] The synthesis method of Example 122 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),7.81(d,J=2.0Hz,1H),7.57(s,1H),7.51-7.5 2(m,2H),7.11(d,J=2.0Hz,1H),6.71(d,J=3.2Hz,1H),4.90(d,J=15.6Hz,1H),4.81(d,J=15. 6Hz,1H),3.94(d,J=15.2Hz,1H),3.50(d,J=15.2Hz,1H),2.82(s,2H),2.63-2.67(m,2H),2. 26-2.32(m,2H),1.27-1.31(m,1H),1.14-1.17(m,2H),1.04-1.07(m,2H),0.72-0.86(m,3H).

[0592] Example 123: 4-((7-(2-((4-(sec-butyl)-2,6-dioxopiperazin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-5-chloro-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0593]

[0594] The synthesis method of Example 123 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.80(d,J=4.8Hz,1H),7.80(d,J=1.6Hz,1H),7.50-7.52(m,3H),7. 09(d,J=2.0Hz,1H),6.71(d,J=3.2Hz,1H),5.10(d,J=15.2Hz,1H),4.99(d,J=15.2Hz,1H),3 .97(d,J=14.8Hz,1H),3.38-3.48(m,5H),2.71-2.77(m,2H),2.49-2.53(m,1H),2.35(t,J=1 2.0Hz,2H),1.35-1.41(m,2H),1.17-1.22(m,1H),0.79-0.92(m,6H),0.73(t,J=7.2Hz,3H).

[0595] Example 124: Benzyl (R)-(1-((7-(5-chloro-1-((4-cyanopiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-2,5-dioxopyrrolidin-3-yl)carbamate trifluoroacetate

[0596]

[0597] The synthesis method of Example 124 is the same as that of Example 21. 1H NMR(400MHz, DMSO-d6),8.82(d,J=4.4Hz,1H),8.06-8.44(br,2H),7.98(d,J=8.0Hz,1H),7.82(t,J=1.6Hz,1H),7.60(s,1H) ,7.55-7.56(m,1H),7.52(d,J=4.8Hz,1H),7.28-7.35(m,4H),7.15-7.26(br,1H),7.12(d,J=2.0Hz,1H),6.73-6.74(m,1H), 4.99(d,J=1.2Hz,2H),4.87(dd,J=16.0Hz,6.4Hz,1H),4.77(dd,J=16.0Hz,7.2Hz,1H),4.44-4.51(m,1H),4.16(d,J=14.8Hz ,1H),3.48(d,J=14.8Hz,1H),3.08-3.16(m,2H),2.97-3.04(m,1H),2.55-2.69(m,3H),1.68-1.74(m,1H),1.01-1.29(m,3H).

[0598] Example 125: (R)-N-(1-((7-(5-chloro-1-((4-cyanopiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-2,5-dioxopyrrolidin-3-yl)acetamide trifluoroacetate

[0599]

[0600] The synthesis method of Example 125 is the same as that of Example 21. 1H NMR(400MHz, DMSO-d6),8.81(d,J=5.2Hz,1H),8.60-8.63(m,1H),8.50-8.59(br,1H),8.29-8.43(br,1H),7. 83(d,J=2.0Hz,1H),7.61(d,J=5.2Hz,1H),7.55-7.57(m,1H),7.51(d,J=4.8Hz,1H),7.13(d,J=2.0Hz,1H),6. 74(d,J=3.2Hz,1H),4.74-4.88(m,2H),4.36-4.42(m,1H),4.18(dd,J=14.8Hz,5.2Hz,1H),3.44-3.50(m,1H) ,3.10-3.20(m,2H),2.91-2.98(m,1H),2.54-2.72(m,3H),1.81(s,3H),1.69-1.78(m,1H),1.01-1.30(m,3H).

[0601] Example 126: 4-((5-chloro-7-(2-((2,6-dioxo-3-(2,2,2-trifluoroethyl)-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0602]

[0603] The synthesis method of Example 126 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),8.81(d,J=4.8Hz,1H),7.68(d,J=2.0Hz,1H),7.65(s,1H),7.37(d,J=4.8Hz,1H),7.3 5(d,J=3.2Hz,1H),7.13(d,J=8.4Hz,1H),7.06(d,J=2.0Hz,1H),6.65(d,J=3.2Hz,1H),5.84(d,J=8.4Hz,1 H),5.39(d,J=14.4Hz,1H),5.31(d,J=14.4Hz,1H),4.30-4.41(m,2H),3.73(d,J=14.8Hz,1H),3.55(d,J=1 4.8Hz,1H),2.80-2.82(m,2H),2.61-2.68(m,2H),1.38-1.42(m,1H),0.92-0.98(m,1H),0.76-0.88(m,2H).

[0604] Example 127: (S)-4-((5-chloro-7-(2-((3-methyl-2,5-dioxopyrrolidin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate

[0605]

[0606] The synthesis method of Example 127 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=4.4Hz,1H),8.01-8.34(br,2H),7.82(d,J=2.0Hz,1H),7.57(s,1H ),7.56(d,J=3.6Hz,1H),7.52(d,J=4.8Hz,1H),7.12(d,J=2.0Hz,1H),6.74(d,J=3.2Hz,1H),4.84(,d J=16.0Hz,1H),4.74(d,J=16.0Hz,1H),4.12(d,J=14.8Hz,1H),3.44-3.49(m,1H),3.04-3.14(m,2 H),2.81-2.91(m,2H),2.57-2.64(m,2H),2.30-2.38(m,1H),1.64-1.68(m,1H),1.01-1.27(m,6H).

[0607] Example 128: 4-((5-chloro-7-(2-((1,1-dioxo-3,5-dioxothiomorpholino)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate

[0608]

[0609] The synthesis method of Example 128 is the same as that of Example 21. 1H NMR(400MHz,DMSO-d6),8.82(d,J=4.8Hz,1H),8.18-8.48(br,2H),7.83(d,J=2.0Hz,1H),7 .56(d,J=3.6Hz,1H),7.52-7.54(m,2H),7.12(d,J=2.0Hz,1H),6.75(d,J=3.6Hz,1H),5.24 (d,J=16.0Hz,1H),5.12(d,.J=16.0Hz,1H),4.88(s,4H),4.15(d,J=15.2Hz,1H),3.44(d,J =15.2Hz,1H),3.10-3.18(m,2H),2.59-2.71(m,2H),1.71-1.74(m,1H),1.02-1.26(m,3H).

[0610] Example 129: 4-((5-chloro-7-(2-((3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0611]

[0612] The synthesis method of Example 129 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),8.82(d,J=4.4Hz,1H),7.68-7.69(m,2H),7.39(d,J=4.8Hz,1H),7.35(d,J=3.2Hz,1H), 7.06(d,J=2.0Hz,1H),6.65(d,J=3.6Hz,1H),6.23(s,1H),5.40(d,J=14.8Hz,1H),5.29(d,J=14.8Hz,1H),3.75(d,J=14.8Hz,1H),3 .54(d,J=14.8Hz,1H),3.47(s,3H),2.80-2.88(m,2H),2.62-2.71(m,2H),2.36-2.59(br,1H),1.42-1.47(m,1H),0.81-0.96(m,3H).

[0613] Example 130: 4-((7-(2-((4-allyl-2,6-dioxopiperazin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-5-chloro-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate

[0614]

[0615] The synthesis method of Example 130 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=4.4Hz,1H),8.44-8.57(br,1H),8.23-8.40(br,1H),7.83(d,J=2.0Hz,1H ),7.26(d,J=3.2Hz,1H),7.54(s,1H),7.51(d,J=4.8Hz,1H),7.11(d,J=2.4Hz,1H),6.74(d,J=3.2Hz,1H),5. 65-5.74(m,1H),5.08-5.13(m,3H),4.99(d,J=15.2Hz,1H),4.13(d,J=15.2Hz,1H),3.46(d,J=15.2Hz,1H), 3.45(s,4H),3.12-3.18(m,2H),3.02-3.08(m,2H),2.60-2.72(m,2H),1.69-1.74(m,1H),1.04-1.30(m,3H).

[0616] Example 131: 4-((5-chloro-7-(2-((5,7-dioxo-6-azaspiro[3.4]octan-6-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate

[0617]

[0618] The synthesis method of Example 131 is the same as that of Example 21. 1H NMR(400MHz, DMSO-d6),8.81(d,J=4.4Hz,1H),8.53-8.69(br,1H),8.29-8.48(br,1H),7.82(d,J=2.0Hz,1H),7.5 6(d,J=3.2Hz,1H),7.55(s,1H),7.52(d,J=4.8Hz,1H),7.12(d,J=2.0Hz,1H),6.74(d,J=3.6Hz,1H),4.84(d,J=16. 0Hz,1H),4.73(d,J=16.0Hz,1H),4.13(d,J=14.8Hz,1H),3.47(d,J=14.8Hz,1H),3.09-3.18(m,2H),2.89(s,2H), 2.59-2.70(m,2H),2.26-2.36(m,2H),2.01-2.05(m,2H),1.86-1.94(m,2H),1.66-1.73(m,1H),1.05-1.30(m,3H).

[0619] Example 132: 4-((5-chloro-7-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)-1-isopropylpiperidine-4-carbonitrile

[0620]

[0621] The synthesis method of Example 132 is the same as that of Example 13. 1 H NMR(400MHz, CDCl3),8.84(d,J=4.0Hz,1H),7.68(d,J=2.0Hz,1H),7.58(s,1H),7.46-7.54( m,1H),7.23-7.26(m,1H),7.05(d,J=2.0Hz,1H),6.65(d,J=3.2Hz,1H),4.79(d,J=15.2Hz,1 H),4.71(d,J=15.2Hz,1H),3.72(d,J=14.8Hz,1H),3.50(d,J=14.8Hz,1H),2.62-3.22(m,3H ),2.24-2.58(m,4H),1.56-1.74(m,2H),1.20(s,3H),0.97-1.19(m,9H),0.81-0.91(m,2H).

[0622] Example 133: N-(1-((7-(5-chloro-1-((4-cyanopiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-2,5-dioxopyrrolidin-3-yl)cyclopropylcarboxamide trifluoroacetate

[0623]

[0624] The synthesis method of Example 133 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.82-8.92(br,1H),8.81(d,J=4.4Hz,1H),8.54-8.68(br,1H),7.82(d,J=2.0Hz,1H),7.58(d ,J=2.8Hz,1H),7.56(d,J=3.2Hz,1H),7.52(d,J=4.8Hz,1H),7.10-7.11(m,1H),6.74(d,J=3.2Hz,1H),4.83-4.88(m, 1H),4.72-4.78(m,1H),4.44-4.51(m,1H),4.14-4.18(m,1H),3.44-3.47(m,1H),3.13-3.22(m,2H),2.92-2.98(m,1H ),2.50-2.72(m,3H),1.70-1.78(m,1H),1.47-1.56(m,1H),1.14-1.35(m,2H),1.01-1.08(m,1H),0.54-0.70(m,4H).

[0625] Example 134: (R)-4-((5-chloro-7-(2-((1,3-dioxotetrahydro-1H-pyrrolo[1,2-c]imidazol-2(3H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate

[0626]

[0627] The synthesis method of Example 134 is the same as that of Example 21. 1H NMR(400MHz, DMSO-d6),8.82(d,J=4.4Hz,1H),8.43-8.59(br,1H),8.21-8.39(br,1H),7.83(d,J=2.0Hz,1H), 7.56-7.58(m,2H),7.52(d,J=5.2Hz,1H),7.13(d,J=2.0Hz,1H),6.74(d,J=3.6Hz ,1H),4.71-4.88(m,2H),4.20-4.24(m,1H),4.12(d,J=15.2Hz,1H),3.50(d,J=15 .2Hz,1H),3.38-3.46(m,1H),3.07-3.18(m,3H),2.59-2.72(m,2H),2.01-2.09(m ,1H),1.87-1.98(m,2H),1.66-1.72(m,1H),1.52-1.62(m,1H),1.07-1.29(m,3H).

[0628] Example 135: 4-((5-chloro-7-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)-4-cyano-1,1-dimethylpiperidin-1-iodide

[0629]

[0630] The synthesis method of Example 135 is the same as that of Example 13. 1 H NMR(400MHz, CDCl3),8.74-9.01(m,1H),7.71(s,1H),7.61-7.68(m,1H),7.50-7 .58(m,1H),7.38-7.46(m,1H),7.12(d,J=1.2Hz,1H),6.65(s,1H),4.84(d,J=14. 8Hz,1H),4.73(d,J=14.8Hz,1H),3.52-3.84(m,4H),3.25(s,3H),2.94-3.16(m,5 H),2.37(s,2H),1.74-2.08(m,3H),1.50-1.60(m,1H),1.22(s,3H),1.12(s,3H).

[0631] Example 136: 4-((5-chloro-7-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)-1-methylpiperidine-4-carbonitrile

[0632]

[0633] The synthesis method of Example 136 is the same as that of Example 13. 1 H NMR(400MHz, CDCl3),8.80-8.88(m,1H),7.69(d,J=1.6Hz,1H),7.59(s,1H),7.41-7. 49(m,1H),7.29-7.34(m,1H),7.06(d,J=2.0Hz,1H),6.66(d,J=3.2Hz,1H),4.80(d,J =14.8Hz,1H),4.73(d,J=14.8Hz,1H),3.75(d,J=15.2Hz,1H),3.49(d,J=15.2Hz,1H) ,1.96-2.80(m,9H),1.21(s,3H),1.07(s,3H),1.48-1.68(m,2H),0.81-0.93(m,2H).

[0634] Example 137: 4-((5-chloro-7-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)-1-(cyclopropylmethyl)piperidine-4-carbonitrile

[0635]

[0636] The synthesis method of Example 137 is the same as that of Example 13. 1H NMR(400MHz, CDCl3),8.82(d,J=4.4Hz,1H),7.69(d,J=2.4Hz,1H),7.58(s,1H),7.42(d,J=4.4Hz,1H),7.32(d ,J=3.2Hz,1H),7.06(d,J=2.0Hz,1H),6.65(d,J=3.2Hz,1H),4.80(d,J=15.2Hz,1H),4.72(d,J=15.2Hz,1H),3 .71(d,J=14.8Hz,1H),3.49(d,J=14.8Hz,1H),2.71-2.88(m,2H),2.33(s,2H),1.96-2.18(m,4H),1.48-1.57( m,1H),1.21(s,3H),1.07(s,3H),0.78-1.06(m,3H),0.65-0.76(m,1H),0.40-0.50(m,2H),-0.03-0.05(m,2H).

[0637] Example 138: 4-((5-chloro-7-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)-1-(2,2,2-trifluoroethyl)piperidine-4-carbonitrile

[0638]

[0639] The synthesis method of Example 138 is the same as that of Example 13. 1 H NMR(400MHz, CDCl3),8.80(d,J=4.4Hz,1H),7.69(d,J=2.0Hz,1H),7.59(s,1H),7.36(d,J=4.8Hz,1H ),7.33(d,J=3.2Hz,1H),7.08(d,J=2.0Hz,1H),6.66(d,J=3.2Hz,1H),4.81(d,J=15.2Hz,1H),4.71(d ,J=15.2Hz,1H),3.72(d,J=15.2Hz,1H),3.56(d,J=15.2Hz,1H),2.83(q,J=9.6Hz,2H),2.62-2.71(m, 2H),2.36-2.44(m,2H),2.34(s,2H),1.31-1.37(m,1H),1.21(s,3H),1.09(s,3H),0.80-1.01(m,3H).

[0640] Example 139: 4-((5-chloro-7-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)-1-ethylpiperidine-4-carbonitrile

[0641]

[0642] The synthesis method of Example 139 is the same as that of Example 13. 1 H NMR(400MHz, CDCl3),8.84(d, J=4.8Hz,1H),7.69(d,J=2.0Hz,1H),7.58(s,1H),7.48(d,J=4.4Hz,1H),7.28(d,J=3.2Hz,1H), 7.06(d,J=2.0Hz,1H),6.66(d,J=3.6Hz,1H),4.79(d,J=15.2Hz,1H),4.72(d,J=15.2Hz,1H),3. 74(d,J=15.2Hz,1H),3.50(d,J=15.2Hz,1H),2.78-3.02(m,2H),2.41-2.61(m,2H),2.32-2.34( m,2H),2.12-2.29(m,2H),1.59-1.63(m,1H),1.20(s,3H),1.02-1.15(m,6H),0.80-0.95(m,3H).

[0643] Example 140: 4-((5-chloro-7-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)-1-cyclopropylpiperidine-4-carbonitrile

[0644]

[0645] The synthesis method of Example 140 is the same as that of Example 13. 1H NMR(400MHz, CDCl3),8.80(d,J=4.8Hz,1H),7.69(d,J=2.4Hz,1H),7.58(s,1H),7.38-7.44(m,1H),7.30( d,J=2.4Hz,1H),7.05(d,J=2.0Hz,1H),6.65(d,J=3.6Hz,1H),4.80(d,J=15.2Hz,1H),4.72(d,J=15.2Hz,1 H),3.69(d,J=15.2Hz,1H),3.49(d,J=15.2Hz,1H),2.66-2.82(m,2H),2.32-2.35(m,2H),2.17-2.31(m,2 H),1.42-1.57(m,2H),1.21(s,3H),1.07(s,3H),0.78-0.96(m,3H),0.32-0.43(m,2H),0.19-0.30(m,2H).

[0646] Example 141: 4-((5-chloro-7-(2-((3-ethyl-3-methyl-2,5-dioxopyrrolidin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0647]

[0648] The synthesis method of Example 141 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),8.82(d,J=4.4Hz,1H),7.70(d,J=1.6Hz,1H),7.55(s,1H),7.40(d,J=4.8Hz,1H),7.35(d, J=3.6Hz,1H),7.09(d,J=2.4Hz,1H),6.66(d,J=3.6Hz,1H),4.92(d,J=15.2Hz,1H),4.85(d,J=15.2Hz,1H),3.72 -3.76(m,1H),3.49-3.54(m,1H),2.80-2.89(m,2H),2.61-2.72(m,3H),2.43(d,J=18.4Hz,1H),2.12-2.32(br, 1H),1.66-1.74(m,1H),1.52-1.62(m,1H),1.40-1.46(m,1H),1.27(s,1.5H),1.26(s,1.5H),0.78-0.97(m,6H).

[0649] Example 142: 3-((7-(5-chloro-1-(2-hydroxy-3-(piperazin-1-yl)propyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0650]

[0651] The synthesis method of Example 142 is the same as that of Example 9. 1 H NMR(400MHz, CDCl3),8.72-8.74(m,1H),7.68-7.69(m,1H),7.58(s,0.5H),7.55(s,0.5H),7.22-7.25(m,2H),7.05( d,J=2.0Hz,0.5H),7.00(d,J=2.0Hz,0.5H),6.55-6.56(m,1H),4.69-4.83(m,2H),3.56-3.61(m,0.5H),3.37-3.48( m,1.5H),3.19-3.27(m,1H),2.68-2.86(m,4H),2.35-2.43(m,3H),2.09-2.21(m,2H),1.89-2.01(br,1H),1.65-1.6 9(m,1H),1.30-1.34(m,1H),1.23(s,1.5H),1.21(s,1.5H),1.14(s,1.5H),1.06-1.13(m,2.5H),0.82-0.85(m,1H).

[0652] Example 143: 3-((7-(5-chloro-1-(2,3-dihydroxypropyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0653]

[0654] The synthesis method of Example 143 is the same as that of Example 9. 1 H NMR(400MHz, CDCl3),8.67-8.74(m,1H),7.69(s,1H),7.54-7.56(m,1H),7.13-7.25(m,2H),7.03-7.05(m,1H),6.50 -6.58(m,1H),4.74-4.81(m,2H),3.24-3.57(m,3H),2.68-3.04(m,2H),2.34(s,2H),1.21(s,3H),1.06-1.14(m,3H).

[0655] Example 144: 4-((5-chloro-7-(2-((3-(cyclopropylmethyl)-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate

[0656]

[0657] The synthesis method of Example 144 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.82(d,J=4.8Hz,1H),8.56-8.73(br,1H),8.33-8.51(br,1H),7.82(d,J=2.0Hz,1H),7.75(d,J=8.0Hz,1H) ,7.57(s,1H),7.55(d,J=3.6Hz,1H),7.52(d,J=4.8Hz,1H),7.10(d,J=2.0Hz,1H),6.74(d,J=3.2Hz,1H),5.69(d,J=8.0Hz,1H),5.28 (d,J=15.2Hz,1H),5.16(d,J=15.2Hz,1H),4.13(d,J=15.2Hz,1H),3.54(d,J=7.2Hz,2H),3.47(d,J=15.2Hz,1H),3.10-3.2 0(m,2H),2.60-2.71(m,2H),1.69-1.76(m,1H),1.13-1.32(m,2H),1.02-1.08(m,2H),0.38-0.43(m,2H),0.26-0.29(m,2H).

[0658] Example 145: 4-((5-chloro-7-(2-((3,5-dimethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate

[0659]

[0660] The synthesis method of Example 145 is the same as that of Example 21. 1H NMR(400MHz, CDCl3),9.18-9.95(br,2H),8.74-8.94(m,1H),7.64-7.75(m,2H),7.47-7.58(m,1H),7.30 (d,J=2.4Hz,1H),7.06(s,1H),6.98(s,1H),6.69(d,J=3.2Hz,1H),5.29-5.41(m,2H),3.84(d,J=14.8Hz 1H),3.53(d,J=14.8Hz,1H),3.16-3.36(m,5H),2.81-2.96(m,2H),1.88(s,3H),1.66-1.76(m,1H),1.38-1.55(m,2H),1.0-1.10(m,1H).

[0661] Example 146: 4-((5-chloro-7-(2-((3-(cyclopropylmethyl)-5-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate

[0662]

[0663] The synthesis method of Example 146 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),8.40-8.50(br,1H),8.18-8.31(br,1H),7.82(d,J=2.0Hz,1 H),7.64(d,J=1.2Hz,1H),7.55-7.56(m,2H),7.51(d,J=4.8Hz,1H),7.10(d,J=2.0Hz,1H),6.75(d,J=3.6H z,1H),5.30(d,J=14.8Hz,1H),5.17(d,J=14.8Hz,1H),4.13(d,J=14.8Hz,1H),3.47-3.52(m,3H),3.10-3. 19(m,2H),2.60-2.74(m,2H),1.71-1.76(m,4H),1.02-1.29(m,4H),0.38-0.43(m,2H),0.26-0.30(m,2H).

[0664] Example 147: 3-((7-(5-chloro-1-(2-(piperazin-1-yl)ethyl)-1H-indol-7-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0665]

[0666] The synthesis method of Example 147 is the same as that of Example 9. 1 H NMR(400MHz, DMSO-d6),8.73(d,J=4.8Hz,1H),7.76(d,J=2.4Hz,1H),7.56(s,1H),7.4 8(d,J=4.8Hz,1H),7.46(d,J=2.8Hz,1H),7.04(d,J=2.0Hz,1H),6.57(d,J=3.2Hz,1H), 4.70-4.79(m,2H),3.58-3.65(m,1H),3.45-3.52(m,1H),2.54(s,2H),2.38-2.41(m,4 H),1.94-2.01(m,1H),1.78-1.86(m,1H),1.63-1.70(m,4H),1.13(s,3H),0.98(s,3H).

[0667] Example 148: 4-(2-(5-chloro-7-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)ethyl)piperidine-4-carbonitrile

[0668]

[0669] The synthesis method of Example 148 is the same as that of Example 9. 1H NMR(400MHz, DMSO-d6),8.74(d,J=4.8Hz,1H),7.78(d,J=2.0Hz,1H),7.56(s,1H),7.53(d,J=3.2Hz,1H ),7.50(d,J=4.4Hz,1H),7.06(d,J=2.0Hz,1H),6.63(d,J=3.2Hz,1H),4.70-4.79(m,2H),3.67-3.75(m ,1H),3.56-3.63(m,1H),2.58-2.68(m,2H),2.53(s,2H),2.30-2.39(m,2H),2.11-2.29(br,1H),1.43- 1.51(m,1H),1.19-1.28(m,1H),1.03-1.13(m,5H),1.00(s,3H),0.69-0.76(m,1H),0.52-0.59(m,1H).

[0670] Example 149: 4-((5-chloro-7-(2-((5-fluoro-3-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0671]

[0672] The synthesis method of Example 149 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),8.14(d,J=6.8Hz,1H),7.81(d,J=2.0Hz,1 H),7.60(s,1H),7.51-7.52(m,2H),7.09(d,J=2.4Hz,1H),6.71(d,J=3.2Hz,1H),5.27(d ,J=15.2Hz,1H),5.17(d,J=15.2Hz,1H),3.94(d,J=14.8Hz,1H),3.48(d,J=14.8Hz,1H), 3.21(s,3H),2.62-2.69(m,2H),2.26-2.35(m,2H),1.29-1.33(m,1H),0.74-0.87(m,3H).

[0673] Example 150: 4-((5-chloro-7-(2-((3-(cyclopropylmethyl)-5-fluoro-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0674]

[0675] The synthesis method of Example 150 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),8.22(d,J=6.8Hz,1H),7.81(d,J=2.4Hz,1H),7.60( s,1H),7.51-7.52(m,2H),7.09(d,J=2.4Hz,1H),6.71(d,J=3.2Hz,1H),5.29(d,J=15.2Hz,1H),5.1 9(d,J=15.2Hz,1H),3.94(d,J=15.2Hz,1H),3.47-3.52(m,3H),2.62-2.68(m,2H),2.26-2.34(m,2 H),1.28-1.33(m,1H),1.03-1.12(m,1H),0.76-0.86(m,3H),0.39-0.43(m,2H),0.28-0.32(m,2H).

[0676] Example 151: 4-((7-(2-((5-bromo-3-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-5-chloro-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0677]

[0678] The synthesis method of Example 151 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=5.2Hz,1H),8.25(s,1H),7.80(d,J=2.4Hz,1H),7.59(s ,1H),7.52(s,1H),7.51(d,J=2.8Hz,1H),7.08(d,J=2.0Hz,1H),6.71(d,J=3.6Hz,1H),5.2 9(d,J=15.2Hz,1H),5.19(d,J=15.2Hz,1H),3.93(d,J=14.8Hz,1H),3.49(d,J=14.8Hz,1H) ,3.25(s,3H),2.60-2.67(m,2H),2.26-2.34(m,2H),1.27-1.30(m,1H),0.74-0.84(m,3H).

[0679] Example 152: 4-((7-(2-((5-bromo-3-(cyclopropylmethyl)-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-5-chloro-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0680]

[0681] The synthesis method of Example 152 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),8.32(s,1H),7.80(d,J=2.0Hz,1H),7.60(s,1H),7.52(d,J=2.4H z,1H),7.51(s,1H),7.09(d,J=2.0Hz,1H),6.71(d,J=3.6Hz,1H),5.31(d,J=15.2Hz,1H),5.21(d,J=15.2Hz,1H) ,3.93(d,J=15.2Hz,1H),3.55(d,J=7.2Hz,2H),3.50(d,J=15.2Hz,1H),2.60-2.70(m,2H),2.26-2.34(m,2H),1. 94-1.98(m,1H),1.19-1.32(m,1H),1.05-1.14(m,1H),0.74-0.85(m,2H),0.38-0.43(m,2H),0.28-0.31(m,2H).

[0682] Example 153: 4-((5-chloro-7-(2-((3-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0683]

[0684] The synthesis method of Example 128 is the same as that of Example 21. 1H NMR(400MHz, DMSO-d6),8.80(d,J=4.8Hz,1H),7.80(d,J=2.0Hz,1H),7.64(d,J=8.0Hz,1H),7. 57(s,1H),7.50-7.52(m,2H),7.09(d,J=2.0Hz,1H),6.71(d,J=3.2Hz,1H),5.65(d,J=8.0Hz,1 H),5.25(d,J=15.2Hz,1H),5.15(d,J=15.2Hz,1H),3.95(d,J=14.8Hz,1H),3.49(d,J=14.8Hz, 1H),3.23(s,3H),2.64-2.71(m,2H),2.28-2.36(m,2H),1.30-1.37(m,1H),0.75-0.89(m,3H).

[0685] Example 154: 4-((5-chloro-7-(2-((4-methyl-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0686]

[0687] The synthesis method of Example 154 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),8.84(d,J=4.8Hz,1H),7.71(d,J=2.0Hz,1H),7.65(s,1H),7.41(d,J =4.8Hz,1H),7.39(s,1H),7.37(d,J=3.6Hz,1H),7.09(d,J=2.0Hz,1H),6.67(d,J=3.6Hz, 1H),5.32-5.40(m,2H),3.75(d,J=15.2Hz,1H),3.57(d,J=15.2Hz,1H),3.30(s,3H),2.76 -2.84(m,2H),2.60-2.70(m,2H),1.36-1.43(m,1H),0.95-1.01(m,1H),0.78-0.89(m,2H).

[0688] Example 155: 4-((5-chloro-7-(2-((3-(cyclopropylmethyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0689]

[0690] The synthesis method of Example 155 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),8.79(d,J=4.4Hz,1H),7.68(d,J=2.0Hz,1H),7.63(s,1H),7.36(d,J=3.6Hz, 1H),7.34(d,J=4.4Hz,1H),7.07(d,J=2.0Hz,1H),6.65(d,J=2.8Hz,1H),5.60(s,1H),5.29-5.41( m,2H),3.71-3.76(m,3H),3.58(d,J=14.8Hz,1H),2.80-2.87(m,2H),2.60-2.71(m,2H),2.26(s,3 H),1.37-1.41(m,1H),0.96-1.06(m,2H),0.76-0.89(m,2H),0.50-0.55(m,2H),0.36-0.40(m,2H).

[0691] Example 156: 4-((5-chloro-7-(2-((4-methyl-3-(methyl-d3)-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0692]

[0693] The synthesis method of Example 156 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),8.79(d,J=4.8Hz,1H),7.68(d,J=2.0Hz,1H),7.65(s,1H),7.37(d,J =3.2Hz,1H),7.34(d,J=4.4Hz,1H),7.06(d,J=2.4Hz,1H),6.65(d,J=3.2Hz,1H),5.61(s, 1H),5.28-5.40(m,2H),3.72(d,J=15.2Hz,1H),3.58(d,J=15.2Hz,1H),2.78-2.84(m,2H) ,2.60-2.70(m,2H),2.20(s,3H),1.36-1.42(m,1H),0.94-1.00(m,1H),0.75-0.89(m,2H).

[0694] Example 157: 4-((5-chloro-7-(2-((5-methyl-2,6-dioxo-3-(2,2,2-trifluoroethyl)-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0695]

[0696] The synthesis method of Example 157 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),8.80(d,J=4.8Hz,1H),7.69(d,J=1.6Hz,1H),7.65(s,1H),7.35-7.37(m,2H),7.08(d,J=2.0Hz,1H),6.98(s,1H) ,6.66(d,J=3.6Hz,1H),5.42(d,J=14.8Hz,1H),5.34(d,J=14.8Hz,1H),4.28-4.40(m,2H),3.74(d,J=15.2Hz,1H),3.57(d,J=15.2Hz, 1H),2.78-2.86(m,2H),2.61-2.71(m,2H),1.94(s,3H),1.38-1.44(m,1H),0.95-1.01(m,1H),0.75-0.89(m,2H).

[0697] Example 158: 4-((5-chloro-7-(2-((3-cyclopropyl-5-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate

[0698]

[0699] The synthesis method of Example 158 is the same as that of Example 21. 1H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),8.42-8.56(br,1H),8.22-8.37(br,1H),7.83(d,J=2.0Hz,1H), 7.55-7.58(m,2H),7.51(d,J=4.8Hz,1H),7.47(s,1H),7.11(d,J=2.4Hz,1H),6.75(d,J=3.2Hz,1H),5.26(d,J =14.8Hz,1H),5.14(d,J=14.8Hz,1H),4.14(d,J=14.8Hz,1H),3.49(d,J=14.8Hz,1H),3.10-3.20(m,2H),3.01 -3.06(m,1H),2.60-2.74(m,2H),1.70-1.78(m,4H),1.04-1.31(m,3H),0.81-0.88(m,2H),0.74-0.78(m,2H).

[0700] Example 159: 4-((5-chloro-7-(2-((5-fluoro-2,6-dioxo-3-(2,2,2-trifluoroethyl)-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0701]

[0702] The synthesis method of Example 159 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.82(d,J=5.2Hz,1H),8.19(d,J=6.4Hz,1H),7.81(d,J=2.0Hz,1H ),7.61(s,1H),7.51-7.53(m,2H),7.09(d,J=2.0Hz,1H),6.71(d,J=3.2Hz,1H),5.29(d,J= 15.2Hz,1H),5.19(d,J=15.2Hz,1H),4.55-4.62(m,2H),3.94(d,J=15.2Hz,1H),3.49(d,J =15.2Hz,1H),2.63-2.72(m,2H),2.28-2.37(m,2H),1.30-1.36(m,1H),0.78-0.88(m,3H).

[0703] Example 160: 4-((5-chloro-7-(2-((3-(deuterated methyl)-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0704]

[0705] The synthesis method of Example 160 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=5.2Hz,1H),7.81(d,J=2.4Hz,1H),7.64(d,J=8.4Hz,1H),7.57 (s,1H),7.52(d,J=3.6Hz,1H),7.50(d,J=4.8Hz,1H),7.09(d,J=2.0Hz,1H),6.72(d,J=3.6Hz,1H) ,5.65(d,J=8.0Hz,1H),5.25(d,J=15.2Hz,1H),5.15(d,J=15.2Hz,1H),3.98(d,J=14.8Hz,1H),3. 48(d,J=14.8Hz,1H),2.72-2.81(m,2H),2.34-2.43(m,2H),1.37-1.44(m,1H),0.77-0.96(m,3H).

[0706] Example 161: 4-((5-chloro-7-(2-((5-chloro-3-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0707]

[0708] The synthesis method of Example 161 is the same as that of Example 21. 1H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),8.19(s,1H),7.80(d,J=2.4Hz,1H),7.60(s, 1H),7.50-7.52(m,2H),7.08(d,J=2.4Hz,1H),6.71(d,J=3.2Hz,1H),5.28(d,J=15.2Hz,1H) ,5.18(d,J=15.2Hz,1H),3.92(d,J=14.8Hz,1H),3.48(d,J=14.8Hz,1H),3.25(s,3H),2.58 -2.66(m,2H),2.23-2.33(m,2H),1.98-2.19(br,1H),1.26-1.29(m,1H),0.73-0.82(m,3H).

[0709] Example 162: 4-((5-chloro-7-(2-((5-chloro-3-(cyclopropylmethyl)-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0710]

[0711] The synthesis method of Example 162 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),8.25(s,1H),7.80(d,J=2.0Hz,1H),7.60(s,1H),7.50-7.52(m,2H),7.09(d,J=2.0Hz, 1H),6.70(d,J=3.6Hz,1H),5.30(d,J=15.2Hz,1H),5.21(d,J=15.2Hz,1H),3.91(d,J=15.2Hz,1H),3.56(d,J=7.6Hz,2H),3.50(d,J= 15.2Hz,1H),2.58-2.65(m,2H),2.23-2.31(m,2H),1.88-2.02(br,1H),1.24-1.28( m,1H),1.04-1.14(m,1H),0.72-0.85(m,3H),0.39-0.43(m,2H),0.28-0.32(m,2H).

[0712] Example 163: 4-((5-chloro-7-(2-((5-chloro-2,6-dioxo-3-(2,2,2-trifluoroethyl)-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0713]

[0714] The synthesis method of Example 163 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),8.24(s,1H),7.80(d,J=2.0Hz,1H),7.61(s,1 H),7.50-7.52(m,2H),7.08(d,J=2.0Hz,1H),6.71(d,J=3.2Hz,1H),5.31(d,J=15.2Hz,1H),5 .20(d,J=15.2Hz,1H),4.59-4.66(m,2H),3.91(d,J=14.8Hz,1H),3.49(d,J=14.8Hz,1H),2.5 8-2.66(m,2H),2.24-2.32(m,2H),1.92-2.06(br,1H),1.25-1.30(m,1H),0.72-0.84(m,3H).

[0715] Example 164: 4-((5-chloro-7-(2-((4-methyl-2,6-dioxo-3-(2,2,2-trifluoroethyl)-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0716]

[0717] The synthesis method of Example 164 is the same as that of Example 21. 1H NMR(400MHz, CDCl3),8.81(d,J=4.8Hz,1H),7.69(d,J=2.0Hz,1H),7.64(s,1H),7.36-7.3 8(m,2H),7.07(d,J=2.0Hz,1H),6.65(d,J=3.2Hz,1H),5.69(s,1H),5.38(d,J=14.8Hz,1H) ,5.31(d,J=14.8Hz,1H),4.43-4.56(m,2H),3.73(d,J=15.2Hz,1H),5.60(d,J=15.2Hz,1H) ,2.78-2.86(m,2H),2.61-2.70(m,2H),2.26(s,3H),1.37-1.43(m,1H),0.76-0.99(m,3H).

[0718] Example 165: 4-((5-chloro-7-(2-((3-isopropyl-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0719]

[0720] The synthesis method of Example 165 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),8.79(d,J=4.4Hz,1H),7.68(d,J=2.0Hz,1H),7.62(s,1H),7.36(d,J=3.6Hz,1H),7.3 4(d,J=4.4Hz,1H),7.08(d,J=2.0Hz,1H),6.65(d,J=2.8Hz,1H),5.54(s,1H),5.35(d,J=14.8Hz,1H),5.27 (d,J=14.8Hz,1H),4.22-4.36(m,1H),3.74(d,J=14.8Hz,1H),3.57(d,J=14.8Hz,1H),2.77-2.84(m,2H),2 .60-2.69(m,2H),2.21(s,3H),1.48-1.51(m,6H),1.35-1.42(m,1H),0.92-0.99(m,1H),0.74-0.89(m,2H).

[0721] Example 166: 4-((5-chloro-7-(2-((2,6-dioxo-3-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0722]

[0723] The synthesis method of Example 166 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.82(d,J=4.8Hz,1H),8.53(s,1H),7.81(d,J=2.4Hz,1H),7.62 (s,1H),7.50-7.53(m,2H),7.09(d,J=2.0Hz,1H),6.71(d,J=3.2Hz,1H),5.29(d,J=15.2 Hz,1H),5.17(d,J=15.2Hz,1H),4.68-4.76(m,2H),3.92(d,J=15.2Hz,1H),3.48(d,J=1 5.2Hz,1H),2.60-2.65(m,2H),2.24-2.32(m,2H),1.26-1.30(m,1H),0.73-0.84(m,3H).

[0724] Example 167: 4-((5-chloro-7-(2-((3-ethyl-2,6-dioxo-5-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0725]

[0726] The synthesis method of Example 167 is the same as that of Example 21. 1H NMR(400MHz,DMSO-d6),8.81(d,J=4.8Hz,1H),8.45(s,1H),7.81(d,J=2.0Hz,1H),7.60(s,1H) ,7.50-7.52(m,2H),7.10(d,J=2.0Hz,1H),6.71(d,J=3.2Hz,1H),5.27(d,J=15.2Hz,1H),5.17 (d,J=15.2Hz,1H),3.93(d,J=14.8Hz,1H),3.79(q,J=7.6Hz,2H),3.51(d,J=14.8Hz,1H),2.60 -2.66(m,2H),2.24-2.34(m,2H),1.24-1.31(m,1H),1.15(t,J=7.2Hz,3H),0.74-0.86(m,3H).

[0727] Example 168: 4-((5-chloro-7-(2-((5-chloro-3-ethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0728]

[0729] The synthesis method of Example 168 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),8.23(s,1H),7.80(d,J=2.4Hz,1H),7.59(s,1H),7.5 0-7.52(m,2H),7.09(d,J=2.0Hz,1H),6.71(d,J=3.2Hz,1H),5.29(d,J=15.2Hz,1H),5.19(d,J=15. 2Hz,1H),3.91(d,J=15.2Hz,1H),3.71(q,J=7.2Hz,2H),3.50(d,J=15.2Hz,1H),2.56-2.65(m,2H), 2.22-2.32(m,2H),1.87-1.94(br,1H),1.22-1.29(m,1H),1.13(t,J=7.2Hz,3H),0.72-0.85(m,3H).

[0730] Example 169: 4-((5-chloro-7-(2-((3-ethyl-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0731]

[0732] The synthesis method of Example 169 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),8.79(d,J=4.8Hz,1H),7.68(d,J=2.0Hz,1H),7.64(s,1H),7.37(d,J=3.2Hz,1H),7.34 (d,J=4.4Hz,1H),7.07(d,J=2.0Hz,1H),6.65(d,J=3.2Hz,1H),5.59(s,1H),5.38(d,J=14.4Hz,1H),5.30(d, J=14.4Hz,1H),3.86(q,J=7.2Hz,2H),3.73(d,J=15.2Hz,1H),3.58(d,J=15.2Hz,1H),2.78-2.84(m,2H),2.6 0-2.70(m,2H),2.23(s,3H),1.36-1.42(m,1H),1.24(t,J=7.2Hz,3H),0.94-1.00(m,1H),0.75-0.89(m,2H).

[0733] Example 170: 4-((7-(2-((5-bromo-2,6-dioxo-3-(2,2,2-trifluoroethyl)-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-5-chloro-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0734]

[0735] The synthesis method of Example 170 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),8.31(s,1H),7.81(d,J=2.0Hz,1H),7.60(s,1H),7.50-7.52(m,2H),7.09(d,J=2.0Hz, 1H),6.71(d,J=3.2Hz,1H),5.31(d,J=15.2Hz,1H),5.20(d,J=15.2Hz,1H),4.59-4.66(m,2H),3.93(d,J=14.8Hz,1H),3.49(d,J=14.8 Hz,1H),2.64-2.70(m,2H),2.26-2.36(m,2H),1.28-1.33(m,1H),0.75-0.87(m,3H).

[0736] Example 171: 4-((5-chloro-7-(2-((3-isopropyl-5-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0737]

[0738] The synthesis method of Example 171 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.80(d,J=4.8Hz,1H),7.80(d,J=2.0Hz,1H),7.63(d,J=1.2Hz,1H),7.56( s,1H),7.49-7.51(m,2H),7.09(d,J=2.4Hz,1H),6.71(d,J=3.2Hz,1H),5.27(d,J=15.2Hz,1H),5. 18(d,J=15.2Hz,1H),4.60-4.67(m,1H),3.93(d,J=15.2Hz,1H),3.51(d,J=15.2Hz,1H),2.59-2.6 7(m,2H),2.24-2.34(m,2H),1.78(s,3H),1.26-1.32(m,1H),1.18-1.20(m,6H),0.72-0.84(m,3H).

[0739] Example 172: 4-((5-chloro-7-(2-((3-cyclopropyl-5-fluoro-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0740]

[0741] The synthesis method of Example 172 is the same as that of Example 21. 1H NMR(400MHz, CDCl3),8.82(d,J=4.0Hz,1H),7.67-7.71(m,2H),7.39(d,J=4.4Hz,1H),7.36(d,J =3.2Hz,1H),7.28(d,J=5.6Hz,1H),7.07(d,J=2.0Hz,1H),6.66(d,J=3.2Hz,1H),5.40(d,J=14.4 Hz,1H),5.30(d,J=14.4Hz,1H),3.75(d,J=15.2Hz,1H),3.56(d,J=15.2Hz,1H),3.06-3.12(m,1H ),2.82-2.92(m,2H),2.63-2.73(m,2H),1.42-1.46(m,1H),1.04-1.09(m,2H),0.8-1.01(m,5H).

[0742] Example 173: 4-((5-chloro-7-(2-((3-cyclopropyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate

[0743]

[0744] The synthesis method of Example 173 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),9.45-9.80(br,1H),8.78-9.26(br,2H),7.78-7.98(m,3H),7.42(s,1 H),7.23-7.27(m,1H),7.12(s,1H),6.76(d,J=2.0Hz,1H),5.71(d,J=2.8Hz,1H),5.31-5.4 4(m,2H),3.91-3.95(m,1H),3.49-3.58(m,1H),3.26-3.44(m,2H),3.03-3.10(m,1H),2.84 -3.02(m,2H),1.42-1.74(m,3H),1.14-1.30(m,1H),1.02-1.10(m,2H),0.78-0.85(m,2H).

[0745] Example 174: 4-((5-chloro-7-(2-((3-(2-chloroethyl)-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate

[0746]

[0747] The synthesis method of Example 174 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),9.50-10.8(br,1H),8.68-9.48(br,2H),7.74-7.95(m,3H), 7.39-7.44(m,1H),7.22-7.25(m,1H),7.13(s,1H),6.76(d,J=2.8Hz,1H),5.77(d ,J=8.0Hz,1H),5.39(s,2H),3.87-4.12(m,3H),3.75-3.81(m,2H),3.48-3.58(m, 1H),3.21-3.44(m,2H),2.84-3.02(m,2H),1.58-1.72(m,1H),1.14-1.36(m,3H).

[0748] Example 175: 4-((5-chloro-7-(2-((3-ethyl-5-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0749]

[0750] The synthesis method of Example 175 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),8.79(d,J=4.8Hz,1H),7.68(d,J=2.0Hz,1H),7.65(s,1H),7.36(d,J=3.6Hz,1H),7 .35(d,J=4.4Hz,1H),7.07(d,J=2.0Hz,1H),6.97(d,J=1.2Hz,1H),6.65(d,J=3.2Hz,1H),5.42(d,J=14. 8Hz,1H),5.32(d,J=14.8Hz,1H),3.72-3.78(m,3H),3.58(d,J=14.8Hz,1H),2.78-2.86(m,2H),2.61-2. 70(m,2H),1.91(s,3H),1.36-1.43(m,1H),1.26(t,J=7.2Hz,3H),0.93-1.00(m,1H),0.79-0.89(m,2H).

[0751] Example 176: 4-((5-chloro-7-(2-((3-isopropyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0752]

[0753] The synthesis method of Example 176 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.80(d,J=4.8Hz,1H),7.81(d,J=2.4Hz,1H),7.75(d,J=8.4Hz,1H),7.56(s, 1H),7.50-7.52(m,2H),7.10(d,J=2.0Hz,1H),6.71(d,J=3.6Hz,1H),5.70(d,J=8.4Hz,1H),5.26(d, J=14.8Hz,1H),5.16(d,J=14.8Hz,1H),4.58-4.65(m,1H),3.95(d,J=14.8Hz,1H),3.51(d,J=14.8Hz ,1H),2.64-2.72(m,2H),2.27-2.36(m,2H),1.29-1.35(m,1H),1.18-1.21(m,6H),0.75-0.90(m,3H).

[0754] Example 177: 4-((5-chloro-7-(2-((5-chloro-3-isopropyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0755]

[0756] The synthesis method of Example 177 is the same as that of Example 21. 1H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),8.19(s,1H),7.80(d,J=2.0Hz,1H),7.60 (s,1H),7.50-7.52(m,2H),7.09(d,J=2.0Hz,1H),6.71(d,J=3.2Hz,1H),5.29(d,J=14.8 Hz,1H),5.19(d,J=14.8Hz,1H),4.60-4.67(m,1H),3.92(d,J=14.8Hz,1H),3.51(d,J=1 4.8Hz,1H),2.58-2.66(m,2H),2.23-2.32(m,2H),1.21-1.28(m,7H),0.73-0.85(m,3H).

[0757] Example 178: 4-((5-chloro-7-(2-((3-isopropyl-2,6-dioxo-5-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0758]

[0759] The synthesis method of Example 178 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),8.22(s,1H),7.81(d,J=2.0Hz,1H),7.61(s ,1H),7.52(s,1H),7.51(s,1H),7.10(d,J=2.0Hz,1H),6.71(d,J=3.2Hz,1H),5.27(d,J=1 5.2Hz,1H),5.17(d,J=15.2Hz,1H),4.60-4.67(m,1H),3.939d,J=14.8Hz,1H),3.51(d,J= 14.8Hz,1H),2.58-2.66(m,2H),2.23-2.32(m,2H),1.21-1.28(m,7H),0.72-0.84(m,3H).

[0760] Example 179: 4-((5-chloro-7-(2-((5-chloro-3-cyclopropyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0761]

[0762] The synthesis method of Example 179 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),8.02(s,1H),7.81(d,J=2.4Hz,1H),7.60 (s,1H),7.51-7.52(m,2H),7.09(d,J=2.0Hz,1H),6.71(d,J=3.2Hz,1H),5.27(d,J=15.2 Hz,1H),5.17(d,J=15.2Hz,1H),3.94(d,J=14.8Hz,1H),3.49(d,J=14.8Hz,1H),3.04-3 .10(m,1H),2.62-2.69(m,2H),2.26-2.35(m,2H),1.26-1.34(m,1H),0.74-0.88(m,7H).

[0763] Example 180: 4-((5-chloro-7-(2-((4-isobutyl-2,6-dioxopiperidin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0764]

[0765] The synthesis method of Example 180 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.79(d,J=4.8Hz,1H),7.80(d,J=2.0Hz,1H),7.49-7.51(m,3H),7. 07(d,J=2.0Hz,1H),6.70(d,J=3.2Hz,1H),5.09(d,J=15.2Hz,1H),4.98(d,J=15.2Hz,1H),3 .94(d,J=15.2Hz,1H),3.47(d,J=15.2Hz,1H),2.60-2.68(m,4H),2.24-2.40(m,4H),2.02-2 .13(m,1H),1.49-1.56(m,1H),1.25-1.31(m,1H),1.06(t,J=7.2Hz,2H),0.70-0.85(m,9H).

[0766] Example 181: 4-((5-chloro-7-(2-((5-chloro-2,6-dioxo-3-propyl-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0767]

[0768] The synthesis method of Example 181 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),8.23(s,1H),7.80(d,J=2.0Hz,1H),7.59(s,1H ),7.51-7.52(m,2H),7.09(d,J=2.4Hz,1H),6.71(d,J=3.2Hz,1H),5.28(d,J=15.2Hz,1H),5. 19(d,J=15.2Hz,1H),3.91(d,J=14.8Hz,1H),3.64(t,J=7.2Hz,2H),3.49(d,J=14.8Hz,1H),2 .58-2.65(m,2H),2.23-2.32(m,2H),1.50-1.60(m,2H),1.24-1.28(m,1H),0.72-0.84(m,6H).

[0769] Example 182: 4-((5-chloro-7-(2-((5-chloro-3-(2,2-difluoroethyl)-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0770]

[0771] The synthesis method of Example 182 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),8.21(s,1H),7.81(d,J=2.4Hz,1H),7.61(s,1 H),7.50-7.52(m,2H),7.09(d,J=2.0Hz,1H),6.71(d,J=3.6Hz,1H),6.07-6.37(m,1H),5.29( d,J=15.2Hz,1H),5.19(d,J=15.2Hz,1H),4.12-4.22(m,2H),3.92(d,J=15.2Hz,1H),3.48(d ,J=15.2Hz,1H),2.58-2.66(m,2H),2.22-2.32(m,2H),1.24-1.30(m,1H),0.72-0.84(m,3H).

[0772] Example 183: 4-((5-chloro-7-(2-((5-fluoro-3-isopropyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0773]

[0774] The synthesis method of Example 183 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),8.20(d,J=6.8Hz,1H),7.81(d,J=2.0Hz,1H),7.60 (s,1H),7.52(s,1H),7.51(s,1H),7.10(d,J=2.4Hz,1H),6.71(d,J=3.6Hz,1H),5.27(d,J=15.2H z,1H),5.18(d,J=15.2Hz,1H),4.61-4.68(m,1H),3.93(d,J=14.8Hz,1H),3.51(d,J=14.8Hz,1H) ,2.60-2.67(m,2H),2.24-2.33(m,2H),1.24-1.30(m,1H),1.18-1.21(m,6H),0.74-0.86(m,3H).

[0775] Example 184: 4-((5-chloro-7-(2-((3-ethyl-5-fluoro-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0776]

[0777] The synthesis method of Example 184 is the same as that of Example 21. 1H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),8.18(d,J=6.8Hz,1H),7.80(d,J=2.0Hz,1H),7 .59(s,1H),7.52(s,1H),7.51(s,1H),7.09(d,J=2.0Hz,1H),6.71(d,J=3.2Hz,1H),5.27(d,J =15.2Hz,1H),5.18(d,J=15.2Hz,1H),3.93(d,J=15.2Hz,1H),3.64-3.70(m,2H),3.50(d,J=15.2Hz,1 H),2.60-2.67(m,2H),2.24-2.34(m,2H),1.26-1.31(m,1H),1.12(t,J=7.2Hz,3H),0.73-0.86(m,3H).

[0778] Example 185: 4-((5-chloro-7-(2-((2-methyl-3,5-dioxo-2,5-dihydro-1,2,4-triazin-4(3H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0779]

[0780] The synthesis method of Example 185 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.82(d,J=4.8Hz,1H),7.81(d,J=2.4Hz,1H),7.64(s,1H),7.55(s ,1H),7.52(d,J=1.6Hz,1H),7.51(s,1H),7.08(d,J=2.4Hz,1H),6.71(d,J=3.2Hz,1H),5.2 3(d,J=15.2Hz,1H),5.13(d,J=15.2Hz,1H),3.94(d,J=15.2Hz,1H),3.48(d,J=15.2Hz,1H) ,3.45(s,3H),2.62-2.69(m,2H),2.26-2.35(m,2H),1.28-1.33(m,1H),0.76-0.88(m,3H).

[0781] Example 186: 4-((7-(2-((5-bromo-3-ethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-5-chloro-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0782]

[0783] The synthesis method of Example 186 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),8.28(s,1H),7.80(d,J=2.4Hz,1H),7.59(s,1H),7. 51(s,1H),7.50(d,J=1.2Hz,1H),7.09(d,J=2.0Hz,1H),6.71(d,J=3.6Hz,1H),5.29(d,J=15.2Hz,1 H),5.20(d,J=15.2Hz,1H),3.92(d,J=15.2Hz,1H),3.71(q,J=7.2Hz,2H),3.50(d,J=15.2Hz,1H), 2.59-2.66(m,2H),2.24-2.34(m,2H),1.25-1.30(m,1H),1.12(t,J=7.2Hz,3H),0.72-0.85(m,3H).

[0784] Example 187: 4-((5-chloro-7-(2-((3-ethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0785]

[0786] The synthesis method of Example 187 is the same as that of Example 21. 1 H NMR(400MHz,DMSO-d6),8.80 (d,J=4.8Hz,1H),7.81(d,J=2.0Hz,1H),7.70(d,J=7.6Hz,1H),7.56(s,1H),7.50-7.52(m,2H) ,7.10(d,J=2.0Hz,1H),6.71(d,J=3.2Hz,1H),5.68(d,J=7.6Hz,1H),5.25(d,J=14.8Hz,1H),5. 16(d,J=14.8Hz,1H),3.95(d,J=14.4Hz,1H),3.69(q,J=7.6Hz,2H),3.49(d,J=14.4Hz,1H),2.6 2-2.74(m,2H),2.28-2.36(m,2H),1.30-1.37(m,1H),1.10(t,J=7.2Hz,3H),0.76-0.87(m,3H).

[0787] Example 188: 4-((5-chloro-7-(2-((3-(2,2-difluoroethyl)-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0788]

[0789] The synthesis method of Example 188 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),7.81(d,J=2.0Hz,1H),7.66(d,J=7.6Hz,1H),7.57(s, 1H),7.50-7.52(m,2H),7.09(d,J=2.0Hz,1H),6.71(d,J=3.2Hz,1H),6.06-6.36(m,1H),5.75(d,J=9 .2Hz,1H),5.26(d,J=15.2Hz,1H),5.16(d,J=15.2Hz,1H),4.13-4.22(m,2H),3.93(d,J=14.8Hz,1H) ,3.49(d,J=14.8Hz,1H),2.62-2.70(m,2H),2.25-2.35(m,2H),1.27-1.34(m,1H),0.73-0.87(m,3H).

[0790] Example 189: 4-((7-(2-((5-bromo-3-isopropyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-5-chloro-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0791]

[0792] The synthesis method of Example 189 is the same as that of Example 21. 1H NMR(400MHz, DMSO-d6),8.81(d,J=5.2Hz,1H),8.23(s,1H),7.80(d,J=2.4Hz,1H),7.59(s,1 H),7.51(s,1H),7.50(d,J=1.6Hz,1H),7.09(d,J=2.0Hz,1H),6.71(d,J=3.2Hz,1H),5.30(d ,J=15.2Hz,1H),5.20(d,J=15.2Hz,1H),4.59-4.66(m,1H),3.92(d,J=15.2Hz,1H),3.51(d, J=15.2Hz,1H),2.59-2.66(m,2H),2.24-2.32(m,2H),1.22-1.29(m,7H),0.72-0.84(m,3H).

[0793] Example 190: 4-((5-chloro-7-(2-((3-(2,2-difluoroethyl)-5-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0794]

[0795] The synthesis method of Example 190 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.80(d,J=4.8Hz,1H),7.81(d,J=2.0Hz,1H),7.56-7.57(m,2H),7.50-7. 52(m,2H),7.09(d,J=2.0Hz,1H),6.71(d,J=3.2Hz,1H),6.21(tt,J=54.8Hz,4.0Hz,1H),5.28(d,J =14.8Hz,1H),5.18(d,J=14.8Hz,1H),4.08-4.18(m,2H),3.93(d,J=14.8Hz,1H),3.49(d,J=14.8 Hz,1H),2.59-2.68(m,2H),2.24-2.34(m,2H),1.76(s,3H),1.26-1.32(m,1H),0.72-0.85(m,3H).

[0796] Example 191: 4-((5-chloro-7-(2-((3-(2,2-difluoroethyl)-5-fluoro-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0797]

[0798] The synthesis method of Example 191 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.82(d,J=4.8Hz,1H),8.17(d,J=6.0Hz,1H),7.81(d,J=2.4Hz,1H),7.61(s,1 H),7.52(d,J=2.4Hz,1H),7.51(s,1H),7.09(d,J=2.4Hz,1H),6.71(d,J=3.6Hz,1H),6.22(tt,J=55.2H z,3.6Hz,1H),5.28(d,J=15.2Hz,1H),5.18(d,J=55.2Hz,1H),4.08-4.18(m,2H),3.48(d,J=14.8Hz,1H ),3.28(d,J=14.8Hz,1H),2.63-2.70(m,2H),2.26-2.35(m,2H),1.28-1.34(m,1H),0.75-0.84(m,3H).

[0799] Example 192: 4-((5-chloro-7-(2-((4-chloro-3-ethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0800]

[0801] The synthesis method of Example 192 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.82(d,J=4.4Hz,1H),7.82(d,J=2.0Hz,1H),7.59(s,1H),7.54(d,J=2.8Hz ,1H),7.53(d,J=4.8Hz,1H),7.10(d,J=2.4Hz,1H),6.73(d,J=3.2Hz,1H),6.08(s,1H),5.23(d,J=15 .2Hz,1H),5.13(d,J=15.2Hz,1H),4.07(d,J=14.8Hz,1H),3.95(q,J=7.2Hz,2H),3.47(d,J=14.8Hz, 1H),2.92-3.02(m,2H),2.47-2.56(m,2H),1.54-1.61(m,1H),1.01-1.18(m,5H),0.90-0.97(m,1H).

[0802] Example 193: 4-((5-chloro-7-(2-((4-chloro-3-(2,2-difluoroethyl)-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0803]

[0804] The synthesis method of Example 193 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.82(d,J=4.8Hz,1H),7.81(d,J=2.0Hz,1H),7.60(s,1H),7.53(s,1H),7.52(d ,J=2.0Hz,1H),7.09(d,J=2.4Hz,1H),6.72(d,J=3.2Hz,1H),6.22(tt,J=54.8Hz,3.6Hz,1H),6.20(s,1H ),5.24(d,J=15.2Hz,1H),5.14(d,J=15.2Hz,1H),4.37(td,J=14.0Hz,3.6Hz,2H),3.99(d,J=15.2Hz,1 H), 3.47 (d, J = 15.2Hz, 1H), 2.73-2.82 (m, 2H), 2.32-2.43 (m, 2H), 1.37-1.44 (m, 1H), 0.78-0.98 (m, 3H).

[0805] Example 194: 4-((5-chloro-7-(2-((3-(2,2-difluoroethyl)-2,6-dioxo-5-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0806]

[0807] The synthesis method of Example 194 is the same as that of Example 21. 1H NMR(400MHz, DMSO-d6),8.82(d,J=4.8Hz,1H),8.47(s,1H),7.81(d,J=2.0Hz,1H),7.62(s,1H), 7.50-7.53(m,2H),7.09(d,J=2.0Hz,1H),6.71(d,J=3.6Hz,1H),6.24(tt,J=54.8Hz,4.0Hz,1H) ,5.28(d,J=15.2Hz,1H),5.16(d,J=15.2Hz,1H),4.23-4.32(m,2H),3.94(d,J=15.2Hz,1H),3.4 9(d,J=15.2Hz,1H),2.62-2.70(m,2H),2.26-2.34(m,2H),1.27-1.34(m,1H),0.73-0.84(m,3H).

[0808] Example 195: 4-((5-chloro-7-(2-((4-chloro-3-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0809]

[0810] The synthesis method of Example 195 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),7.81(d,J=2.4Hz,1H),7.59(s,1H),7.52 (s,1H),7.51(s,1H),7.08(d,J=1.6Hz,1H),6.71(d,J=3.2Hz,1H),6.08(s,1H),5.24(d, J=15.2Hz,1H),5.13(d,J=15.2Hz,1H),3.95(d,J=14.8Hz,1H),3.46(d,J=14.8Hz,1H),3 .37(s,3H),2.62-2.69(m,2H),2.26-2.34(m,2H),1.30-1.35(m,1H),0.72-0.88(m,3H).

[0811] Example 196: 4-((5-chloro-7-(2-((4-chloro-2,6-dioxo-3-(2,2,2-trifluoroethyl)-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0812]

[0813] The synthesis method of Example 196 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),7.81(d,J=2.4Hz,1H),7.60(s,1H),7.51- 7.53(m,2H),7.08(d,J=2.0Hz,1H),6.71(d,J=3.6Hz,1H),6.27(s,1H),5.25(d,J=15.2H z,1H),5.15(d,J=15.2Hz,1H),4.81(q,J=8.8Hz,2H),3.93(d,J=14.8Hz,1H),3.47(d,J= 14.8Hz,1H),2.60-2.66(m,2H),2.25-2.33(m,2H),1.26-1.34(m,1H),0.73-0.86(m,3H).

[0814] Example 197: 4-((5-chloro-7-(2-((3-(2,2-difluoroethyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0815]

[0816] The synthesis method of Example 197 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.80(d,J=4.8Hz,1H),7.80(d,J=2.0Hz,1H),7.57(s,1H),7.51(s,1H),7.50(s, 1H),7.08(d,J=2.0Hz,1H),6.71(d,J=3.2Hz,1H),6.20(tt,J=55.2Hz,4.0Hz,1H),5.71(s,1H),5.25(d, J=15.2Hz,1H),5.16(d,J=15.2Hz,1H),4.21(td,J=14.4Hz,3.6Hz,2H),3.92(d,J=15.2Hz,1H),3.19(d, J=15.2Hz,1H),2.58-2.66(m,2H),2.24-2.32(m,2H),2.20(s,3H),1.25-1.31(m,1H),0.71-0.85(m,3H).

[0817] Example 198: 4-((5-chloro-7-(2-((3-ethyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0818]

[0819] The synthesis method of Example 198 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),8.82(d,J=4.8Hz,1H),7.69(d,J=1.6Hz,1H),7.68(s,1H),7.38(d,J=4.8Hz,1H),7. 37(d,J=3.6Hz,1H),7.08(d,J=1.6Hz,1H),6.66(d,J=3.6Hz,1H),6.22(s,1H),5.41(d,J=14.4Hz,1H),5. 30(d,J=14.4Hz,1H),3.94(q,J=7.2Hz,2H),3.75(d,J=14.8Hz,1H),3.56(d,J=14.8Hz,1H),2.77-2.84(m ,2H),2.60-2.70(m,2H),1.38-1.44(m,1H),1.28(t,J=7.2Hz,3H),0.92-0.99(m,1H),0.75-0.89(m,2H).

[0820] Example 199: 4-((7-(2-((5-bromo-3-(2,2-difluoroethyl)-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-5-chloro-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0821]

[0822] The synthesis method of Example 199 is the same as that of Example 21. 1H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),8.27(s,1H),7.81(d,J=2.0Hz,1H),7.60(s,1H),7 .52(s,1H),7.51(s,1H),7.09(d,J=2.0Hz,1H),6.71(d,J=3.2Hz,1H),6.22(tt,J=55.2Hz,3.2Hz, 1H),5.30(d,J=15.2Hz,1H),5.20(d,J=15.2Hz,1H),4.13-4.23(m,2H),3.93(d,J=14.8Hz,1H),3. 49(d,J=14.8Hz,1H),2.62-2.69(m,2H),2.25-2.35(m,2H),1.26-1.33(m,1H),0.68-0.84(m,3H).

[0823] Example 200: 4-((5-chloro-7-(2-((3-ethyl-4-methoxy-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0824]

[0825] The synthesis method of Example 200 is the same as that of Example 21. 1 H NMR(400MHz,DMSO-d6),8.80(d,J=4.8Hz,1H),7.81(d,J=2.0Hz,1H),7.55(s,1H),7.52(d,J=3.6Hz,1H) ,7.50(d,J=4.8Hz,1H),7.09(d,J=2.0Hz,1H),6.72(d,J=3.2Hz,1H),5.23(d,J=14.4Hz,1H),5.21(s,1H ),5.14(d,J=14.4Hz,1H),3.99(d,J=14.4Hz,1H),3.84(s,3H),3.76(q,J=7.2Hz,2H),3.49(d,J=14.4Hz ,1H),2.72-2.80(m,2H),2.33-2.43(m,2H),1.36-1.44(m,1H),1.04(t,J=7.2Hz,3H),0.80-0.94(m,3H).

[0826] Example 201: 4-((5-chloro-7-(2-((6,8-dioxo-5-(2,2,2-trifluoroethyl)-5,7-diazaspiro[3.4]octan-7-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0827]

[0828] The synthesis method of Example 201 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.82(d,J=4.8Hz,1H),7.81(d,J=1.6Hz,1H),7.57(s,1H),7.50-7.54(m,2H ),7.12(d,J=2.4Hz,1H),6.71(d,J=3.2Hz,1H),4.91(d,J=16.4Hz,1H),4.83(d,J=16.4Hz,1H),4.31 (q,J=9.6Hz,2H),3.93(d,J=14.8Hz,1H),3.50(d,J=14.8Hz,1H),2.50-2.68(m,4H),2.24-2.33(m, 2H),2.14-2.21(m,2H),1.89-1.99(m,1H),1.66-1.76(m,1H),1.24-1.31(m,1H),0.70-0.84(m,3H).

[0829] Example 202: 4-((5-chloro-7-(2-((2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0830]

[0831] Under ice bath, to a solution of tert-butyl-4-((5-chloro-7-(2-(hydroxymethyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)-4-cyanopiperidine-1-carboxylate (0.2 g) and triethylamine (0.1 mL) in dichloromethane (2 mL) was added methanesulfonic anhydride (98 mg). The reaction solution was stirred for 1.5 hours under ice bath. After the reaction was completed, water (15 mL) was added to quench the reaction, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was used directly in the next reaction without further purification. To a solution of the above residue in acetonitrile (3 mL) were added 7-azaindolone (75 mg) and anhydrous cesium carbonate (243 mg). The reaction solution was stirred at 50°C for 2 hours. After the reaction is completed, the reaction solution is cooled to room temperature and poured into water. The obtained aqueous phase is extracted with ethyl acetate (20 mL x 3), and the organic phases are combined. The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue is separated and purified by rapid silica gel column chromatography (dichloromethane:methanol = 100:1 to 20:1) to obtain the title compound (75 mg). The obtained title compound is used to remove the N-tert-butyloxycarbonyl protecting group using trifluoroacetic acid using the method for removing the N-tert-butyloxycarbonyl group in other examples to obtain Example 202 compound (35 mg). 1 H NMR(400MHz, CDCl3),8.78(d,J=4.4Hz,1H),8.14(d,J=4.4Hz,1H),7.64-7.70(m,2H),7 .47(d,J=7.2Hz,1H),7.32-7.38(m,2H),7.06(s,1H),6.93-6.96(m,1H),6.65(d,J=2.8 Hz,1H),5.27(d,J=15.6Hz,1H),5.20(d,J=15.6Hz,1H),3.75(d,J=15.2Hz,1H),3.52-3 .60(m,3H),2.82-2.95(m,2H),2.63-2.74(m,2H),1.39-1.46(m,1H),0.80-1.02(m,3H).

[0832] Example 203: 4-((5-chloro-7-(2-((3-(2-hydroxy-2-methylpropyl)-5-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0833]

[0834] The synthesis method of Example 203 is the same as that of Example 21.1 H NMR(400MHz, DMSO-d6),8.80(d,J=4.8Hz,1H),7.80(d,J=2.4Hz,1H),7.55(s,1H),7.49-7.51(m,2 H),7.43(s,1H),7.08(d,J=1.6Hz,1H),6.71(d,J=3.2Hz,1H),5.29(d,J=15.2Hz,1H),5.20(d,J=1 5.2Hz,1H),4.61-4.72(br,1H),3.95(d,J=14.8Hz,1H),3.61(s,2H),3.48(d,J=14.8Hz,1H),2.69 -2.76(m,2H),2.30-2.40(m,2H),1.75(s,3H),1.34-1.42(m,1H),0.99(s,6H),0.77-0.92(m,3H).

[0835] Example 204: 4-((5-chloro-7-(2-((3-(methyl-d3)-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0836]

[0837] The synthesis method of Example 204 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),8.81(d,J=5.2Hz,1H),7.68-7.70(m,2H),7.36-7.39(m,2H), 7.07(d,J=2.0Hz,1H),6.66(d,J=3.2Hz,1H),6.23(s,1H),5.40(d,J=14.8Hz,1H),5 .31(d,J=14.8Hz,1H),3.74(d,J=15.2Hz,1H),3.56(d,J=15.2Hz,1H),2.77-2.84( m,2H),2.60-2.70(m,2H),1.38-1.44(m,1H),0.93-0.99(m,1H),0.76-0.89(m,2H).

[0838] Example 205: 4-((5-chloro-7-(2-((7-methyl-1,3-dioxohexahydroimidazo[1,5-a]piperazin-2(3H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0839]

[0840] The synthesis method of Example 205 is the same as that of Example 21. 1 H NMR(400MHz, CDCl3),8.85(d,J=4.8Hz,1H),7.70(s,1H),7.56(s,1H),7.44(d,J=2.0Hz ,1H),7.34(d,J=1.6Hz,1H),7.09(s,1H),6.67(d,J=3.2Hz,1H),4.83-5.00(m,2H),3.9 8-4.11(m,3H),3.79(d,J=14.8Hz,1H),3.54(d,J=14.8Hz,1H),2.96-3.18(m,4H),2.68 -2.82(m,3H),2.59(t,J=7.2Hz,1H),2.32(s,3H),1.78-1.98(m,2H),0.76-0.90(m,2H).

[0841] Example 206: 4-((5-chloro-7-(2-((2-(2,2-difluoroethyl)-3,5-dioxo-2,5-dihydro-1,2,4-triazin-4(3H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0842]

[0843] The synthesis method of Example 206 is the same as that of Example 21. 1H NMR (400 MHz, DMSO-d6), 8.82 (d, J = 4.4 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.67 (s, 1H), 7.65 (s, 1H), 7.51-7.53 (m, 2H), 7.09 (d, J = 2.0 Hz, 1H), 6.71 (d, J = 3.2 Hz, 1H), 6.24 (tt, J = 55.2 Hz, 4.0 Hz, 1H), 5.24 (d, J = 15.2Hz,1H),5.13(d,J=15.2Hz,1H),4.23-4.32(m,2H),3.93(d,J=14.8Hz,1H),3.48(d,J =14.8Hz,1H),2.61-2.70(m,2H),2.24-2.34(m,2H),1.26-1.32(m,1H),0.74-0.85(m,3H).

[0844] Example 207: 4-((5-chloro-7-(2-((3,5-dioxo-2-(2,2,2-trifluoroethyl)-2,5-dihydro-1,2,4-triazin-4(3H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0845]

[0846] The synthesis method of Example 207 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.82(d,J=4.4Hz,1H),7.81(d,J=2.0Hz,1H),7.71(s,1H),7.65 (s,1H),7.51-7.53(m,2H),7.08(d,J=2.0Hz,1H),6.71(d,J=3.2Hz,1H),5.25(d,J=15.2 Hz,1H),5.14(d,J=15.2Hz,1H),4.70-4.77(m,2H),3.93(d,J=14.8Hz,1H),3.49(d,J=1 4.8Hz,1H),2.61-2.69(m,2H),2.26-2.35(m,2H),1.26-1.33(m,1H),0.75-0.86(m,3H).

[0847] Example 208: 4-((5-chloro-7-(2-((2-ethyl-3,5-dioxo-2,5-dihydro-1,2,4-triazin-4(3H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0848]

[0849] The synthesis method of Example 208 is the same as that of Example 21. 1H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),7.81(d,J=2.0Hz,1H),7.64(s,1H),7.58(s,1H),7 .52(d,J=2.8Hz,1H),7.51(s,1H),7.09(d,J=2.4Hz,1H),6.71(d,J=3.2Hz,1H),5.23(d,J=15.2Hz ,1H),5.14(d,J=15.2Hz,1H),3.93(d,J=15.2Hz,1H),3.83-3.89(m,2H),3.50(d,J=15.2Hz,1H),2 .60-2.67(m,2H),2.24-2.34(m,2H),1.24-1.30(m,1H),1.16(t,J=7.2Hz,3H),0.74-0.86(m,3H).

[0850] Example 209: 4-((5-chloro-7-(2-((2-isopropyl-3,5-dioxo-2,5-dihydro-1,2,4-triazin-4(3H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0851]

[0852] The synthesis method of Example 209 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),7.81(d,J=2.0Hz,1H),7.64(s,1H),7.62(s,1 H),7.50-7.53(m,2H),7.09(d,J=2.0Hz,1H),6.71(d,J=3.2Hz,1H),5.24(d,J=14.8Hz,1H),5 .13(d,J=14.8Hz,1H),4.70-4.76(m,1H),3.92(d,J=15.2Hz,1H),3.51(d,J=15.2Hz,1H),2. 58-2.66(m,2H),2.22-2.32(m,2H),1.22-1.29(m,1H),1.17-1.19(m,6H),0.72-0.85(m,3H).

[0853] Example 210: 4-((5-chloro-7-(2-((2-(cyclopropylmethyl)-3,5-dioxo-2,5-dihydro-1,2,4-triazin-4(3H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0854]

[0855] The synthesis method of Example 210 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),7.81(d,J=2.0Hz,1H),7.64(s,1H),7.59(s,1H),7.50-7 .53(m,2H),7.09(d,J=2.0Hz,1H),6.71(d,J=3.6Hz,1H),5.25(d,J=15.2Hz,1H),5.15(d,J=15.2Hz,1H ),3.91(d,J=15.2Hz,1H),3.70(d,J=6.8Hz,2H),3.50(d,J=15.2Hz,1H),2.58-2.66(m,2H),2.22-2.32 (m,2H),1.22-1.30(m,1H),1.04-1.14(m,1H),0.72-0.85(m,3H),0.39-0.44(m,2H),0.25-0.29(m,2H).

[0856] Example 211: 4-((5-chloro-7-(2-((4-methoxy-3-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0857]

[0858] The synthesis method of Example 211 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.80(d,J=5.2Hz,1H),7.80(d,J=1.6Hz,1H),7.56(s,1H),7.50-7.52( m,2H),7.08(d,J=1.6Hz,1H),6.71(d,J=3.2Hz,1H),5.23(d,J=15.2Hz,1H),5.20(s,1H),5.14 (d,J=15.2Hz,1H),3.95(d,J=15.2Hz,1H),3.82(s,3H),3.47(d,J=15.2Hz,1H),3.14 (s,3H),2.63-2.71(m,2H),2.26-2.36(m,2H),1.30-1.38(m,1H),0.73-0.86(m,3H).

[0859] Example 212: 4-((5-chloro-7-(2-((4-cyclopropyl-3-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0860]

[0861] The synthesis method of Example 212 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.80(d,J=4.8Hz,1H),7.80(d,J=2.0Hz,1H),7.56(s,1H),7.49-7.51(m ,2H),7.07(d,J=1.6Hz,1H),6.70(d,J=3.2Hz,1H),5.44(s,1H),5.24(d,J=14.8Hz,1H),5.14(d ,J=14.8Hz,1H),3.92(d,J=14.8Hz,1H),3.48(d,J=14.8Hz,1H),3.39(s,3H),2.57-2.65(m,2H) ,2.22-2.32(m,2H),1.81-1.88(m,1H),1.24-1.31(m,1H),0.89-0.94(m,2H),0.70-0.86(m,5H).

[0862] Example 213: 4-((5-chloro-7-(2-((4-methoxy-2,6-dioxo-3-(2,2,2-trifluoroethyl)-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0863]

[0864] The synthesis method of Example 213 is the same as that of Example 21. 1H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),7.81(d,J=2.0Hz,1H),7.56(s,1H),7.52(s,1H), 7.51(d,J=2.4Hz,1H),7.08(d,J=2.0Hz,1H),6.71(d,J=3.6Hz,1H),5.34(s,1H),5.25(d,J=15.2 Hz,1H),5.16(d,J=15.2Hz,1H),4.58(q,J=8.4Hz,2H),3.95(d,J=14.8Hz,1H),3.87(s,3H),3.4 8(d,J=14.8Hz,1H),2.67-2.74(m,2H),2.30-2.39(m,2H),1.37-1.40(m,1H),0.77-0.92(m,3H).

[0865] Example 214: 4-((5-chloro-7-(2-((4-chloro-3-isopropyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0866]

[0867] The synthesis method of Example 214 is the same as that of Example 21. 1 H NMR(400MHz,DMSO-d6),8.81 (d,J=5.2Hz,1H),7.81(d,J=2.0Hz,1H),7.58(s,1H),7.52(d,J=2.4Hz,1H),7.51(s,1H), 7.10(d,J=2.0Hz,1H),6.71(d,J=3.6Hz,1H),6.04(s,1H),5.21(d,J=14.8Hz,1H),5.12(d ,J=14.8Hz,1H),4.80-4.94(m,1H),3.95(d,J=14.8Hz,1H),3.49(d,J=14.8Hz,1H),2.63- 2.70(m,2H),2.26-2.36(m,2H),1.38-1.40(m,6H),1.28-1.34(m,1H),0.75-0.87(m,3H).

[0868] Example 215: 4-((5-chloro-7-(2-((3-isopropyl-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0869]

[0870] The synthesis method of Example 215 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),9.25(s,1H),8.63(d,J=4.4Hz,1H),7.78(d,J=2.4Hz,1H),7.52(d,J=3.6Hz,1H),7.2 5(s,1H),7.18(d,J=4.8Hz,1H),7.09(d,J=2.0Hz,1H),6.74(d,J=3.2Hz,1H),4.94-5.02(m,1H),3.98(d,J=14 .0Hz,1H),3.80(d,J=16.0Hz,1H),3.68(d,J=16.0Hz,1H),3.40(d,J=14.0Hz,1H),3.06-3.14(m,2H),2.58-2. 68(m,3H),1.36-1.44(m,1H),1.25(d,J=6.8Hz,6H),1.02-1.08(m,1H),0.78-0.85(m,1H),0.54-0.64(m,1H).

[0871] Example 216: 4-((5-chloro-7-(2-((4-cyclopropyl-2,6-dioxo-3-(2,2,2-trifluoroethyl)-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0872]

[0873] The synthesis method of Example 216 is the same as that of Example 21. 1H NMR(400MHz, DMSO-d6),8.80(d,J=4.8Hz,1H),7.80(d,J=2.0Hz,1H),7.56(s,1H),7.51(d,J=2.0Hz,1 H),7.50(s,1H),7.08(d,J=2.0Hz,1H),6.70(d,J=3.2Hz,1H),5.57(s,1H),5.26(d,J=14.8Hz,1H),5.1 5(d,J=14.8Hz,1H),4.87(q,J=8.8Hz,2H),3.91(d,J=14.8Hz,1H),3.48(d,J=14.8Hz,1H),2.57-2.66( m,2H),2.22-2.32(m,2H),1.76-1.83(m,1H),1.24-1.29(m,1H),0.96-1.01(m,2H),0.70-0.86(m,5H).

[0874] Example 217: 4-((5-chloro-7-(2-((4-cyclopropyl-3-ethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0875]

[0876] The synthesis method of Example 217 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.80(d,J=4.8Hz,1H),7.80(d,J=2.4Hz,1H),7.55(s,1H),7.49-7.51(m,2H),7. 08(d,J=2.0Hz,1H),6.70(d,J=3.2Hz,1H),5.43(s,1H),5.24(d,J=14.8Hz,1H),5.14(d,J=14.8Hz,1H), 3.99(q,J=7.2Hz,2H),3.92(d,J=14.8Hz,1H),3.50(d,J=14.8Hz,1H),2.57-2.66(m,2H),2.23-2.32(m, 2H), 1.83-1.90 (m, 1H), 1.24-1.30 (m, 1H), 1.14 (t, J = 7.2Hz, 3H), 0.91-0.96 (m, 2H), 0.71-0.84 (m, 5H).

[0877] Example 218: 4-((5-chloro-7-(2-((3,5-dioxo-4-(2,2,2-trifluoroethyl)-4,5-dihydro-1,2,4-triazin-2(3H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0878]

[0879] The synthesis method of Example 218 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.83(d,J=4.4Hz,1H),7.81(d,J=2.0Hz,1H),7.71(s,1H),7.70(s,1H) ,7.54(d,J=4.4Hz,1H),7.51(d,J=3.2Hz,1H),7.10(d,J=2.0Hz,1H),6.71(d,J=3.2Hz,1H),5.4 0(d,J=16.0Hz,1H),5.34(d,J=16.0Hz,1H),4.55(q,J=8.8Hz,2H),3.94(d,J=14.8Hz,1H),3.48 (d,J=14.8Hz,1H),2.60-2.67(m,2H),2.24-2.34(m,2H),1.27-1.32(m,1H),0.73-0.86(m,3H).

[0880] Example 219: 4-((5-chloro-7-(2-((3-(2,2-difluoroethyl)-4-methoxy-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0881]

[0882] The synthesis method of Example 219 is the same as that of Example 21. 1H NMR(400MHz, DMSO-d6),8.81(d,J=4.8Hz,1H),7.81(d,J=2.0Hz,1H),7.56(s,1H),7.50-7.52(m,2H),7.08(d, J=2.0Hz,1H),6.71(d,J=3.6Hz,1H),6.16(tt,J=55.6Hz,4.0Hz,1H),5.29 (s,1H),2.54(d,J=15.2Hz,1H),5.15(d,J=15.2Hz,1H),4.16(td,J=14.4Hz ,4.0Hz,2H),3.97(d,J=14.8Hz,1H),3.85(s,3H),3.48(d,J=14.8Hz,1H),2 .69-2.76(m,2H),2.31-2.40(m,2H),1.35-1.42(m,1H),0.77-0.94(m,3H).

[0883] Example 220: 4-((5-chloro-7-(2-((4-cyclopropyl-3-(2,2-difluoroethyl)-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0884]

[0885] The synthesis method of Example 220 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.80(d,J=4.8Hz,1H),7.80(d,J=2.4Hz,1H),7.57(s,1H),7.51(s,1H),7.50(s,1H),7 .08(d,J=2.0Hz,1H),6.71(d,J=3.2Hz,1H),6.24(tt,J=55.6Hz,4.0Hz,1H),5.54(s,1H),5.24(d,J=14.8Hz,1H ),5.14(d,J=14.8Hz,1H),4.40(td,J=14.0Hz,4.0Hz,2H),3.93(d,J=14.8Hz,1H),3.48(d,J=14.8Hz,1H),2.5 9-2.66(m,2H),2.24-2.33(m,2H),1.76-1.83(m,1H),1.26-1.32(m,1H),0.94-0.98(m,2H),0.72-0.85(m,5H).

[0886] Example 221: 4-((5-chloro-7-(2-((2-(deuterated methyl)-3,5-dioxo-2,5-dihydro-1,2,4-triazin-4(3H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile

[0887]

[0888] The synthesis method of Example 221 is the same as that of Example 21. 1 H NMR(400MHz, DMSO-d6),8.82(d,J=4.8Hz,1H),7.81(d,J=2.0Hz,1H),7.64(s,1H),7.55 (s,1H),7.52(d,J=2.0Hz,1H),7.51(s,1H),7.08(d,J=2.0Hz,1H),6.71(d,J=2.4Hz,1H ),5.23(d,J=15.2Hz,1H),5.13(d,J=15.2Hz,1H),3.94(d,J=15.2Hz,1H),3.48(d,J=15 .2Hz,1H),2.62-2.68(m,2H),2.26-2.34(m,2H),1.26-1.33(m,1H),0.77-0.86(m,3H).

[0889] Biological activity test:

[0890] 1. Determination of compound inhibition of USP7 in vitro enzymatic activity

[0891] In this patent, USP7 enzymatic activity was assayed using a rapid fluorescence assay, using Ubiquitin-Rhodamine 110 as a surrogate substrate. A high-throughput screening platform was optimized and established. Compounds were assayed for their inhibitory activity against USP7 using this platform. The specific method is as follows: Compounds were serially diluted five-fold starting at 1 mM in 100% DMSO (7 concentrations total). 2 μL of each compound was added to 48 μL of reaction buffer (20 mM Tris, pH 8.0, 2 mM CaCl2, 1 mM reduced glutathione, 0.01% (v / v) Triton X-100, 0.01% (w / v) BSA) and mixed thoroughly. 5 μL of the final diluted compound was added to a black 384-well plate (OptiPlate-384, Cat. No. 6007270, purchased from PerkinElmer), followed by the addition of 10 μL of His-USP7 (final concentration 0.05 nM). After the 384-well plate was incubated at 23°C for 30 minutes, 5 μL of the surrogate substrate Ubiquitin-Rhodamine 110 (Cat. No. U-555, purchased from Boston Biochem, final concentration 10 nM) was added to each well and the reaction was continued in a 23°C incubator for 1.5 hours. The reaction was terminated by adding 5 μL of citric acid (Cat. No. 77-92-9, purchased from Sinopharm Group, final concentration 10 mM) to each well. The fluorescence value was read using a BMG Lariostar Microplate Reader (excitation 485 nm / emission 535 nm). The IC value of the compound for inhibition of USP7 enzymatic activity was calculated using GraphPad Prism software. 50 value.

[0892] Table 1. Inhibitory effects of example compounds on USP7

[0893]

[0894]

[0895] 2. Determination of the activity of compounds in inhibiting RS4;11 cell proliferation

[0896] Human acute lymphoblastic leukemia cell line RS4;11 cells were cultured using RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS, purchased from Biological Industries, BI) and 1% penicillin / streptomycin (P / S, purchased from Thermo Fisher Scientific) at 37°C and 5% CO2. RS4;11 cells were plated in a 96-well plate (catalog number #3917, purchased from CORNING) at a concentration of 4000 cells / 195μL / well. After 24 hours, the compound was diluted 3-fold starting from 10mM using 100% DMSO and mixed (a total of 10 concentrations). Then, 4μL of the compound at each concentration was added to 96μL of RPMI-1640 medium for dilution and mixing. 5μL of the diluted compound at each concentration was added to the plated cell suspension, and the compound and cells were incubated in a cell culture incubator for 72 hours (3 days). Then, 35μL of Cell-Titer The reagent (Cat. No. G7570, purchased from Promega) was shaken at room temperature for 5-10 minutes. The chemiluminescence value was read on a BMG Clariostar Microplate Reader, and the data was processed using GraphPad Prism software to calculate the IC value of the compound for cell proliferation inhibition. 50 value.

[0897] Table 2. Inhibitory effects of compounds on RS4;11 cell lines

[0898]

[0899]

[0900] 3. Pharmacokinetic data

[0901] Male SD rats were obtained from Beijing Weitonglihua Experimental Animal Technology Co., Ltd. The rats were divided into groups of 3 in each group and were orally administered a single oral gavage with the test sample suspension (5 mg / kg). The animals were fasted overnight before the experiment, and the fasting period was from 10 hours before administration to 4 hours after administration. Blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. After anesthesia with isoflurane using a small animal anesthesia machine, 0.3 mL of whole blood was collected through the fundus venous plexus and placed in a heparin anticoagulant tube. The sample was centrifuged at 4°C and 4000 rpm for 5 minutes. The plasma was transferred to a centrifuge tube and stored at -80°C until analysis. The sample in the plasma was extracted using protein precipitation, and the extract was analyzed by LC / MS / MS.

[0902]

Claims

1. A compound of formula (II) or a pharmaceutically acceptable salt or isomer thereof, in, The C ring is a 5-membered or 6-membered aromatic ring or non-aromatic ring containing 1-2 N atoms, and the carbon atoms on the C ring may be optionally oxidized (=O) or sulfided (=S). One of Y1, Y2, Y3 and Y4 is CR 30 , the remaining three are each independently selected from N and CR3, R 30 for Ring A and Ring B are aromatic rings. X1 and X2 are each independently selected from CR4 and N, X3 and X4 are each independently selected from C and N, X5 and X6 are each independently selected from N, NR5, O, S and CR6, and X5 and X6 are not CR6 at the same time, L1 and L2 are each independently selected from -(CR 12 R 13 ) n -、-O-、-S-、-NR 10 -、-(CO)-、-(CO)NR 10 -, -(CO)O-, -S(O)2- and -S(O)2NR 10 -, n is 0, 1, 2, 3, or 4, R1 and R3 are each independently selected from H, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR 10 、-NR 10 R 11 、C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl may be optionally substituted with halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR 10 、-NR 10 R 11 、C 3-8 Cycloalkyl, or 3-8 membered heterocycloalkyl substituted, R4 is selected from H, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR 10 、-NR 10 R 11 、C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl may be optionally substituted with halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR 10 、-NR 10 R 11 、C 3-8 Cycloalkyl, or 3-8 membered heterocycloalkyl substituted, R5 is selected from H, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl may be optionally substituted with halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR 10 、-NR 10 R 11 、C 3-8 Cycloalkyl, or 3-8 membered heterocycloalkyl substituted, R6 is selected from H, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR 10 、-NR 10 R 11 、C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl may be optionally substituted with halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR 10 、-NR 10 R 11 、C 3-8 Cycloalkyl, or 3-8 membered heterocycloalkyl substituted, R2 is a 3-12 membered cycloalkyl or a 3-12 membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl may be optionally substituted by (=O), halogen, -CN, -OR 10 、-NR 10 R 11 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR 10 、-NR 10 R 11 、C 3-8 The alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl optionally substituted on the cycloalkyl and heterocycloalkyl groups may be optionally substituted with halogen, -CN, -OR 10 、-NR 10 R 11 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR 10 、-NR 10 R 11 、C 3-8 Cycloalkyl, or 3-8 membered heterocycloalkyl substituted, R7 is a 5-12 membered heteroaryl, a 3-12 membered cycloalkyl or a 3-12 membered heterocycloalkyl, and may be optionally replaced by R 40 The cycloalkyl and heterocycloalkyl groups may be optionally fused with 5-10 membered aryl or 5-12 membered heteroaryl groups, and the aryl or heteroaryl groups fused with the cycloalkyl or heterocycloalkyl groups may be optionally fused with R 40 replace, R 40 Selected from (=O), halogen, -CN, -OR 10 、-NR 10 R 11 、-NR 10 (COR 11 ), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 6-10 membered aryl, 5-12 membered heteroaryl, C 3-8 Cycloalkyl, or 3-8 membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl may be optionally substituted with (=O), halogen, -CN, -OR 10 、-NH-(CO)-C 1-6 Alkyl, -NH-Cbz, -NR 10 R 11 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR 10 、-NR 10 R 11 、C 3-8 Cycloalkyl, or 3-8 membered heterocycloalkyl substituted, R 10 and R 11 Each independently selected from H, C 1-6 Alkyl and C 3-8 Cycloalkyl, R 12 and R 13 are each independently selected from H, halogen and C 1-6 alkyl, p is 0, 1, or 2.

2. A compound of formula (II) or a pharmaceutically acceptable salt or isomer thereof, in, The C ring is a 5-membered or 6-membered aromatic ring or non-aromatic ring containing O or S. The carbon atoms on the C ring may be optionally oxidized (=O) or sulfidized (=S). Other groups are as defined in claim 1.

3. The compound according to claim 1 or a pharmaceutically acceptable salt or isomer thereof, wherein R 40 Selected from (=O), halogen, -CN, -OR 10 、-NR 10 R 11 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, or 3-8 membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl may be optionally substituted by halogen, -CN, -OR 10 、-NR 10 R 11 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR 10 、-NR 10 R 11 、C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl.

4. A compound of formula (I) or a pharmaceutically acceptable salt or isomer thereof, which has the structure of formula (I), in, Ring A and Ring B are aromatic rings. The C ring is a 5-membered or 6-membered aromatic ring or non-aromatic ring containing 1-2 N atoms, and the carbon atoms on the C ring may be optionally oxidized (=O) or sulfided (=S). X1 and X2 are each independently selected from CR4 and N, X3 and X4 are each independently selected from C and N, X5 and X6 are each independently selected from N, NR5, O, S and CR6, and X5 and X6 are not CR6 at the same time, Y2, Y3 and Y4 are each independently selected from N and CR3, L1 and L2 are each independently -(CR 12 R 13 ) n -, n is 0, 1, 2, 3, or 4, R1 and R3 are each independently selected from H, halogen, -CN, C 1-6 Alkyl, -OR 10 、-NR 10 R 11 、C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl, R4 is selected from H, halogen and C 1-6 alkyl, R5 is selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl, R6 is selected from H, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl, R2 is a 3-12 membered cycloalkyl or a 3-12 membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl may be optionally substituted by (=O), halogen, -CN, -OR 10 、-NR 10 R 11 , or C 1-6 Alkyl substituted, said alkyl group may be optionally substituted with halogen, -CN, -OR 10 , or -NR 10 R 11 replace, R7 is a 3-12 membered cycloalkyl or a 3-12 membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl may be optionally substituted by (=O), halogen, or C 1-6 Alkyl substituted, said alkyl group may be optionally substituted with halogen, -CN, -OR 10 , or -NR 10 R 11 replace, R 10 and R 11 Each independently selected from H, C 1-6 Alkyl and C 3-8 Cycloalkyl, R 12 and R 13 are each independently selected from H, halogen and C 1-6 alkyl, p is 0, 1, or 2.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or an isomer thereof, wherein n is 1 or 2, R 12 and R 13 is hydrogen, and R4 is H.

6. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or an isomer thereof, wherein X5 is CR6, X6 is S, and R6 is selected from H, halogen, and C 1-6 alkyl.

7. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or an isomer thereof, wherein R7 is a 3-12 membered heterocycloalkyl group, which may be optionally substituted with (=O), or C 1-6 Alkyl substitution.

8. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or an isomer thereof, wherein Y2, Y3 and Y4 are each independently selected from CR3, and R3 are each independently selected from H, halogen and C 1-6 alkyl.

9. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or an isomer thereof, wherein R 10 and R 11 Each independently selected from H and C 1-6 alkyl.

10. The following compound or its pharmaceutically acceptable salt or isomer, 11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt or isomer thereof, and optionally comprising a pharmaceutically acceptable carrier.

12. Use of the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt or isomer thereof, or the pharmaceutical composition according to claim 11 in the preparation of a medicament for treating a disease associated with USP7 activity.

13. The use according to claim 12, wherein the disease associated with USP7 activity is ovarian cancer, breast cancer, lung cancer, pancreatic cancer, kidney cancer, melanoma, liver cancer, colon cancer, sarcoma, brain cancer, prostate cancer, leukemia, lymphoma, or multiple myeloma.

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