USP7 inhibitors

Abstract

This application relates to the USP7 inhibitor shown in formula (I), its preparation method, and its therapeutic use in tumor diseases. During the preparation process, the compound of this invention is obtained through a series of reactions including substitution, coupling, reduction, and deprotection.

Description

Technical Field

[0001] This application relates to a USP7 inhibitor, its preparation method, and its therapeutic use in oncological diseases. Background Technology

[0002] Post-translational modifications (PTMs) are 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 intracellular proteolytic mechanisms and regulates many intracellular physical activities. The process of adding ubiquitin to a substrate protein 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 with the participation of adenosine triphosphate (ATP) and transferred to E2 via trans-thiolation, then binds to the lysine or α-amino group of the substrate protein in the presence of E3. Finally, protein markers with four or more ubiquitin molecules can be recognized and affected by the 26S proteasome, where they are degraded to produce small polypeptides.

[0003] Deubiquitinating enzymes (DUBS) are responsible for removing ubiquitin and maintaining substrate stability by degrading ubiquitin. To date, approximately 100 DUBs have been identified, which can be divided into five subclasses based on their Ub protease domains: ubiquitin-specific proteases (USPS), ubiquitin C-terminal hydrolases (UCHs), ovarian tumor proteases (OTUS), cysteine-dependent proteases such as Machado-Joseph disease proteases (MJDS), and zinc metalloproteinases such as JAB1 / MPN / Mov34 (JAMMS).

[0004] With nearly 50 members, the USPS family is the largest of all DUB subfamilies. These members all include conserved domains, namely the three main functional domains of the Cys, His, and Asp / Asn boxes, which are responsible for the recombination of ubiquitin-binding molecules.

[0005] 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 immediate early protein (Vmw110) of herpes simplex virus type 1. Later, USP7 was found to interact with other viral proteins, such as Epstein-Barr nuclear antigen 1 (EBNA1) of Epstein-Barr virus (EBV) and vIRF1 (viral interferon regulatory factor 1) protein of Kaposi's sarcoma-associated herpesvirus (KSHV), thus indicating that it is a universal target of herpesviruses, and it was named 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 the patient's immune response to tumors.

[0006] USP7 is highly expressed in a variety of cancers and influences disease progression. Furthermore, USP7 plays different roles in different tumors. In prostate cancer, high USP7 expression is directly associated with tumor invasiveness. In non-small cell lung cancer (NSCLC), USP7 plays a crucial role in carcinogenesis via a p53-dependent pathway. Studies have shown that in vivo changes in USP7 regulate the growth and apoptosis sensitivity of colon cancer. USP7 maintains DNA damage responses and promotes cervical cancer, and is positively correlated with low survival rates in cervical cancer patients. USP7 regulates terminal differentiation of human erythroid cells by stabilizing GATA1, providing some therapeutic potential for leukemia. In short, USP7 plays an important role in multiple pathological processes and is a promising target from a therapeutic perspective.

[0007] USP7 plays a vital role in cellular pathways regulating viral proteins, immune responses, oncogenes, and DNA damage, and is anomalously expressed in various cancers, making it a promising target. However, due to the lack of protein co-crystal structures between USP7 and small molecule inhibitors, effective selective USP7 inhibitors have remained elusive for a long time. In recent years, several small molecule USP7 inhibitors and their crystal structures with USP7 have been published, providing guidance for obtaining structure-based small molecule inhibitors. While some small molecule USP7 inhibitors have been reported in recent years, their in vivo efficacy data has been unsatisfactory, preventing them from entering clinical trials. Therefore, the development of USP7 inhibitors with good in vivo activity is urgently needed for the treatment of cancer patients with anomalous USP7 expression.

[0008] The compound described in this invention is a USP7 deubiquitinase inhibitor with independent intellectual property rights. It can selectively inhibit USP7 deubiquitinase, aiming to safely and effectively treat tumor patients with abnormal USP7 expression. Summary of the Invention

[0009] In one aspect, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts, solvates, polymorphs, or isomers thereof.

[0010]

[0011] in,

[0012] One of Y1, Y2, Y3, Y4, and Y5 is CR30, and the remaining four are independently selected from N and CR3.

[0013] R 30 for

[0014] Rings A and B are aromatic rings.

[0015] X1 and X2 are each independently selected from CR4 and N.

[0016] X3 and X4 are each independently selected from C or N.

[0017] X5 and X6 are each independently selected from N, NR5, O, S, and CR6, and X5 and X6 are not both CR6.

[0018] L is selected from -(CR) 12 R 13 ) n -、-O-、-S-、-NR 10 -、-(CO)-、-(CO)NR 10 -, -(CO)O-, -S(O)2- and -S(O)2NR 10 -,

[0019] n is 0, 1, 2, 3, or 4.

[0020] R9 is selected from H, halogens, -CN, and C. 1-6 Alkyl groups, which may optionally be substituted with halogens,

[0021] R1 and R2 are each independently selected from H, halogen, -CN, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OR 10 -NR 10 R 11 C 3-8Cycloalkyl and 3-8 membered heterocyclic alkyl groups, wherein the alkyl, alkenyl, ynyl, cycloalkyl and heterocyclic alkyl groups may optionally be converted by halogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OR 10 -NR 10 R 11 C 3-8 Cycloalkyl, or 3-8 membered heterocyclic alkyl substitution, or

[0022] R1 and R2 can be connected together to form C. 3-12 Cycloalkyl or 3-12-membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl may optionally be R 50 replace,

[0023] R 50 Selected from halogens, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OR 10 -NR 10 R 11 C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups, wherein the alkyl, alkenyl, ynyl, cycloalkyl and heterocyclic alkyl groups may optionally be converted by halogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OR 10 -NR 10 R 11 C 3-8 Cycloalkyl or 3-8 membered heterocyclic alkyl substitution,

[0024] R3 is selected from H, halogens, -CN, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OR 10 -NR 10 R 11 C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups, wherein the alkyl, alkenyl, ynyl, cycloalkyl and heterocyclic alkyl groups may optionally be converted by halogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OR 10 -NR 10 R 11 C 3-8 Cycloalkyl or 3-8 membered heterocyclic alkyl substitution,

[0025] R4 groups are independently selected from H, halogens, -CN, and C. 1-6Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OR 10 -NR 10 R 11 C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups, wherein the alkyl, alkenyl, ynyl, cycloalkyl and heterocyclic alkyl groups may optionally be converted by halogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OR 10 -NR 10 R 11 C 3-8 Cycloalkyl or 3-8 membered heterocyclic alkyl substitution,

[0026] R5 is independently selected from H, -CN, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups, wherein the alkyl, alkenyl, ynyl, cycloalkyl and heterocyclic alkyl groups may optionally be converted by halogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OR 10 -NR 10 R 11 C 3-8 Cycloalkyl or 3-8 membered heterocyclic alkyl substitution,

[0027] R6 is selected from H, halogens, -CN, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OR 10 -NR 10 R 11 C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups, wherein the alkyl, alkenyl, ynyl, cycloalkyl and heterocyclic alkyl groups may optionally be converted by halogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OR 10 -NR 10 R 11 C 3-8 Cycloalkyl or 3-8 membered heterocyclic alkyl substitution,

[0028] R7 is a 5-12-membered heteroaryl, 3-12-membered cycloalkyl, or 3-12-membered heterocycloalkyl, and may optionally be R 40The cycloalkyl and heterocycloalkyl groups may optionally be fused with 5-10 aryl or 5-12 heteroaryl groups, and the aryl or heteroaryl group fused with the cycloalkyl or heterocycloalkyl group may optionally be R 40 replace,

[0029] 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 group, C 3-8 Cycloalkyl, or 3-8 membered heterocycloalkyl, wherein the alkyl, alkenyl, ynyl, cycloalkyl, or heterocycloalkyl group may optionally be halogenated, -CN, or -OR. 10 -NR 10 R 11 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OR 10 -NR 10 R 11 C 3-8 Cycloalkyl or 3-8 membered heterocyclic alkyl substitution,

[0030] R 10 and R 11 Each is independently selected from H and C. 1-6 Alkyl and C 3-8 cycloalkyl,

[0031] R 12 and R 13 Each is independently selected from H, halogens, and C. 1-6 alkyl;

[0032] In another aspect, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts, solvates, polymorphs, or isomers thereof.

[0033]

[0034] in,

[0035] Rings A and B are aromatic rings.

[0036] L stands for -(CH2) n -,

[0037] n is 1, 2, 3, or 4.

[0038] X1 and X2 are each independently selected from CR4 and N.

[0039] X3 and X4 are each independently selected from C or N.

[0040] X5 and X6 are each independently selected from N, NR5, O, S, and CR6, and X5 and X6 are not both CR6.

[0041] Y1, Y2, Y3, and Y4 are each independently selected from N and CR3.

[0042] R9 is selected from H, halogens, -CN, and C. 1-6 Alkyl groups, which may optionally be substituted with halogens,

[0043] R1 and R2 are each independently selected from H and C. 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic alkyl groups, wherein the alkyl, cycloalkyl, and heterocyclic alkyl groups may optionally be converted by halogen, -CN, -OR. 10 -NR 10 R 11 Or C 1-6 Alkyl substitution, or

[0044] R1 and R2 can be connected together to form C. 3-12 Cycloalkyl or 3-12-membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl may optionally be converted by halogen, -CN, -OR 10 -NR 10 R 11 Or C 1-6 Alkyl substitution, wherein the alkyl group may optionally be substituted with a halogen.

[0045] R3 is independently selected from H, halogen, C. 1-6 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups, wherein the alkyl, cycloalkyl, and heterocyclic alkyl groups may optionally be converted to halogen, -CN, -OR 10 -NR 10 R 11 Or C 1-6 Alkyl substitution,

[0046] R4 is independently selected from H, halogens, and C. 1-6 Alkyl groups, which may optionally be halogenated, -CN, or -OR 10 , or -NR 10 R 11 replace,

[0047] R5 is selected from H and C. 1-6 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups,

[0048] R6 is selected from H, halogens, and C. 1-6 Alkyl, C3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups,

[0049] R7 is a 3-12 membered cycloalkyl or a 3-12 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl may optionally be (=O) or C. 1-6 Alkyl substitution, wherein the alkyl group may optionally be halogenated, -CN, or -OR. 10 , or -NR 10 R 11 ,replace,

[0050] R 10 and R 11 Each is independently selected from H and C. 1-6 Alkyl and C 3-8 cycloalkyl;

[0051] In some implementations, n is 1 or 2, preferably 1;

[0052] In some implementations, X1 is CR4 and X2 is N, or X2 is CR4 and X1 is N, wherein...

[0053] R4 is selected from H, halogens, and C. 1-6 Alkyl groups, which may optionally be halogenated, -CN, or -OR 10 , or -NR 10 R 11 Replace, R 10 and R 11 Each is independently selected from H and C. 1-6 Alkyl and C 3-8 Cycloalkyl, preferably, R4 is H;

[0054] In some implementations, X5 is NR5, O, or S, and X6 is CR6, or X6 is NR5, O, or S, and X5 is CR6, wherein...

[0055] R5 is selected from H and C. 1-6 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups, preferably H and C 1-6 Alkyl, more preferably H,

[0056] R6 is selected from H, halogens, and C. 1-6 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups, preferably H and C 1-6 Alkyl, more preferably H;

[0057] In some embodiments, R7 is a 3-12 membered cycloalkyl or a 3-12 membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl may optionally be converted to (=O) or C. 1-6 Alkyl substitution;

[0058] In some implementations, R7 is

[0059] In some implementations, R3 is independently selected from H, halogens, and C. 1-6 alkyl;

[0060] In some implementations, R9 is selected from H and C. 1-6 Alkyl group, wherein the alkyl group may optionally be substituted with a halogen;

[0061] In some implementations, R9 is H;

[0062] In some embodiments, Y1, Y2, Y3, and Y4 are each independently selected from CR3, and R3 is each independently selected from H, halogen, and C. 1-6 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups;

[0063] In some embodiments, Y1, Y2, Y3, and Y4 are each independently selected from CR3, and R3 is each independently selected from H, halogens, and C. 1-6 alkyl;

[0064] In some embodiments, the compound of formula (I) is a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof.

[0065]

[0066]

[0067]

[0068]

[0069] 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.

[0070] In another aspect, the present invention provides a method for treating diseases associated with USP7 activity, the method comprising administering to a subject an effective amount of the 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 diseases associated with USP7 activity are 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;

[0071] In some embodiments of the present invention, the object of the present invention is a mammal including humans;

[0072] In another aspect, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts, solvates, polymorphs or isomers thereof, or pharmaceutical compositions of the present invention, in the preparation of medicaments for treating diseases associated with USP7 activity; in some embodiments, the diseases associated with USP7 activity are 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. Invention Details

[0073] Exemplary embodiments utilizing the principles of the invention are set forth in the following detailed description of the invention. The features and advantages of the invention can be better understood by referring to the following summary of the invention.

[0074] It should be understood that the scope of protection of each aspect of the present invention is determined by the claims, and the methods and structures within the scope of these claims, as well as their equivalents, are all within the scope of these claims.

[0075] Unless otherwise defined, all technical terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains. Unless otherwise stated, all patents, patent applications, and publications cited in this document are incorporated herein in their entirety through reference.

[0076] It should be understood that the above summary and the following detailed description are exemplary and explanatory, and not intended to limit any subject matter of the invention. Unless otherwise specified, the singular form includes the plural form. Unless otherwise specified, the use of "or" or "or" means "and / or". Furthermore, the use of the term "comprising" and other forms such as "including," "containing," and "containing" are not limiting.

[0077] Some chemical terms

[0078] The terms “optional,” “optional,” or “optionally” mean that the event or condition described below may or may not occur, including both the occurrence and non-occurrence of the event or condition. For example, “optionally substituted alkyl” means “unsubstituted alkyl” or “substituted alkyl.” Furthermore, the optionally substituted group can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or any level between monosubstituted and fully substituted (e.g., -CH2CHF2, -CF2CH3, -CFHCHF2, etc.). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution mode that is spatially impossible and / or cannot be synthesized is introduced.

[0079] Unless otherwise stated, conventional methods within the scope of the art, such as mass spectrometry, nuclear magnetic resonance, high-performance liquid chromatography, infrared and ultraviolet / visible spectroscopy, and pharmacological methods, are employed. Unless specifically defined herein, the terminology, experimental procedures, and techniques used herein in analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and patient treatment. For example, reactions and purifications can be carried out using the manufacturer's instructions for use of reagent kits, or in accordance with methods known in the art or the description of this invention. The techniques and methods described herein are generally carried out according to conventional methods well known in the art, based on descriptions in several summary and more specific documents cited and discussed herein. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0080] When a substituent is described using a conventional chemical formula written from left to right, it also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0081] As used in this article, the terms "group" and "chemical group" refer to a specific part or functional group of a molecule. Chemical groups are often considered as chemical entities that are embedded in or attached to a molecule.

[0082] Some chemical groups named herein may be indicated by abbreviations to represent the total number of carbon atoms. For example, C1-C6 alkyl describes an alkyl group having a total of 1 to 6 carbon atoms, as defined below. The total number of carbon atoms indicated by the abbreviations does not include carbon atoms on possible substituents.

[0083] The compounds of the present invention may contain one or more (e.g., one, two, three, or four) isotopic substitutions. For example, in said compounds, H may be any isotopic form, including 1 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 and O can be any isotopic form, including 16 O and 18 O etc.

[0084] The terms “halogen,” “halogenated,” or “halogenated” refer to bromine, chlorine, fluorine, or iodine.

[0085] As used herein, the terms "aromatic," "aromatic ring," "aromatic," "aromatic," and "aromatic ring" refer to a planar ring or ring portion of one or more rings having a delocalized electronic conjugated system containing 4n+2 electrons, where n is an integer. An aromatic ring can be formed from 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 carbocyclic rings (such as benzene rings) and rings containing one or more heteroatoms (such as pyridine).

[0086] The term "heteroatom" or "heteroatom" as used herein, alone or as part of other components, refers to an atom other than carbon and hydrogen. Heteroatoms are independently selected from, but not limited to, oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may be identical to each other, or some or all of the two or more heteroatoms may be different from each other.

[0087] The term “dense” or “dense ring” as used alone or in combination in this article refers to a ring structure in which two or more rings share one or more bonds.

[0088] The term “spiral” or “spiral ring” as used alone or in combination in this article refers to a ring structure in which two or more rings share one or more atoms.

[0089] The term "alkyl" as used hereby, either alone or as part of other components (e.g., monoalkylamino), refers to a monovalent saturated hydrocarbon with optional substituted straight or optional substituted branched chains having 1-12 carbon atoms, preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms, and connected to other parts of the molecule by single bonds, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, n-nonyl, n-decyl, etc.

[0090] The term "alkenyl" as used alone or in combination herein refers to a monovalent hydrocarbon group of optional substituted straight or optional substituted branched form, 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 may be in cis or trans conformations 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. When alkenyl as defined herein appears in numerical ranges, for example, "C2-C6 alkenyl" or "C 2-6 "Alkenyl" refers to an alkenyl group that can be composed of 2, 3, 4, 5, or 6 carbon atoms. In this article, alkenyl also includes cases where no numerical range is specified.

[0091] The term "alkynyl" as used alone or in combination herein refers to an optionally substituted straight-chain or branched monovalent hydrocarbon group having one or more C≡C triple bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1,3-butadiynyl. When alkynyl as defined herein appears in a numerical range, such as "C2-C6 alkynyl" or "C 2-6 "Alynyl" refers to an alkynyl group that can be composed of 2, 3, 4, 5, or 6 carbon atoms. In this article, alkynyl also includes cases where no numerical range is specified.

[0092] The term "aryl" refers to a fully carbon monocyclic or fused ring having a fully conjugated π-electron system, having 6-14 carbon atoms, preferably 6-12 carbon atoms, and most preferably 6 carbon atoms. The aryl group 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 heterocyclic groups. Non-limiting examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl, and anthraceneyl.

[0093] The term "heteroaryl" refers to a monocyclic or fused ring with 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, and S, and the remaining ring atoms are C, and possessing a fully conjugated π-electron system. Heteroaryl groups can be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxyl, cyano, nitro, carbonyl, and heterocyclic groups. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrole, furanyl, thiophene, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, and triazineyl.

[0094] The term "cycloalkyl" as used herein, alone or as part of other components, refers to a stable, monovalent, non-aromatic monocyclic or polycyclic hydrocarbon group containing only carbon and hydrogen atoms. It may include fused ring, spirocyclic, or bridged ring systems, containing 3-15 cyclic carbon atoms, preferably 3-10 cyclic carbon atoms, more preferably 3-8 cyclic carbon atoms, and may be saturated or unsaturated, linked to other parts of the molecule by single bonds. Non-limiting examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0095] As used alone or as part of other components herein, the terms "heterocyclic group," "heterocyclic alkyl group," and "heterocycle" refer to a stable 3-18 member monovalent non-aromatic ring comprising 2-12 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise stated, the heterocyclic group can be a monocyclic, bicyclic, tricyclic, or tetracyclic system, which may contain fused, spirocyclic, or bridged ring systems. The nitrogen, carbon, or sulfur on the heterocyclic group may be selectively oxidized, the nitrogen atom may be selectively quaternized, and the heterocyclic group may be partially or completely saturated. The heterocyclic group can be connected to the rest of the molecule by a single bond via a carbon atom or heteroatom on the ring. The heterocyclic group containing the fused ring may contain one or more aromatic rings or heteroaromatic rings, as long as the atoms attached to the rest of the molecule are atoms on non-aromatic rings. For the purposes of this application, the heterocyclic group is preferably a stable 4-11 valent non-aromatic monocyclic or bicyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, and more preferably a stable 4-8 valent non-aromatic monocyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclic groups include azirheptanyl, azirheptanyl, decahydroisoquinolinyl, dihydrofuranyl, dihydroindolyl, dioxopentyl, 1,1-dioxo-thiomorpholinyl, imidazolinyl, imidazolinyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piperazinyl, piperidinyl, 4-piperidinoneyl, pyranyl, pyrazolyl, pyrrolidinyl, quinazinyl, quininecycloyl, tetrahydrofuranyl, tetrahydropyranyl, etc.

[0096] The term "polymorph" or "polymorphism" as used in this invention refers to the fact that the compounds of this invention have multiple crystal lattice forms. Some compounds of this invention may have more than one crystal form, and this invention covers all polymorphs or mixtures thereof.

[0097] Intermediate compounds and polymorphs of the compounds of this invention are also within the scope of this invention.

[0098] Unless otherwise specified, the olefin double bonds contained in the compounds of this invention include E and Z isomers.

[0099] It should be understood that the compounds of the present invention may contain asymmetric centers. These asymmetric centers may independently be R or S configurations. Some compounds of the present invention may also exhibit cis-trans isomerism, which will be 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, as well as mixtures thereof, including racemic mixtures. These isomers can be isolated from mixtures thereof by implementing or modifying known methods, such as chromatography and recrystallization techniques, or they can be prepared separately from suitable isomers of their intermediates.

[0100] The term “pharmaceutically acceptable salt” as used in this article includes both salts with added acid salts and salts with added alkali salts.

[0101] "Pharmaceutically acceptable salts" refer to salts that retain the biological potency and properties of the free base of a compound, are not biologically or otherwise undesirable, and are formed with inorganic acids, such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids, such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, decanoic acid, hexanoic acid, carbonic acid, cinnamic acid, citric acid, etc. "Pharmaceutically acceptable base salts" refer to salts that retain the biological potency and properties of the free acid of a compound, and are not biologically or otherwise undesirable. These salts are prepared by reacting a free acid with an inorganic or organic base. Salts formed by reacting with an inorganic base include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, etc. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts, and manganese salts.

[0102] Organic bases that form salts include, but are not limited to, primary amines, secondary amines, tertiary amines, and cyclic amines, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purines, piperazine, piperidine, choline, and caffeine. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0103] Crystallization often produces solvates of the compounds of this invention. As used herein, the term "solvate" refers to a combination of one or more molecules of the compounds of this invention and one or more solvent molecules.

[0104] The solvent can be water, in which case the solvate is a hydrate. Alternatively, it can be an organic solvent. Therefore, the compounds of this invention can exist as hydrates, including monohydrates, dihydrates, hemihydrates, trihydrates, tetrahydrates, etc., and the corresponding solvated forms. The compounds of this invention can be true solvates, but in other cases, they may simply retain water or a mixture of water and some other solvents by chance. The compounds of this invention can react in a solvent or precipitate or crystallize in a solvent. The solvates of the compounds of this invention are also included within the scope of this invention.

[0105] As used herein, the term "pharmaceutical composition" refers to a formulation containing the compounds of the present invention and a medium generally accepted in the art for delivering biologically active compounds to mammals, such as humans. This medium includes all pharmaceutically acceptable carriers.

[0106] As used in this article, the term "acceptable" in relation to formulations, compositions, or ingredients means that it does not have a lasting harmful effect on the overall health of the treated subject.

[0107] As used herein, the term "pharmaceutically acceptable" means 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, i.e., that the substance can be administered to an individual without causing an adverse biological reaction or interacting adversely with any component contained in the composition.

[0108] "Pharmaceutically acceptable carriers" include, but are not limited to, adjuvants, carriers, excipients, auxiliaries, deodorants, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants and wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the relevant government administrative departments for use in humans and domesticated animals.

[0109] As used herein, the terms “subject,” “patient,” “object,” or “individual” refer to an individual suffering from a disease, disorder, or symptom, including both 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, and pigs; domesticated animals such as rabbits, dogs, and cats; and 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.

[0110] The term "treatment" as used in this article refers to the treatment of relevant diseases or conditions in mammals, particularly humans, including...

[0111] (i) To prevent mammals, especially those previously exposed to a disease or condition but not yet diagnosed with it, from developing the corresponding disease or condition.

[0112] (ii) To suppress a disease or symptom, that is, to control its development;

[0113] (iii) To alleviate the disease or symptom, that is, to make the disease or symptom subside;

[0114] (iv) Relieve symptoms caused by disease or illness.

[0115] The terms “disease” and “symptom” used in this article can be used interchangeably or have different meanings, because some specific diseases or symptoms do not yet have known causative factors (so the cause of the disease is still unclear), so they cannot be recognized as diseases but can only be regarded as unwanted conditions or syndromes. These syndromes have more or less some specific symptoms that have been confirmed by clinical researchers.

[0116] As used herein, the terms "effective amount," "therapeutic effective amount," or "pharmaceutical effective amount" refer to an amount of at least one drug or compound that, when taken, is sufficient to alleviate, to some extent, one or more symptoms of the disease or condition being treated. The result may be a reduction and / or relief of signs, symptoms, or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition containing the compounds disclosed herein that is clinically necessary to provide significant symptom relief. Effective amounts suitable for any individual case can be determined using techniques such as dose escalation testing.

[0117] As used herein, the terms “administration,” “application,” “dosage,” etc., refer to methods that deliver a compound or composition to the desired site for biological action. These methods include, but are not limited to, oral administration, duodenal administration, parenteral administration (including intravenous, subcutaneous, intraperitoneal, intramuscular, intra-arterial injection or infusion), local administration, and rectal administration. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.

[0118] Preparation of the compounds of the present invention

[0119] It should be understood that, in the following description, the combination of substituents and / or variables of the molecular formula is permitted only in the case of forming a stable compound.

[0120] Those skilled in the art will also understand that the functional groups of intermediate compounds may need to be protected by suitable protecting groups. Protecting groups can be added or removed using standard techniques known to those skilled in the art.

[0121]

[0122] Example 1: Synthesis of 3-((7-(2-((4-aminocyclohexene)methyl)-5-chloro-3-methylphenyl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

[0123] Step 1: Synthesis of Compound 3

[0124] At 0°C, DIAD (9.14 g) was added dropwise to a THF (150 mL) solution of compound 1 (6.00 g), compound 2 (6.29 g), and triphenylphosphine (11.84 g). The reaction mixture was then brought to room temperature and stirred overnight. The reaction mixture was concentrated under vacuum, and the resulting residue was dissolved in ethyl acetate (500 mL). The residue was washed with 5% Na₂CO₃ aqueous solution (100 mL × 3) and saturated brine (100 mL × 3), respectively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 100:1–100:2) to give a pale yellow solid 3 (11.7 g).

[0125] Step 2: Synthesis of Compound 5

[0126] Under nitrogen protection, 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 step without further purification.

[0127] Step 3: Synthesis of Compound 7

[0128] At 0°C, an aqueous solution of NaNO2 (8.26 g) (40 mL) was slowly added dropwise to a mixture of compound 6 (24 g) and 3M sulfuric acid (80 mL). The reaction mixture was stirred at 0°C for 30 minutes. Subsequently, an aqueous solution of KI (21.7 g) (80 mL) was slowly added dropwise at the same temperature. After the addition was complete, the reaction mixture was heated to room temperature and stirred overnight. Dichloromethane (100 mL) was added to the reaction mixture, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (100 mL × 2), and the organic phases were combined. The obtained organic phase was washed with saturated NaHCO3 aqueous solution (100 mL), saturated sodium thiosulfate aqueous solution (100 mL), and saturated brine (100 mL), respectively. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (petroleum ether as the mobile phase) to obtain a white solid compound 7 (28 g).

[0129] Step 4: Synthesis of Compound 10

[0130] At -78°C, a solution of n-butyllithium (1.1 mL, 2.82 mmol) was slowly added dropwise to a solution of 2,2,6,6-tetramethylpiperidine (400 mg) in tetrahydrofuran (10 mL). The reaction mixture was allowed to react at this temperature for 30 minutes, followed by the addition of a solution of compound 9 (628 mg) in tetrahydrofuran (5 mL). The reaction mixture was allowed to react at -78°C for 30 minutes, followed by the addition of a solution of compound 8 (500 mg) in tetrahydrofuran (2 mL). The temperature of the reaction mixture was then slowly raised to room temperature and stirred overnight. The reaction was quenched by adding a saturated aqueous solution of ammonium chloride (20 mL). The organic solvent was removed by concentration under reduced pressure, and ethyl acetate / water (50 mL / 50 mL) was added to separate the organic phase. The aqueous phase was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain compound 10 (143 mg).

[0131] Step 5: Synthesis of Compound 11

[0132] Under nitrogen protection, a mixture of compound 10 (143 mg), compound 7 (140 mg), tetraphenylphosphine palladium (46 mg), and anhydrous sodium carbonate (89 mg) in dioxane / water (4 mL / 1 mL) was heated to 80 °C and stirred overnight. After cooling to room temperature, 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 = 20:1) to obtain compound 11 (87 mg).

[0133] Step 6: Synthesis of Compound 12

[0134] Under nitrogen protection, a mixture of compound 11 (87 mg), compound 5 (132 mg), tetraphenylphosphine palladium (23 mg), and anhydrous sodium carbonate (45 mg) in dioxane / water (4 mL / 1 mL) was heated to 80 °C and stirred overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by rapid silica gel column chromatography (dichloromethane:ethyl acetate = 5:1) to obtain compound 12 (85 mg).

[0135] Step 7: Synthesis of Compound 13

[0136] Trifluoroacetic acid (0.2 mL) was added dropwise to a dichloromethane (2 mL) solution of compound 12 (85 mg), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and diluted with dichloromethane (30 mL). The resulting organic phase was washed with saturated sodium carbonate aqueous solution (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 20:1 to 10:1) to obtain compound 13 (65 mg). 1 H NMR(400MHz, CDCl3), 8.50-8.66(m, 1H), 7.70-8.24(br, 3H), 7.44-7.59(m, 1H), 7.30(s, 1H), 7.21(s, 1H), 6.94-7.18(m, 1H), 5.90-6.02(m, 1H) ), 4.69-4.85(m, 2H), 2.96-3.10(m, 1H), 2.32-2.43(m, 2H), 2.12-2.28( m, 5H), 1.85-2.10 (m, 4H), 1.52-1.80 (m, 2H), 1.21 (s, 3H), 1.10 (s, 3H).

[0137] Example 2: 3-((7-(5-chloro-3-methyl-2-((E)-2-((R)-pyrrolo-2-yl)vinyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

[0138]

[0139] Step 1: Synthesis of Compound 15

[0140] Borane dimethyl sulfide (2M, 64 mL) was slowly added dropwise to a tetrahydrofuran (200 mL) solution of compound 14 (18.8 g) at 0 °C. The reaction mixture was then heated to 50 °C overnight. The reaction mixture was cooled to 0 °C and quenched by slow dropwise addition of methanol. The reaction mixture was concentrated, and the residue was purified by rapid silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 3:1) to give compound 15 (16.2 g).

[0141] Step 2: Synthesis of Compound 16

[0142] PBr3 (37.2 g) was added to a 200 mL solution of compound 15 (16.2 g) in dichloromethane at 0 °C. The reaction mixture was then heated to room temperature and stirred overnight. The reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution, the organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by rapid silica gel column chromatography (petroleum ether:ethyl acetate = 100:1) to give compound 16 (21.3 g).

[0143] Step 3: Synthesis of Compound 17

[0144] Triethyl phosphite (15 mL) was added to compound 16 (4.4 g), and the reaction mixture was heated to 160 °C by microwave and reacted overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by rapid silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 to 1:1) to give a colorless oily compound 17 (5.0 g).

[0145] Step 4: Synthesis of Compound 19

[0146] At 0 °C, LiHMDS (1 M, 0.26 mL) was slowly added dropwise to a tetrahydrofuran (0.75 mL) solution of compound 17 (70 mg). The resulting reaction mixture was stirred at this temperature for 30 minutes, followed by the addition of a tetrahydrofuran (0.25 mL) solution of compound 18 (50 mg). After the addition was complete, the temperature of the reaction mixture was slowly raised to room temperature and stirred overnight. The reaction was quenched with a saturated ammonium chloride aqueous solution (0.1 mL). The mixture was concentrated under reduced pressure, and ethyl acetate / water (20 mL / 20 mL) was added. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 50:1) to give compound 19 (30 mg).

[0147] Step 6: Synthesis of Compound 20

[0148] Under nitrogen protection, a mixture of compound 19 (30 mg), compound 5 (41 mg), tetraphenylphosphine palladium (8 mg), and anhydrous sodium carbonate (14 mg) in dioxane / water (2 mL / 0.5 mL) was heated to 80 °C and stirred overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by rapid silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 2:1) to obtain compound 20 (35 mg).

[0149] Step 7: Synthesis of Compound 21

[0150] Trifluoroacetic acid (0.2 mL) was added dropwise to a solution of compound 20 (35 mg) in dichloromethane (2 mL), 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 purified by rapid silica gel column chromatography (dichloromethane:methanol = 20:1 to 10:1) to obtain compound 21 (21 mg). 1 H NMR (400MHz, CDCl3), 8.78-10.04 (br, 2H), 8.60 (s, 1H), 7.50 (s, 1H), 7.24 (s, 1H), 7.15 (s, 1H), 7.09 (s, 1H), 6.50 (d, J=15.6Hz, 1H), 5.20 -5.38 (m, 1H), 4.76 (s, 2H), 3.66-3.78 (m, 1H), 2.97-3.09 (m, 2H), 2.35 (s, 2H), 2.27 (s, 3H), 1.34-1.82 (m, 4H), 1.21 (s, 3H), 1.09 (s, 3H).

[0151] Example 3: 3-((7-(5-chloro-3-methyl-2-(pyrrolidine-3-ylenylmethyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

[0152]

[0153] The synthesis method of Example 3 is the same as that of Example 1. 1 H NMR(400MHz, CDCl3), 8.62-8.71(m, 1H), 7.46-7.58(m, 1H), 7.31-7.35(m, 1H), 7.18-7.20( m, 0.5H), 7.14-7.16 (m, 0.5H), 6.97-7.05 (m, 1H), 6.21-6.28 (m, 1H), 4.78 (s, 2H), 3.57-3. 68 (m, 1H), 3.37-3.46 (m, 1H), 3.12-3.24 (m, 2H), 2.45-2.53 (m, 1H), 2.36-2.39 (m, 2H), 2.2 8(s, 3H), 2.15-2.23(m, 1H), 1.23(s, 1.5H), 1.22(s, 1.5H), 1.12(s, 1.5H), 1.10(s, 1.5H).

[0154] Example 4: 3-((7-(3,5-dichloro-2-(piperidin-4-ylenylmethyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0155]

[0156] The synthesis method of Example 4 is the same as that of Example 1. 1 H NMR (400MHz, CD3OD), 8.66 (s, 1H), 7.70 (d, J=2.0Hz, 1H), 7.46-7.50 (m, 2H), 7.29 (d, J=4.4Hz, 1H), 6. 22 (s, 1H), 4.83 (s, 2H), 2.60-3.14 (m, 4H), 2.49 (s, 2H), 1.76-2.45 (m, 5H), 1.22 (s, 3H), 1.08 (s, 3H).

[0157] Example 5: 3-((7-(5-chloro-3-fluoro-2-(piperidin-4-ylenylmethyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0158]

[0159] The synthesis method of Example 5 is the same as that of Example 1. 1 H NMR12 (400MHz, CD3OD), 8.67 (d, J=4.8Hz, 1H), 7.49 (s, 1H), 7.45 (dd, J=10.0Hz, 2.0Hz, 1H), 7.35 (d, J=2.0Hz, 1H), 7.29 (d, J=4.8Hz, 1H), 5. 97(s, 1H), 4.83(s, 2H), 2.97-3.01(m, 2H), 2.89-2.93(m, 2H), 2.49(s , 2H), 2.33-2.37(m, 2H), 2.22-2.25(m, 2H), 1.23(s, 3H), 1.08(s, 3H).

[0160] Example 6: 3-((7-(2-((8-azabicyclo[3.2.1]oct-3-ylene)methyl)-5-chloro-3-methylphenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0161]

[0162] The synthesis method of Example 6 is the same as that of Example 1. 1H NMR(400MHz, CDCl3), 9.28-9.62(br, 2H), 8.64(s, 1H), 7.55(s, 1H), 7.30(s, 1H), 7.21(s, 1H), 7.04(s, 1H), 6.24(s, 1H ), 4.77(s, 2H), 3.74-4.13(m, 2H), 2.88-3.02(m, 1H), 2.42-2.56(m, 1H), 2.37-1.50(m, 11H), 1.22(s, 3H), 1.10(s, 3H).

[0163] Example 7: 3-((7-(5-chloro-3-methyl-2-(1-(piperidin-4-ylenyl)ethyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0164]

[0165] The synthesis method of Example 7 is the same as that of Example 1. 1 H NMR (400MHz, DMSO-d6), 8.60 (d, J=4.8Hz, 1H), 7.48 (s, 2H), 7.33 (s, 1H), 7.06 (d, J=5.2Hz, 1H), 4.70-4.79 (m, 2H), 2.70-2.80 (m, 1H), 2.56 (s, 2H), 2.46-2.55 (m, 2H), 2.10-2.24 (m, 4H), 1.91-2.05 (m, 2H), 1.71-1.81 (m, 1H), 1.40-1.67 (m, 4H), 1.13 (s, 3H), 0.95 (s, 3H).

[0166] Example 8: 3-((7-(5-chloro-3-methyl-2-((tetrahydro-4H-pyran-4-ylene)methyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0167]

[0168] The synthesis method of Example 8 is the same as that of Example 1. 1H NMR (400MHz, CDCl3), 8.62 (d, J=5.2Hz, 1H), 7.53 (s, 1H), 7.29 (d, J=2.0Hz, 1H), 7.20-7.23 (m, 1H), 7.01 (d, J=5.2Hz, 1H), 5.96 (s, 1H), 4.7 9(s, 2H), 3.02-3.64(m, 3H), 2.52-2.88(m, 1H), 2.35(s, 2H), 2.26(s, 3H), 1.87-2.20(m, 3H), 1.70-1.84(m, 1H), 1.21(s, 3H), 1.08(s, 3H).

[0169] Example 9: 3-((7-(5-chloro-3-methyl-2-((E)-2-((S)-pyrrolidine-2-yl)vinyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

[0170]

[0171] The synthesis method of Example 9 is the same as that of Example 2. 1 H NMR (400MHz, CDCl3), 9.20-9.66 (br, 1H), 8.54-8.94 (m, 2H), 7.65 (s, 1H), 7. 26 (d, J=1.2Hz, 1H), 7.21 (d, J=4.4Hz, 1H), 7.16 (d, J=2.0Hz, 1H), 6.54 (d, J=1 6.4Hz, 1H), 5.34-5.52(m, 1H), 4.78(s, 2H), 3.83-3.92(m, 1H), 3.05-3.24(m , 2H), 2.38(s, 2H), 2.34(s, 3H), 1.48-1.82(m, 4H), 1.22(s, 3H), 1.12(s, 3H).

[0172] Example 10: 3-((7-(5-chloro-2-(piperidin-4-ylenylmethyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0173]

[0174] The synthesis method of Example 10 is the same as that of Example 1. 1H NMR (400MHz, CDCl3), 8.69 (d, J=4.8Hz, 1H), 7.53 (s, 1H), 7.42 (dd, J=8.0Hz, 2.0Hz, 1H), 7.33 (d, J=2.4Hz, 1H), 7.19 (d, J=8.4Hz, 1H), 7.05 (d, J=4.8Hz, 1H), 5.96 (s, 1H), 4.78 (s, 2H), 3.09-3.13 (m, 2H), 2.98-3.03 ( m, 2H), 2.63-2.68 (m, 2H), 2.34-2.39 (m, 5H), 1.20 (s, 3H), 1.09 (s, 3H).

[0175] Example 11: 3-((7-(5-chloro-3-methyl-2-(piperidinyl-4-ylenylmethyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0176]

[0177] The synthesis method of Example 11 is the same as that of Example 1. 1 H NMR (400MHz, CDCl3), 8.63 (d, J=4.8Hz, 1H), 7.52 (s, 1H), 7.30 (d, J=1.6Hz, 1H), 7.18 (d, J=1.6Hz, 1H), 6.97 (d, J=4.8 Hz, 1H), 6.07 (s, 1H), 4.78 (s, 2H), 2.6-3.18 (m, 2H), 2.32-2.62 (m, 4H), 1.78-2.30 (m, 7H), 1.21 (s, 3H), 1.10 (s, 3H).

[0178] Example 12: 3-((7-(5-chloro-2-(fluoro(piperidin-4-ylenylmethyl)methyl)-3-methylphenyl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0179]

[0180] The synthesis method of Example 12 is the same as that of Example 1. 1H NMR (400MHz, CDCl3), 8.65 (d, J=4.4Hz, 1H), 7.55-7.59 (m, 1H), 7.35-7.41 (m, 2H), 7.08-7.13 (m, 1H), 4.79 (s, 2H), 3.11-3.20 (m, 1H), 2.71-2 .80(m,1H),2.44-2.63(m,2H),2.41(s,2H),2.34(s,3H),2.09-2.28(m , 2H), 1.96-2.05(m, 1H), 1.56-1.72(m, 1H), 1.23(s, 3H), 1.13(s, 3H).

[0181] Example 13: 3-((7-(5-chloro-3-methyl-2-((E)-2-((S)-pyrrolidine-3-yl)vinyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

[0182]

[0183] The synthesis method of Example 13 is the same as that of Example 2. 1 H NMR (400MHz, CDCl3), 8.76-9.50 (br, 2H), 8.71 (d, J=4.8Hz, 1H), 7.62 (s, 1H), 7.26 (d, J=2.0Hz, 1H), 7.17 (d, J=4.8Hz, 1H), 7.14 (d, J=2.0Hz, 1H), 6.32 (d, J=16.0Hz, 1H), 5. 00(dd, J=16.0Hz, 8.0Hz, 1H), 4.79(s, 2H), 2.99-3.28(m, 3H), 2.65-2.77(m, 1H), 2.38 (s, 2H), 2.31 (s, 3H), 2.08-2.28 (m, 1H), 1.52-1.78 (m, 2H), 1.21 (s, 3H), 1.09 (s, 3H).

[0184] Example 14: (E)-3-((7-(2-(3-amino-3-methylbut-1-en-1-yl)-5-chloro-3-methylphenyl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0185]

[0186] The synthesis method of Example 14 is the same as that of Example 2. 1H NMR (400MHz, CDCl3), 8.65 (d, J=5.2Hz, 1H), 7.53 (s, 1H), 7.21 (d, J=2.0Hz, 1H), 7.18 (d, J=2.0Hz, 1H), 7.11 (d, J=5.2Hz, 1H), 6.41 (d, J=16.4Hz, 1H), 5.24 (d, J=16.4Hz, 1H), 4.78 (s, 2H), 2.35 (s, 2H), 2.27 (s, 3H), 1.24 (s, 6H), 1.21 (s, 3H), 1.09 (s, 3H).

[0187] Example 15: 3-((7-(5-chloro-3-methyl-2-((E)-2-((R)-morpholin-3-yl)vinyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0188]

[0189] The synthesis method of Example 15 is the same as that of Example 2. 1 H NMR (400MHz, CDCl3), 8.68 (d, J=5.2Hz, 1H), 7.54 (s, 1H), 7.25 (d, J=1.6Hz, 1H), 7.15 (d, J=1.6Hz, 1H), 7.11 (d, J=4.4Hz, 1H), 6.53 (d, J=16.8Hz, 1H), 5.26 (dd, J=16.8Hz, 6 .8Hz, 1H), 4.78 (s, 2H), 3.64-3.73 (m, 1H), 3.44-3.54 (m, 1H), 3.28-3.39 (m, 1H), 2.98 -3.24 (m, 1H), 2.74-2.95 (m, 3H), 2.37 (s, 2H), 2.35 (s, 3H), 1.22 (s, 3H), 1.11 (s, 3H).

[0190] Example 16: 3-((7-(5-chloro-3-methyl-2-((E)-2-((R)-pyrrolidine-3-yl)vinyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

[0191]

[0192] The synthesis method of Example 16 is the same as that of Example 2. 1H NMR (400MHz, CDCl3), 8.82-9.44 (br, 2H), 8.74 (d, J=4.8Hz, 1H), 7.68 (s, 1H), 7.28 (d, J=1.6Hz, 1H), 7.19 (d, J=4.8Hz, 1H), 7.16 (d, J=1.6Hz, 1H), 6.33 (d, J=16.0Hz, 1H), 4. 99(dd, J=16.0Hz, 8.0Hz, 1H), 4.80(s, 2H), 2.95-3.33(m, 3H), 2.66-2.78(m, 1H), 2.39 (s, 2H), 2.32 (s, 3H), 2.06-2.28 (m, 1H), 1.52-1.80 (m, 2H), 1.22 (s, 3H), 1.11 (s, 3H).

[0193] Example 17: 3-((7-(2-(azacyclobut-3-ylenylmethyl)-5-chloro-3-methylphenyl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

[0194]

[0195] The synthesis method of Example 17 is the same as that of Example 1. 1 H NMR (400MHz, DMSO-d6), 8.72-9.22 (br, 2H), 8.69 (d, J=4.8Hz, 1H), 7.48-7.53 (m, 2H), 7.33 (d, J=2.0Hz, 1H), 7.27 (d, J =4.8Hz, 1H), 6.31 (s, 1H), 4.76 (s, 2H), 4.30 (s, 2H), 3.73 (s, 2H), 2.56 (s, 2H), 2.31 (s, 3H), 1.13 (s, 3H), 0.97 (s, 3H).

[0196] Example 18: (z)-3-((7-(5-chloro-3-methyl-2-(piperidin-3-ylenylmethyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

[0197]

[0198] The synthesis method of Example 18 is the same as that of Example 1. 1H NMR (400MHz, DMSO-d6), 8.63 (d, J=4.8Hz, 1H), 8.04-8.62 (br, 2H), 7.51 (s, 1H), 7.4 6(s, 1H), 7.34(s, 1H), 7.22-7.31(m, 1H), 6.23(s, 1H), 4.74(s, 2H), 3.05-3.21(m, 1H ), 2.89-3.04(m, 1H), 2.70-2.86(m, 1H), 2.57(s, 2H), 2.42-2.55(m, 1H), 2.30(s, 3H) , 2.10-2.25(m, 1H), 1.68-1.85(m, 1H), 1.52-1.66(m, 2H), 1.15(s, 3H), 1.01(s, 3H).

[0199] Example 19: 3-((7-(5-chloro-2-((4-(dimethylamino)cyclohexenyl)methyl)-3-methylphenyl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0200]

[0201] The synthesis method of Example 19 is the same as that of Example 1. 1 H NMR (400MHz, CD3OD), 8.66 (d, J=4.8Hz, 1H), 7.50 (s, 1H), 7.41 (s, 1H), 7.38 (s, 1H), 7.32 (d, J=4.8Hz, 1H), 6.17 (s, 1H), 4.88 (s, 2H), 3.04-3 .14(m, 1H), 2.65-2.78(m, 2H), 2.51(s, 6H), 2.29-2.38(m, 2H), 2.24(s , 3H), 1.80-2.15(m, 4H), 1.52-1.65(m, 2H), 1.14(s, 3H), 1.08(s, 3H).

[0202] Example 20: 3-((7-(5-chloro-3-methyl-2-((2,2,6,6-tetramethylpiperidin-4-ene)methyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0203]

[0204] The synthesis method of Example 20 is the same as that of Example 1. 1H NMR (400MHz, CDCl3), 8.65 (d, J=4.8Hz, 1H), 7.59 (s, 1H), 7.31 (s, 1H), 7.18-7.26 (m, 1H), 7.03 (d, J=4.8Hz, 1H), 6.32 (s, 1H), 4.77 (s, 2H), 2.36(s, 2H), 2.26(s, 3H), 1.88-2.06(m, 3H), 1.37-1.86(m, 7H), 1.27-1.36(m, 3H), 1.21(s, 3H), 1.10(s, 3H), 0.98-1.09(m, 3H).

[0205] Example 21: 3-((7-(5-chloro-3-methyl-2-((E)-2-((S)-piperidin-2-yl)vinyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

[0206]

[0207] The synthesis method of Example 21 is the same as that of Example 2. 1 H NMR (400MHz, DMSO-d6), 8.65 (d, J=4.8Hz, 1H), 7.62-8.42 (br, 2H), 7.49 (d, J=2.0Hz, 1H), 7.47 (s, 1H), 7.30 (d, J=2.0Hz, 1H), 7.22-7.29 (m, 1H), 6.48 (d, J=16.4Hz, 1H), 5.13 (dd, J=16.4Hz, 8 .0Hz, 1H), 4.73 (s, 2H), 3.32-3.42 (m, 1H), 2.93-3.02 (m, 1H), 2.63-2.73 (m, 1H), 2.56 (s, 2H), 2 .35(s, 3H), 1.49-1.58(m, 1H), 1.36-1.45(m, 1H), 1.17-1.32(m, 4H), 1.15(s, 3H), 1.02(s, 3H).

[0208] Example 22: 3-((7-(5-chloro-3-methyl-2-((E)-2-((S)-morpholin-3-yl)vinyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0209]

[0210] The synthesis method of Example 22 is the same as that of Example 2. 1H NMR (400MHz, DMSO-d6), 8.63 (d, J=5.2Hz, 1H), 7.47 (s, 1H), 7.43 (d, J=2.0Hz, 1H), 7.2 2-7.24 (m, 2H), 6.37 (d, J=16.0Hz, 1H), 4.97 (dd, J=16.0Hz, 6.8Hz, 1H), 4.73 (s, 2H), 3 .42-3.49(m, 1H), 3.20-3.28(m, 1H), 2.99-3.09(m, 1H), 2.90-2.97(m, 1H), 2.62-2.82 (br, 1H), 2.50-2.58 (m, 4H), 2.31 (s, 3H), 2.12-2.21 (m, 1H), 1.14 (s, 3H), 0.99 (s, 3H).

[0211] Example 23: 3-((4-(5-chloro-3-methyl-2-(piperidin-4-ylenylmethyl)phenyl)thiopheno[2,3-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

[0212]

[0213] The synthesis method of Example 23 is the same as that of Example 1. 1 H NMR (400MHz, DMSO-d6), 8.54 (s, 1H), 7.90-8.40 (br, 2H), 7.48 (d, J=2.0Hz, 1H), 7.13-7.42 (m, 2H), 6.86-7.12 (m, 1H), 6.14 (s, 1H), 4.72 (s, 2H), 2 .82-3.02(m,1H),2.60-2.74(m,1H),2.56(s,2H),2.25(s,3H),2.01-2.2 2(m, 2H), 1.54-1.92(m, 3H), 1.32-1.50(m, 1H), 1.15(s, 3H), 1.01(s, 3H).

[0214] Example 24: (E)-3-((7-(5-chloro-3-methyl-2-(pyrrolidine-2-ylenylmethyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0215]

[0216] The synthesis method of Example 24 is the same as that of Example 1. 1H NMR (400MHz, DMSO-d6), 8.70 (d, J=4.4Hz, 1H), 7.55 (d, J=1.6Hz, 1H), 7.50 (s, 1H), 7.40 (d, J=2.0Hz, 1H), 7.35 (d, J=5.2Hz, 1H), 6.90-7.30 (br, 1H), 4.76 (s, 2H), 2.57 (s, 2H), 2.50 (t, J=7.6Hz, 2H), 2.43 (s, 3H), 2.26 (t, J=6.8Hz, 2H), 1.40-1.47 (m, 2H), 1.14 (s, 3H), 1.01 (s, 3H).

[0217] Example 25: 3-((7-(5-chloro-3-methyl-2-((4-(methylamino)cyclohexenyl)methyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

[0218]

[0219]

[0220] Step 1: Synthesis of Compound 22

[0221] Sodium hydride (10 mg) was added to a 2 mL solution of 100 mg of compound 12 in tetrahydrofuran at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes, followed by the slow addition of iodomethane (92 mg). The reaction mixture was then heated to room temperature and the reaction was continued for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 100:1 to 100:3) to obtain compound 22 (65 mg).

[0222] Step 2: Synthesis of Compound 23

[0223] At room temperature, trifluoroacetic acid (0.3 mL) was added to a solution of compound 22 (65 mg) in dichloromethane (3 mL). The reaction mixture was stirred at room temperature for 2 hours until the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 100:1 to 10:1) to obtain compound 23 (25 mg). 1H NMR (400MHz, DMSO-d6), 8.58-8.69 (m, 1H), 8.22-8.50 (br, 2H), 7.44-7.50 (m, 2H), 7.33 (s, 1H), 7.11-7.23 (m, 1H), 5.87-6.03 (m, 1H ), 4.75 (s, 2H), 2.81-2.92 (m, 1H), 2.57 (s, 2H), 2.08-2.53 (m, 10H), 1.76-1.90 (m, 2H), 1.40-1.58 (m, 2H), 1.14 (s, 3H), 0.99 (s, 3H).

[0224] Example 26: 3-((7-(5-chloro-3-methyl-2-(piperidin-4-ylenylmethyl)phenyl)thieno[3,2-b]pyridin-2-yl)methyl)thiazolidin-2,4-dione trifluoroacetate)

[0225]

[0226] Step 1: Synthesis of Compound 25

[0227] At room temperature, TBSCl (11.32 g) was added to a 100 mL solution of compound 24 (5.0 g) and imidazole (10.23 g) in dichloromethane. The reaction mixture was reacted at room temperature for 2 hours, and then concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 200:1 to 100:1) to give compound 25 (7.5 g).

[0228] Step 2: Synthesis of Compound 26

[0229] Under nitrogen protection, a solution of compound 25 (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 step without further purification.

[0230] Step 3: Synthesis of Compound 28

[0231] Under nitrogen protection, a mixture of compound 26 (300 mg), compound 27 (320 mg), tetraphenylphosphine palladium (90 mg), and anhydrous sodium carbonate (190 mg) in dioxane / water (8 mL / 2 mL) was heated to 80 °C and stirred overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 100:1 to 100:3) to obtain compound 28 (200 mg).

[0232] Step 4: Synthesis of Compound 29

[0233] At room temperature, TBAF (100 mg) was added to a tetrahydrofuran (3 mL) solution of compound 28 (150 mg). The reaction mixture was stirred overnight at room temperature until the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 100:1 to 100:3) to obtain compound 29 (124 mg).

[0234] Step 5: Synthesis of Compound 31

[0235] At 0 °C, DIAD (103 mg) was added dropwise to a 2 mL solution of anhydrous tetrahydrofuran containing compound 29 (124 mg), compound 30 (60 mg), and triphenylphosphine (134 mg). The reaction mixture was then heated to room temperature and stirred overnight. After the reaction was complete, the reaction mixture was concentrated. The resulting residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 200:1 to 100:1) to obtain compound 31 (110 mg).

[0236] Step 6: Synthesis of Compound 32

[0237] At room temperature, 0.5 mL of trifluoroacetic acid was added to a 5 mL solution of compound 31 (110 mg) in dichloromethane. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 100:1 to 10:1) to obtain compound 32 (43 mg). 1 H NMR (400MHz, DMSO-d6), 8.50-8.78 (m, 3H), 7.52 (s, 1H), 7.49 (d, J=2.0Hz, 1H), 7.36 (s, 1H), 7.22 (d, J=4.4Hz, 1H), 6.15 (s, 1H), 4.95 ( s, 2H), 4.27 (s, 2H), 2.86-3.06 (m, 1H), 2.60-2.78 (m, 1H), 2.36-2.53 (m, 1H), 2.15-2.32 (m, 4H), 1.77-2.10 (m, 3H), 1.44-1.66 (m, 1H).

[0238] Example 27: (E)-3-((7-(2-(2-(1-aminocyclopropyl)vinyl)-5-chloro-3-methylphenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0239]

[0240] The synthesis method of Example 27 is the same as that of Example 2. 1 H NMR (400MHz, CD3OD), 8.62 (d, J=4.4Hz, 1H), 7.47 (s, 1H), 7.39 (d, J=1.6Hz, 1H), 7.27 (d, J=4.8Hz, 1H), 7.22 (d, J=2.0Hz, 1H), 6.4 4 (d, J=16.4Hz, 1H), 5.11 (d, J=16.4Hz, 1H), 4.81 (s, 2H), 2.48 (s, 2H), 2.40 (s, 3H), 1.22 (s, 3H), 1.08 (s, 3H), 0.78-0.91 (m, 4H).

[0241] Example 28: 3-((4-(5-chloro-3-methyl-2-(piperidin-4-ylenylmethyl)phenyl)-7-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-6-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0242]

[0243] Step 1: Synthesis of Compound 34

[0244] SEMCl (1.7 g) was added to a DMF (5 mL) solution of compound 33 (1 g) and cesium carbonate (3.1 g) at room temperature. The reaction mixture was stirred overnight at room temperature until the reaction was complete. Subsequently, the reaction mixture was poured into water (30 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give compound 34 (1.2 g).

[0245] Step 2: Synthesis of Compound 35

[0246] At -78°C, a 2.5 M hexane solution of n-butyllithium (1.75 mL) was added dropwise to an anhydrous tetrahydrofuran (30 mL) solution of compound 34 (1 g). After the addition was complete, the reaction mixture was stirred at this temperature for 30 minutes. Then, anhydrous DMF (0.9 mL) was added dropwise to slowly raise the temperature to -20°C, and the reaction was continued at this temperature for 4 hours. After the reaction was completed, a saturated ammonium chloride solution (50 mL) was added to quench the reaction. The tetrahydrofuran was removed by concentration under reduced pressure. The resulting solution was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to rapid silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give compound 35 (670 mg).

[0247] Step 3: Synthesis of Compound 36

[0248] Sodium borohydride (104 mg) was added in portions to a methanol (20 mL) solution of compound 35 (670 mg) at 0 °C, and the reaction mixture was then heated to room temperature. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. Water (40 mL) was added to the residue, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to rapid silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give compound 36 (430 mg).

[0249] Step 4: Synthesis of Compound 37

[0250] At 0°C, DIAD (590 mg) was added dropwise to a tetrahydrofuran (10 mL) solution of compound 36 (430 mg), compound 2 (406 mg), and PPh3 (766 mg), and then the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 4:1) to obtain compound 37 (530 mg).

[0251] Step 5: Synthesis of Compound 38

[0252] At room temperature, TBAF (480 mg) was added to a tetrahydrofuran (10 mL) solution of compound 37 (510 mg), and the reaction mixture was heated to 45 °C and reacted overnight. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 100:1 to 20:1) to obtain compound 39 (230 mg).

[0253] Step 6: Synthesis of Compound 39

[0254] At 0°C, trifluoromethanesulfonic anhydride (0.2 mL) was added to a solution of compound 39 (230 mg), triethylamine (0.4 mL), and dichloromethane (5 mL). The reaction mixture was allowed to react for 6 hours at room temperature. After the reaction was complete, the mixture was poured into ice water (30 mL) and extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give compound 39 (110 mg).

[0255] Step 7: Synthesis of Compound 40

[0256] Phosphorus oxychloride (40 μL) was slowly added dropwise to a DMF (2 mL) solution of compound 39 (110 mg) at 0 °C. After the addition was complete, the reaction solution was heated to room temperature and the reaction was continued for 6 hours. After the reaction was completed, the reaction solution was poured into ice water (15 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give compound 40 (80 mg).

[0257] Step 8: Synthesis of Compound 41

[0258] Sodium borohydride (11 mg) was added in portions to a methanol (2 mL) solution of compound 40 (80 mg) at 0 °C, and the reaction mixture was then heated to room temperature. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. Water (10 mL) was added to the residue, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to rapid silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give compound 36 (43 mg).

[0259] Step 9: Synthesis of Compound 42

[0260] Under nitrogen protection, a mixture of compound 41 (43 mg), compound 42 (50 mg), tetraphenylphosphine palladium (11 mg), and anhydrous sodium carbonate (20 mg) in dioxane / water (1 mL / 0.2 mL) was heated to 80 °C and stirred overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 20:1 to 5:1) to obtain compound 42 (5.3 mg). 1 H NMR (400MHz, CDCl3), 8.13 (d, J=4.4Hz, 1H), 7.29 (s, 1H), 7.17 (s, 1H), 6.33 (d, J=4.4Hz, 1H), 6. 16 (s, 1H), 6.08 (s, 1H), 5.14 (s, 2H), 4.66 (s, 2H), 1.84-3.34 (m, 13H), 1.19 (s, 3H), 1.05 (s, 3H).

[0261] Example 29: (E)-3-((7-(2-(2-(3-azabicyclo[3.1.0]hexane-6-yl)vinyl)-5-chloro-3-methylphenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

[0262]

[0263] The synthesis method of Example 29 is the same as that of Example 2. 1 H NMR (400MHz, CDCl3), 8.84-10.28 (br, 2H), 8.62 (d, J=4.4Hz, 1H), 7.50 (s, 1H), 7.24 (d, J=2.0Hz, 1H), 7.12 (d, J=2.0Hz, 1H), 7.04 (d, J=4.8Hz, 1H), 6.21 (d, J=16.0Hz, 1H), 4.7 8 (s, 2H), 4.64 (dd, J=16.0Hz, 7.6Hz, 1H), 3.31 (d, J=11.6Hz, 2H), 3.17-3.23 (m, 2H), 2. 38(s, 2H), 2.30(s, 3H), 1.56-1.60(m, 1H), 1.22(s, 3H), 1.11(s, 3H), 1.02-1.10(m, 2H).

[0264] Example 30: 3-((7-(5-chloro-3-methoxy-2-(piperidin-4-ylenylmethyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

[0265]

[0266] The synthesis method of Example 30 is the same as that of Example 1. 1 H NMR (400MHz, DMSO-d6), 8.56-8.80 (m, 3H), 7.48 (s, 1H), 7.26 (d, J = 2.0Hz, 1H), 7.24 (d, J = 5.2Hz, 1H), 7.10 (d, J = 2.0Hz, 1 H), 5.94 (s, 1H), 4.76 (s, 2H), 3.84 (s, 3H), 3.05-3.09 (m, 4H), 2.57 (s, 2H), 2.39-2.42 (m, 4H), 1.14 (s, 3H), 0.99 (s, 3H).

[0267] Example 31: 3-((4-(5-chloro-3-methyl-2-(piperidin-4-ylenylmethyl)phenyl)thiopheno[2,3-d]pyrimidin-6-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione hydrochloride

[0268]

[0269] The synthesis method of Example 31 is the same as that of Example 1.1 H NMR (400MHz, DMSO-d6), 9.11 (s, 1H), 8.62-8.88 (br, 1H), 8.18-8.37 (br, 1H), 7.55 (d, J = 2.0Hz, 1H), 7.42 (d, J = 2.4Hz, 1H), 7.13 (s, 1H), 6.23 (s, 1H) , 4.77(s, 2H), 2.82-2.99(m, 1H), 2.60-2.74(m, 1H), 2.58(s, 2H), 2.14-2. 34(m, 5H), 1.73-1.99(m, 3H), 1.23-1.39(m, 1H), 1.16(s, 3H), 1.03(s, 3H).

[0270] Example 32: 3-((4-(5-chloro-3-methyl-2-(piperidin-4-ylenylmethyl)phenyl)thiopheno[3,2-d]pyrimidin-6-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione hydrochloride

[0271]

[0272] The synthesis method of Example 32 is the same as that of Example 1. 1 H NMR (400MHz, DMSO-d6), 9.20 (s, 1H), 8.70-8.92 (m, 1H), 8.26-8.46 (m, 1H), 7. 58 (s, 1H), 7.56 (d, J = 2.0Hz, 1H), 7.46 (d, J = 2.0Hz, 1H), 6.21 (s, 1H), 4.83 (s, 2 H), 2.83-3.01(m, 1H), 2.61-2.73(m, 1H), 2.59(s, 2H), 2.37-2.53(m, 1H), 2.19 -2.34(m, 4H), 1.77-2.18(m, 3H), 1.35-1.53(m, 1H), 1.15(s, 3H), 1.02(s, 3H).

[0273] Example 33: 3-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)-5-methyl-4-(piperidin-4-ylenylmethyl)benzamide

[0274]

[0275] The synthesis method of Example 33 is the same as that of Example 1. 1H NMR (400MHz, DMSO-d6), 8.66 (d, J=4.8Hz, 1H), 7.99 (s, 1H), 7.92 (s, 1H), 7.82 (s, 1H), 7.47 (s, 1H), 7.41 (s, 1H), 7.21 (d, J=4.4Hz , 1H), 6.25(s, 1H), 4.57(s, 2H), 2.84-3.06(m, 1H), 2.43-2.80(m, 4H), 2.32(s, 3H), 1.60-2.30(m, 5H), 1.22(s, 3H), 1.17(s, 3H).

[0276] Example 34: 3-((7-(2-((4-amino-4-methylcyclohexenyl)methyl)-5-chloro-3-methylphenyl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

[0277]

[0278] The synthesis method of Example 34 is the same as that of Example 1. 1 H NMR (400MHz, CDCl3), 8.82-8.96 (m, 0.7H), 8.55-8.66 (m, 0.3H), 7.84-7.99 (m, 0.7H), 7.48-7.55 (m, 0.3H), 7.17-7.36 (m, 3H ), 5.92-6.06(m, 1H), 4.76-4.90(m, 2H), 2.44(s, 2H), 2.24(s, 3H), 1.54-2.19(m, 8H), 1.38(s, 3H), 1.24(s, 3H), 1.11(s, 3H).

[0279] Example 35: 3-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)-5-methyl-4-(piperidin-4-ylenylmethyl)benzonitrile

[0280]

[0281] The synthesis method of Example 35 is the same as that of Example 1. 1H NMR (400MHz, DMSO-d6), 8.28-9.04 (m, 3H), 7.89 (s, 1H), 7.81 (s, 1H), 7.50 (s, 1H), 7.26 (d, J=4.4Hz, 1H), 6.23 (s, 1H), 4.76 (s, 2H), 2.87-3.04(m, 1H), 2.50-2.76(m, 4H), 2.26-2.36(m, 4H), 1.74-2.14(m, 3H), 1.35-1.58(m, 1H), 1.14(s, 3H), 1.00(s, 3H).

[0282] Example 36: 3-((7-(5-chloro-2-((1-ethylpiperidin-4-ylenyl)methyl)-3-methylphenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione hydrobromide

[0283]

[0284] 65 mg of bromomethane was added to a tetrahydrofuran (1 mL) solution of compound 11 (100 mg) and potassium carbonate (82 mg). The reaction mixture was reacted overnight at room temperature, and then concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 30:1 to 5:1) to obtain compound 36 (35 mg). 1 H NMR (400MHz, CDCl3), 11.10-12.10 (br, 1H), 8.69 (s, 1H), 7.58 (s, 1H), 7.33 (s, 1H), 7.26 (s, 1H), 7.07 (s, 1H), 6.17 (s, 1H), 4.80 (s, 2H), 3.18-3.42(m, 1H), 2.62-3.14(m, 4H), 2.33-2.56(m, 3H), 2.12-2.29(m, 4H), 1.53-2.03(m, 3H), 1.18-1.26(m, 6H), 1.15(s, 3H).

[0285] Example 37: 3-((4-(5-chloro-3-methyl-2-(piperidin-4-ylenylmethyl)phenyl)pyrrole[2,1-f][1,2,4]triazine-6-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0286]

[0287] Step 1: Synthesis of Compound 46

[0288] Under nitrogen protection, a mixture of compound 44 (150 mg), compound 45 (447 mg), tetraphenylphosphine palladium (77 mg), and anhydrous sodium carbonate (141 mg) in dioxane / water (4 mL / 1 mL) was heated to 80 °C and stirred overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 200:1 to 50:1) to obtain compound 42 (110 mg).

[0289] Step 2: Synthesis of Compound 47

[0290] Under nitrogen protection at 0°C, a toluene solution (0.75 mL, 1 M) of DIBAl-H was added dropwise to a tetrahydrofuran (5 mL) solution of compound 47 (110 mg). The reaction mixture was then heated to room temperature and stirred for 2 hours. After the reaction was complete, the reaction mixture was quenched with saturated sodium sulfate solution. The resulting mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 100:1 to 100:3) to obtain compound 47 (42 mg).

[0291] Step 3: Synthesis of Compound 48

[0292] DIAD (36 mg) was added dropwise to a tetrahydrofuran (1 mL) solution of compound 47 (42 mg), compound 2 (25 mg), and PPh3 (47 mg) at 0 °C. The reaction mixture was allowed to react overnight at room temperature. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 200:1 to 100:1) to obtain compound 48 (21 mg).

[0293] Step 4: Synthesis of Compound 49

[0294] At room temperature, trifluoroacetic acid (0.1 mL) was added to a 1 mL solution of dichloromethane containing 21 mg of compound 48. The reaction mixture was stirred at room temperature for 2 hours until the reaction was complete. The reaction was quenched with 5 mL of saturated sodium bicarbonate solution, and the aqueous phase was extracted with dichloromethane (5 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by rapid silica gel column chromatography (dichloromethane:methanol = 20:1 to 5:1) to obtain compound 23 (7.4 mg). 1H NMR(400MHz, CD3OD), 8.45(s, 1H), 7.95(s, 1H), 7.49(s, 1H), 7.40(s, 1H), 6.58(s, 1H), 6.32(s, 1H), 4.62(s, 2H), 2.82-2.98(m , 1H), 2.52-2.65(m, 1H), 2.13-2.48(m, 8H), 1.97-2.11(m, 1H), 1.78-1.91(m, 1H), 1.52-1.62(m, 1H), 1.21(s, 3H), 1.03(s, 3H).

[0295] Example 38: 1-((7-(5-chloro-3-methyl-2-(piperidin-4-ylenylmethyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)pyrrolidine-2,5-dione

[0296]

[0297] The synthesis method of Example 38 is the same as that of Example 26. 1 H NMR (400MHz, CD3OD), 8.63 (d, J=4.4Hz, 1H), 7.49 (s, 1H), 7.43 (d, J=2.0Hz, 1H), 7.34 (s, 1H), 7.26 (d, J=4.8Hz, 1H), 6.33 (s, 1H), 4.94 (s, 2H) ,2.99-3.15(m,1H),2.77-2.92(m,1H),2.75(s,4H),2.32-2.60(m,2H) , 2.30(s, 3H), 2.10-2.26(m, 1H), 1.85-2.09(m, 2H), 1.64-1.83(m, 1H).

[0298] Example 39: 3-((7-(5-chloro-3-methyl-2-(piperidin-4-ylenylmethyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-1-(2,2,2-trifluoroethyl)pyrimidin-2,4(1H,3H)-dione trifluoroacetate

[0299]

[0300] The synthesis method of Example 39 is the same as that of Example 26. 1H NMR (400MHz, DMSO-d6), 8.63 (d, J=4.8Hz, 1H), 7.75 (d, J=8.0Hz, 1H), 7.46-7.51 (m, 2H), 7.35 (s, 1H), 7.20 (d, J=4.8Hz, 1H), 6.14 (s, 1H), 5.89 (d, J=8.4Hz, 1H), 5.24 (s, 2H), 4.69 (q, J=9.2Hz, 2H), 2.86-3.05 (m, 1H) , 2.58-2.77(m, 1H), 2.23(s, 3H), 1.75-2.19(m, 4H), 1.36-1.66(m, 2H).

[0301] Example 40: (E)-3-((7-(2-(2-(azacyclobut-3-yl)vinyl)-5-chloro-3-methylphenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0302]

[0303] The synthesis method of Example 40 is the same as that of Example 2. LC-MS (ESI): [M+H]492.3.

[0304] Example 41: 3-((7-(5-chloro-2-((hexahydrocyclopentano[c]pyrrole-5(1H)-ylene)methyl)-3-methylphenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate)

[0305]

[0306] The synthesis method of Example 41 is the same as that of Example 1. 1 H NMR (400MHz, DMSO-d6), 8.68-8.92 (br, 2H), 8.63 (d, J=4.8Hz, 1H), 7.46-7.48 (m, 2H), 7.31 (d, J=1.6Hz, 1H), 7.19 (d, J=4.4Hz, 1H), 6.09 (s, 1H), 4.75 (s, 2H ), 3.16-3.25(m, 1H), 3.02-3.15(m, 1H), 2.56(s, 2H), 2.32-2.52(m, 2H), 2.10 -2.31 (m, 5H), 1.90-2.04 (m, 2H), 1.38-1.64 (m, 2H), 1.14 (s, 3H), 0.97 (s, 3H).

[0307] Example 42: 2-((7-(5-chloro-3-methyl-2-(piperidin-4-ylenylmethyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)isoindole-1,3-dione trifluoroacetate

[0308]

[0309] The synthesis method of Example 42 is the same as that of Example 26. 1 H NMR (400MHz, CD3OD), 8.63 (d, J=4.4Hz, 1H), 7.87-7.90 (m, 2H), 7.81-7.84 (m, 2H), 7.53 (s, 1H), 7.41 (d, J=2.0Hz, 1H), 7.34 (s, 1 H), 7.25 (d, J=4.8Hz, 1H), 6.31 (s, 1H), 5.14 (s, 2H), 2.97-3.14 (m, 1H), 2.68-2.87 (m, 1H), 2.06-2.57 (m, 6H), 1.54-2.06 (m, 3H).

[0310] Example 43: 3-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]yl-3-yl)methyl)thiopheno[3,2-b]pyridin-7-yl)-4-((1-ethylpiperidin-4-ylene)methyl)-5-methylbenzonitrile

[0311]

[0312] The synthesis method of Example 43 is the same as that of Example 36. 1 H NMR (400MHz, DMSO-d6), 8.63-8.70 (m, 1H), 7.89 (s, 1H), 7.81 (s, 1H), 7.50 (s, 1H), 7.19-7.30 (m, 1H), 6.04-6.36 (m, 1H ), 4.76 (s, 2H), 2.66-3.12 (m, 4H), 2.57 (s, 2H), 2.18-2.54 (m, 7H), 1.70-2.01 (m, 2H), 1.14 (s, 3H), 0.96-1.11 (m, 6H).

[0313] Example 44: 2-((7-(5-chloro-3-methyl-2-(piperidin-4-ylenylmethyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)tetrahydrocyclopenteno[c]pyrrole-1,3(2H,3aH)-dione trifluoroacetate

[0314]

[0315] The synthesis method of Example 44 is the same as that of Example 26. 1 H NMR (400MHz, DMSO-d6), 8.64 (d, J=4.8Hz, 1H), 8.38-8.58 (br, 1H), 8.12-8.29 (br, 1H), 7.50 (d, J=2.0Hz, 1H), 7.47 (s, 1H), 7.35-7.40 (m, 1H), 7.22 (d, J=4.8Hz, 1H), 6.19 (s, 1H), 4.82 (s, 2H), 3.20-3.26(m, 2H), 2.87-3.04(m, 1H), 2.55-2.72(m, 1H), 2.40-2.51(m, 1H), 2.18-2.32(m, 4H), 1.92-2.10(m, 1H), 1.70-1.90(m, 5H), 1.58-1.68(m, 1H), 1.32-1.52(m, 1H), 1.02-1.20(m, 2H).

[0316] Example 45: 2-((7-(5-chloro-3-methyl-2-(piperidin-4-ylenylmethyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)hexahydro-1H-isoindole-1,3(2H)-dione trifluoroacetate

[0317]

[0318] The synthesis method of Example 45 is the same as that of Example 26. 1 H NMR (400MHz, DMSO-d6), 8.64 (d, J=4.8Hz, 1H), 8.35-8.54 (br, 1H), 8.07-8.27 (br, 1H), 7.49-7.50 (m, 2H), 7.36-7.39 (m, 1H), 7.22 (d, J=4.4Hz, 1 H), 6.20 (s, 1H), 4.85 (s, 2H), 2.86-3.06 (m, 3H), 2.38-2.74 (m, 2H), 2.1 4-2.33(m, 4H), 1.65-2.14(m, 5H), 1.30-1.61(m, 5H), 1.14-1.28(m, 2H).

[0319] Example 46: (3aR,4S,7R,7aS)-2-((7-(5-chloro-3-methyl-2-(piperidin-4-ylenylmethyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)hexahydro-1H-4,7-methyleneisoindole-1,3(2H)-dione trifluoroacetate

[0320]

[0321] The synthesis method of Example 46 is the same as that of Example 26. 1 H NMR(400MHz, CDCl3), 9.60-9.98(br, 1H), 8.58-9.01(m, 2H), 7.65-7.72(m, 1H) ,7.34-7.38(m,1H),7.14-7.24(m,2H),6.10(s,1H),4.90(s,2H),2.99-3.16(m , 1H), 2.81-2.98(m, 1H), 2.56-2.76(m, 5H), 3.41-3.56(m, 1H), 2.01-2.37(m, 6 H), 1.78-1.99 (m, 1H), 1.58-1.72 (m, 3H), 1.16-1.36 (m, 2H), 0.99-1.05 (m, 1H).

[0322] Example 47: 1-((7-(5-chloro-3-methyl-2-(piperidin-4-ylenylmethyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione

[0323]

[0324] The synthesis method of Example 47 is the same as that of Example 26. 1 H NMR (400MHz, CD3OD), 8.60 (d, J=4.8Hz, 1H), 7.86 (s, 1H), 7.53 (s, 1H), 7.40 (d, J=2.0Hz, 1H), 7.30 (s, 1H), 7.22 (s, 1H), 6.29 (s, 1H), 5.41 (s , 2H), 3.95(s, 3H), 3.51(s, 3H), 3.01-3.15(m, 1H), 2.75-2.91(m, 1H), 2.31-2.60 (m, 2H), 2.28 (s, 3H), 1.92-2.25 (m, 3H), 1.67-1.85 (m, 1H).

[0325] Example 48: 1-((7-(5-chloro-3-methyl-2-(piperidin-4-ylenylmethyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-3,3-dimethylpyrrolidine-2,5-dione trifluoroacetate

[0326]

[0327] The synthesis method of Example 48 is the same as that of Example 26. 1H NMR(400MHz, CDCl3), 8.84-9.72(br, 2H), 8.61-8.71(m, 1H), 7.53(s, 1H), 7.33(s, 1H), 7.21(s, 1H), 7.01-7.07(m, 1H ), 6.10 (s, 1H), 4.89 (s, 2H), 3.57-4.12 (m, 1H), 2.73-3.17 (m, 2H), 2.32-2.64 (m, 4H), 1.80-2.31 (m, 6H), 1.29 (s, 6H).

[0328] Example 49: (3aR,4S,7R,7aS)-2-((7-(5-chloro-3-methyl-2-piperidin-4-ylenylmethyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-3a,4,7,7a-tetrahydro-1H-4,7-methyleneisoindole-1,3(2H)-dione trifluoroacetate

[0329]

[0330] The synthesis method of Example 49 is the same as that of Example 26. 1 H NMR (400MHz, CDCl3), 9.33-9.70 (br, 1H), 8.79-9.12 (br, 1H), 8.60-8.74 (m, 1H), 7.4 3-7.56(m, 1H), 7.34(s, 1H), 7.21(s, 1H), 7.02-7.11(m, 1H), 6.10(s, 1H), 5.98(s, 2H ), 4.74(s, 2H), 3.62-4.27(m, 2H), 3.30(s, 2H), 2.74-3.16(m, 2H), 2.34-2.65(m, 2H) , 1.99-2.31 (m, 6H), 1.80-1.98 (m, 1H), 1.71 (d, J=8.4Hz, 1H), 1.52 (d, J=8.4Hz, 1H).

[0331] Example 50: 4-(4-chloro-2-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hex-3-yl)methyl)thiopheno[3,2-b]pyridin-7-yl)-6-methylphenylene)piperidin-1-carboxylon

[0332]

[0333] BrCN (40 mg) was added to a 5 mL solution of compound 100 mg (62 μL) and DIEA in dichloromethane. The reaction mixture was reacted overnight at room temperature, and then concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (dichloromethane:methanol = 200:1 to 50:1) to obtain compound 50 (34 mg). 1 H NMR(400MHz, CD3OD), 8.57-8.67(m, 1H), 7.50(s, 1H), 7.41(s, 1H), 7.30(s, 1H), 7.24 (d, J=4.8Hz, 1H), 6.18 (s, 1H), 4.83 (s, 2H), 3.06-3.21 (m, 1H), 2. 78-2.93(m, 1H), 2.52-2.68(m, 1H), 2.48(s, 2H), 2.15-2.32(m, 4H), 1.96-2 .12(m, 2H), 1.81-1.95(m, 1H), 1.56-1.72(m, 1H), 1.22(s, 3H), 1.07(s, 3H).

[0334] Example 51: 3-((7-(5-chloro-3-methyl-2-((1-methylpiperidin-4-ylene)methyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0335]

[0336] The synthesis method of Example 51 is the same as that of Example 36. 1 H NMR (400MHz, CD3OD), 8.61-8.68 (m, 1H), 7.50 (s, 1H), 7.44 (d, J=1.6Hz, 1H), 7.32 (s, 1H), 7.26 (d, J=4.8Hz, 1H), 4.83 (s, 2H), 3.01-3.22 (m, 1H), 2.78-2.98(m, 1H), 2.56-2.75(m, 4H), 2.38-2.55(m, 4H), 2.31(s , 3H), 1.72-2.28(m, 3H), 1.62-1.84(m, 1H), 1.23(s, 3H), 1.10(s, 3H).

[0337] Example 52: 3-((7-(2-((2-azaspiro[3.3]hept-6-ylene)methyl)-5-chloro-3-methylphenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0338]

[0339] The synthesis method of Example 52 is the same as that of Example 1. 1 H NMR (400MHz, CD3OD), 8.62 (d, J=4.4Hz, 1H), 7.47 (s, 1H), 7.39 (d, J=2.0Hz, 1H), 7.24-7.26 (m, 2H), 6.11 (s, 1H), 4.83 (s, 2 H), 3.81 (d, J=10.8Hz, 2H), 3.72 (d, J=10.8Hz, 2H), 2.73 (s, 2H), 2.49 (s, 2H), 2.27-2.32 (m, 5H), 1.23 (s, 3H), 1.09 (s, 3H).

[0340] Example 53: (3aR,4S,7R,7aS)-2-((7-(5-chloro-3-methyl-2-(piperidin-4-ylenylmethyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-3a,7a-dimethylhexahydro-1H-4,7-epoxyisoindole-1,3(2H)-dione trifluoroacetate

[0341]

[0342] The synthesis method of Example 53 is the same as that of Example 26. 1 H NMR (400MHz, CDCl3), 9.52-9.94 (br, 1H), 8.44-8.86 (m, 2H), 7.56 (s, 1H), 7.33 (s, 1H), 7.23 (s, 1H), 7.04-7.09 (m, 1H), 6.11 (s, 1H), 4.83-4.95 (m, 2H), 4.55 (s, 2H), 2.75-3.21 (m, 4H), 2.33-2.54 (m, 1H), 2.23 (s, 3H) , 1.82-2.22(m, 3H), 1.75-1.81(m, 2H), 1.62-1.70(m, 2H), 1.13(s, 6H).

[0343] Example 54: 3-((7-(5-chloro-3-methyl-2-(piperidin-4-ylenylmethyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-3-azabicyclo[3.2.0]hept-2,4-dione trifluoroacetate

[0344]

[0345] The synthesis method of Example 54 is the same as that of Example 26. 1H NMR(400MHz, CDCl3), 9.33-9.61(br, 1H), 8.78-9.08(br, 1H), 8.62-8.73(m, 1H), 7.59 (s, 1H), 7.33 (d, J=2.0Hz, 1H), 7.22 (s, 1H), 7.07 (d, J=4.0Hz, 1H), 6.11 (s, 1 H), 4.96 (s, 2H), 3.85-4.24 (m, 2H), 3.28-3.36 (m, 2H), 2.97-3.17 (m, 1H), 2.75-2 .95 (m, 1H), 2.60-2.71 (m, 2H), 2.36-2.58 (m, 2H), 2.24 (s, 3H), 2.02-2.22 (m, 4H).

[0346] Example 55: 3-((7-(5-chloro-2-((1-ethylazacyclobutyl-3-ylene)methyl)-3-methylphenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0347]

[0348] The synthesis method of Example 55 is the same as that of Example 36. 1 H NMR (400MHz, CDCl3), 8.73 (d, J=4.8Hz, 1H), 7.58 (s, 1H), 7.32 (s, 1H), 7.22 (s, 1H), 7.08 (d, J=4.8Hz, 1H), 6.32 (s, 1H), 4.8 0 (s, 2H), 3.28-4.64 (m, 4H), 2.55-2.69 (m, 2H), 2.37 (s, 2H), 2.34 (s, 3H), 1.23 (s, 3H), 1.12 (s, 3H), 1.03 (t, J=7.2Hz, 3H).

[0349] Example 56: 3-((7-(5-chloro-2-((1-isopropylpiperidin-4-ylene)methyl)-3-methylphenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0350]

[0351] The synthesis method of Example 56 is the same as that of Example 36. 1H NMR (400MHz, CDCl3), 8.62 (d, J=4.4Hz, 1H), 7.48 (s, 1H), 7.28 (s, 1H), 7.24 (s, 1H), 7.04 (d, J=4.0Hz, 1H), 6.11 (s, 1H), 4.69-4.89 (m, 2 H), 2.76-3.11 (m, 3H), 2.29-2.64 (m, 4H), 2.08-2.25 (m, 4H), 1.68-1.92 (m, 2H), 1.18-1.23 (m, 4H), 1.12 (s, 3H), 1.04 (d, J=6.8Hz, 6H).

[0352] Example 57: 3-((7-(5-chloro-2-((1-(cyclopropylmethyl)piperidin-4-ylene)methyl)-3-methylphenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0353]

[0354] The synthesis method of Example 57 is the same as that of Example 36. 1 H NMR (400MHz, CDCl3), 8.62 (d, J=4.8Hz, 1H), 7.50 (s, 1H), 7.30 (d, J=1.6Hz, 1 H), 7.23-7.27 (m, 1H), 7.04 (d, J=4.8Hz, 1H), 6.11 (s, 1H), 4.79 (s, 2H), 2.99- 3.21(m, 1H), 2.62-2.88(m, 2H), 2.08-2.52(m, 10H), 1.72-1.98(m, 2H), 1.22( s, 3H), 1.12 (s, 3H), 0.85-1.05 (m, 1H), 0.56-0.65 (m, 2H), 0.09-0.21 (m, 2H).

[0355] Example 58: 3-((7-(5-chloro-3-methyl-2-((E)-2-((S)-morpholin-2-yl)vinyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0356]

[0357] The synthesis method of Example 58 is the same as that of Example 2. 1H NMR (400MHz, CDCl3), 8.67-8.75 (m, 1H), 7.61 (s, 1H), 7.29 (d, J=2.0Hz, 1H), 7.12-7.18 (m, 2H), 6.54 (d, J=16.4Hz, 1H), 5.03 (dd, J=16.4Hz, 4.8Hz, 1H), 4.82 (s, 2H), 4.15-4.23 (m, 1H), 3.86-3.99 (m, 2H), 3.24-3.34 (m, 1H), 2.90-3.05 (m, 1H), 2.50-2.59 (m, 1H), 2. 44 (d, J=5.2Hz, 1H), 2.40 (d, J=5.2Hz, 1H), 2.28-2.37 (m, 4H), 1.22 (s, 3H), 1.12 (s, 3H).

[0358] Example 59: 3-((7-(5-chloro-3-methyl-2-((8-methyl-8-azabicyclo[3.2.1]oct-3-ylene)methyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0359]

[0360] The synthesis method of Example 59 is the same as that of Example 36. 1 H NMR (400MHz, CDCl3), 8.68 (d, J=4.8Hz, 1H), 7.57 (s, 1H), 7.31 (d, J=2.0Hz, 1H), 7.18-7.26 (m, 1H), 7.04-7.12 (m, 1H), 6.25-6.37 (m, 1H) , 4.74-4.83(m, 2H), 3.20-3.69(m, 3H), 2.60(s, 3H), 2.15-2.44(m, 6H), 1.94-2.10(m, 2H), 1.48-1.91(m, 4H), 1.22(s, 3H), 1.11(s, 3H).

[0361] Example 60: 3-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hex-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)-4-((1-isopropylpiperidin-4-ylene)methyl)-5-methylbenzonitrile trifluoroacetate

[0362]

[0363] The synthesis method of Example 60 is the same as that of Example 36. 1H NMR (400MHz, DMSO-d6), 8.68 (s, 1H), 7.75-7.92 (m, 2H), 7.50 (s, 1H), 7.16-7.38 (m, 1H), 6.29 (s, 1H), 4.77 (s, 2H), 3.12-3.40 (m, 2 H), 2.68-3.10(m, 2H), 2.51-2.63(m, 3H), 2.20-2.40(m, 4H), 2.03-2.19(m, 1H), 1.54-1.87(m, 2H), 1.15(s, 3H), 0.86-1.14(m, 9H).

[0364] Example 61: 3-((7-(2-((6-aminospiro[3.3]heptylene)methyl)-5-chloro-3-methylphenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0365]

[0366] The synthesis method of Example 61 is the same as that of Example 1. 1 H NMR (400MHz, CD3OD), 8.59-8.61 (m, 1H), 7.47 (s, 1H), 7.36-7.38 (m, 1H), 7.24-7.2 6(m, 2H), 6.03-6.06(m, 1H), 4.84(s, 1.2H), 4.83(s, 0.8H), 2.50-2.53(m, 0.8H), 2 .49(s, 0.8H), 2.48(s, 1.2H), 2.43-2.46(m, 1.2H), 2.30(s, 3H), 1.88-2.09(m, 6H) , 1.74-1.82(m, 1H), 1.23(s, 1.2H), 1.22(s, 1.8H), 1.07(s, 1.2H), 1.06(s, 1.8H).

[0367] Example 62: 3-((7-(5-chloro-2-((1-cyclopropylpiperidin-4-ylene)methyl)-3-methylphenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0368]

[0369] The synthesis method of Example 62 is the same as that of Example 36. 1H NMR (400MHz, CD3OD), 8.60 (d, J=5.2Hz, 1H), 7.47 (s, 1H), 7.41 (d, J=2.0Hz, 1H), 7.30-7.33 (m, 1H), 7.24 (d, J=5.2Hz, 1H), 6.17 (s, 1H), 4.83 (s, 2 H), 2.70-2.87(m, 1H), 2.41-2.60(m, 3H), 2.13-2.35(m, 5H), 1.40-1.91 (m, 4H), 1.26-1.35 (m, 1H), 1.22 (s, 3H), 1.08 (s, 3H), 0.39-0.58 (m, 4H).

[0370] Example 63: 3-((7-(5-chloro-3-methyl-2-(piperidin-4-ylenylmethyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)oxazolin-2,4-dione trifluoroacetate

[0371]

[0372] The synthesis method of Example 63 is the same as that of Example 26. 1 H NMR (400MHz, CDCl3), 8.67-9.68 (br, 2H), 8.66 (s, 1H), 7.61 (s, 1H), 7.32 (d, J=2.0Hz, 1H), 7.22 (s, 1H), 7.03 (d, J=4.4Hz, 1H), 6.1 2(s, 1H), 4.89-5.01(m, 2H), 4.75(s, 2H), 2.96-3.14(m, 1H), 2.74-2.92(m, 1H), 2.33-2.54(m, 2H), 2.23(s, 3H), 1.79-2.22(m, 4H).

[0373] Example 64: 3-((7-(5-chloro-2-((1-isopropylazacyclobutyl-3-ylene)methyl)-3-methylphenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0374]

[0375] The synthesis method of Example 64 is the same as that of Example 36. 1H NMR (400MHz, CDCl3), 8.70 (d, J=4.4Hz, 1H), 7.55 (s, 1H), 7.31 (d, J=1.6Hz, 1H), 7.21 (d, J=1.6Hz, 1H), 7.07 (d, J=5.2Hz, 1H), 6.29 (s, 1H), 4.7 9(s, 2H), 3.98-4.40(m, 2H), 3.30-3.86(m, 2H), 2.55-2.66(m, 1H), 2.3 6(s, 2H), 2.34(s, 3H), 1.22(s, 3H), 1.11(s, 3H), 1.01(d, J=6.4Hz, 6H).

[0376] Example 65: 6,6-Dimethyl-3-((7-(3-methyl-5-nitro-2-(piperidin-4-ylenylmethyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate

[0377]

[0378] The synthesis method of Example 65 is the same as that of Example 1. 1 H NMR (400MHz, DMSO-d6), 8.69 (d, J=5.2Hz, 1H), 8.18-8.40 (m, 3H), 8.13 (s, 1H ), 7.53(s, 1H), 7.30(d, J=4.8Hz, 1H), 6.30(s, 1H), 4.77(s, 2H), 2.90-3.04(m , 1H), 2.60-2.74(m, 1H), 2.57(s, 2H), 2.44-2.56(m, 1H), 2.39(s, 3H), 2.20- 2.35 (m, 1H), 1.72-2.13 (m, 3H), 1.33-1.53 ​​(m, 1H), 1.14 (s, 3H), 1.00 (s, 3H).

[0379] Example 66: 6,6-Dimethyl-3-((7-(3-methyl-2-(piperidin-4-ylenylmethyl)-5-(trifluoromethyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-2,4-dione

[0380]

[0381] The synthesis method of Example 66 is the same as that of Example 1. 1H NMR (400MHz, CDCl3), 8.65 (d, J=4.8Hz, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 7.44 (s, 1H), 7.01 (d, J=4.8Hz, 1H), 6.12 (s, 1H), 4.78 (s, 2H ), 2.95-3.15(m, 1H), 2.74-2.94(m, 1H), 2.37-2.56(m, 2H), 2.36(s, 2H), 2.31(s, 3H), 1.75-2.24(m, 4H), 1.20(s, 3H), 1.09(s, 3H).

[0382] Example 67: 3-((7-(5-chloro-3-methyl-2-(piperidin-4-ylenylmethyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-1-methylimidazoline-2,4-dione trifluoroacetate

[0383]

[0384] The synthesis method of Example 67 is the same as that of Example 26. 1 H NMR (400MHz, CDCl3), 8.74-9.76 (br, 2H), 8.63 (d, J=4.8Hz, 1H), 7.54 (s, 1H), 7.31 (d, J=1.6Hz, 1H), 7.20 (s, 1H), 6.98 (d, J=4.8Hz, 1H), 6. 10(s, 1H), 4.89(s, 2H), 3.90(s, 2H), 2.98-3.17(m, 1H), 2.97(s, 3H), 2.76-2.96 (m, 1H), 2.32-2.65 (m, 4H), 2.22 (s, 3H), 1.86-2.21 (m, 2H).

[0385] Example 68: 3-((7-(5-chloro-3-methyl-2-((1-(2,2,2-trifluoroethyl)azacyclobutyl-3-ylene)methyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0386]

[0387] The synthesis method of Example 68 is the same as that of Example 36. 1H NMR (400MHz, CDCl3), 8.69 (d, J=4.0Hz, 1H), 7.55 (s, 1H), 7.27 (s, 1H), 7.18 (s, 1H), 7.06 (d, J=4.0Hz, 1H), 6.06 (s, 1H), 4.7 9 (s, 2H), 3.72-3.80 (m, 2H), 3.16-3.26 (m, 2H), 2.79 (q, J=9.6Hz, 2H), 2.34 (s, 2H), 2.32 (s, 3H), 1.20 (s, 3H), 1.07 (s, 3H).

[0388] Example 69: 3-((7-(2-((3-azaspiro[5.5]undecane-9-ylene)methyl)-5-chloro-3-methylphenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0389]

[0390] The synthesis method of Example 69 is the same as that of Example 1. 1 H NMR (400MHz, CD3OD), 8.58 (d, J=5.2Hz, 1H), 7.45 (s, 1H), 7.39 (d, J=2.4Hz , 1H), 7.31 (d, J=2.4HZ, 1H), 7.24 (d, J=4.8Hz, 1H), 6.03 (s, 1H), 4.83 (s, 2H ), 2.90-3.08(m, 4H), 2.49(s, 2H), 2.26(s, 3H), 1.85-2.16(m, 2H), 1.40-1. 72(m, 6H), 1.24-1.35(m, 2H), 1.23(s, 3H), 1.10(s, 3H), 0.73-0.88(m, 2H).

[0391] Example 70: 3-((7-(2-((2-azaspiro[3.5]nonane-7-ylene)methyl)-5-chloro-3-methylphenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0392]

[0393] The synthesis method of Example 70 is the same as that of Example 1. 1H NMR (400MHz, CD3OD), 8.56 (d, J=5.2Hz, 1H), 7.44 (s, 1H), 7.40 (d, J=2.0Hz, 1H), 7.29 (d, J=2.0Hz, 1H), 7.22 (d, J=5.2Hz, 1H), 6.06 (s, 1H), 4 .82(s, 2H), 3.45-3.71(m, 4H), 2.50(s, 2H), 2.26(s, 3H), 1.84-1.98(m , 1H), 1.38-1.80 (m, 6H), 1.23 (s, 3H), 1.10 (s, 3H), 0.83-0.88 (m, 1H).

[0394] Example 71: 3-(2-((6,6-dimethyl-2,4-dioxo-3-aza[3.1.0]hexane-3-yl)methyl)thiopheno[3,2-b]pyridin-7-yl)-5-methyl-4-((1-methylpiperidin-4-ylene)methyl)benzonitrile

[0395]

[0396] The synthesis method of Example 71 is the same as that of Example 36. 1 H NMR(400MHz, CD3OD), 8.65(d, J=5.2Hz, 1H), 7.78(s, 1H), 7.70(s, 1H), 7.49(s , 1H), 7.28 (d, J=5.2Hz, 1H), 6.36 (s, 1H), 4.83 (s, 2H), 2.86-3.07 (m, 1H), 2.60 -2.83(m,2H),2.54(s,3H),2.49(s,2H),2.37(s,3H),2.08-2.24(m,1H),1.86 -2.07 (m, 1H), 1.50-1.80 (m, 2H), 1.23 (s, 3H), 1.09 (s, 3H), 0.83-0.89 (m, 1H).

[0397] Example 72: 3-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-3-yl)methyl)thiopheno[3,2-b]pyridin-7-yl)-5-methyl-4-((8-methyl-8-azabicyclo[3.2.1]oct-3-ylene)methyl)benzonitrile

[0398]

[0399] The synthesis method of Example 72 is the same as that of Example 36. 1H NMR(400MHz, CDCl3), 8.68-8.74(m, 1H), 7.63(s, 1H), 7.50-7.60(m, 2H), 7. 06-7.11 (m, 1H), 6.35 (s, 1H), 4.76-4.85 (m, 2H), 3.34-3.64 (m, 3H), 2.92-3. 10(m,1H),2.72-2.79(m,1H),2.59(s,2H),2.39(s,3H),2.30(s,3H),1.97-2 .11 (m, 2H), 1.66-1.85 (m, 2H), 1.24 (s, 3H), 1.13 (s, 3H), 0.76-0.85 (m, 1H).

[0400] Example 73: 4-(azacyclobutyl-3-ylenylmethyl)-3-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)-5-methylbenzonitrile

[0401]

[0402] The synthesis method of Example 73 is the same as that of Example 1. 1 H NMR (400MHz, CDCl3), 8.69 (d, J=4.8Hz, 1H), 7.56 (s, 1H), 7.55 (s, 1H), 7.49 (s, 1H), 7.04 (d, J=4.8Hz, 1H), 6.04-6. 08 (m, 1H), 4.81 (s, 2H), 3.98-4.02 (m, 2H), 3.40-3.48 (m, 2H), 2.39 (s, 3H), 2.36 (s, 2H), 1.21 (s, 3H), 1.07 (s, 3H).

[0403] Example 74: 4-((1-cyclopropylpiperidin-4-ylene)methyl)-3-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)-5-methylbenzonitrile

[0404]

[0405] The synthesis method of Example 74 is the same as that of Example 36. 1H NMR (400MHz, CD3OD), 8.64 (d, J=4.4Hz, 1H), 7.75 (s, 1H), 7.68 (s, 1H), 7.49 (s, 1H), 7.28 (d, J=4.8Hz, 1H), 6.24 (s, 1H), 4.83 (s, 2H), 2.76-2 .94(m,1H),2.48(s,2H),2.36(s,3H),2.21-2.35(m,2H),1.95-2.10(m , 1H), 1.47-1.94(m, 5H), 1.22(s, 3H), 1.08(s, 3H), 0.44-0.59(m, 4H).

[0406] Example 75: 3-((7-(5-chloro-3-methyl-2-(piperidin-4-ylenylmethyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-1-(2,2,2-trifluoroethyl)imidazoline-2,4-dione trifluoroacetate)

[0407]

[0408] The synthesis method of Example 75 is the same as that of Example 26. 1 H NMR (400MHz, CDCl3), 8.90-9.66 (br, 2H), 8.66 (s, 1H), 7.57 (s, 1H), 7.32 (d, J=2.0Hz, 1H), 7.22 (s, 1H), 6.99-7.05 (m, 1H), 6. 11 (s, 1H), 4.94 (s, 2H), 4.07 (s, 2H), 3.92-4.04 (m, 2H), 2.73-3.17 (m, 4H), 2.33-2.52 (m, 2H), 2.23 (s, 3H), 1.99-2.22 (m, 2H).

[0409] Example 76: 3-((7-(5-chloro-2-((1-(cyclopropylmethyl)azacyclobutane-3-ylene)methyl)-3-methylphenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[0410]

[0411] The synthesis method of Example 76 is the same as that of Example 36. 1H NMR (400MHz, DMSO-d6), 8.66 (d, J=4.8Hz, 1H), 7.46-7.51 (m, 2H), 7.32 (d, J=1.6Hz, 1H), 7.26 (d, J=4.8Hz, 1H), 6.23 (s, 1H), 4.76 (s, 2H), 4.14 -4.28(m, 2H), 3.61-3.75(m, 4H), 2.54(s, 2H), 2.30(s, 3H), 1.12(s, 3H) , 0.96 (s, 3H), 0.88-0.95 (m, 1H), 0.38-0.44 (m, 2H), 0.12-0.16 (m, 2H).

[0412] Example 77: 3-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)-4-((1-isopropylazacyclobutyl-3-ylene)methyl)-5-methylbenzonitrile

[0413]

[0414] The synthesis method of Example 77 is the same as that of Example 36. 1 H NMR (400MHz, CDCl3), 8.74 (d, J=2.8Hz, 1H), 7.61 (s, 1H), 7.57 (s, 1H), 7.51 (s, 1H), 7.09 (d, J=2.8Hz, 1H), 6.36 (s, 1H), 4 .79 (s, 2H), 3.04-4.63 (m, 4H), 2.63-2.78 (m, 1H), 2.42 (s, 3H), 2.36 (s, 2H), 1.22 (s, 3H), 1.11 (s, 3H), 0.97-1.10 (m, 6H).

[0415] Example 78: 3-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)-4-((1-ethylazacyclobutyl-3-ylene)methyl)-5-methylbenzonitrile hydrochloride

[0416]

[0417] The synthesis method of Example 78 is the same as that of Example 36. 1H NMR (400MHz, DMSO-d6), 10.41-10.97 (br, 1H), 8.71 (d, J=4.8Hz, 1H), 7.90 (s, 1H), 7.78 (s, 1H), 7.52 (s, 1H), 7.32 (d, J=5.2Hz, 1H), 6.36 (s, 1H), 4.76(s, 2H), 4.20-4.36(m, 2H), 3.71-3.91(m, 2H), 2.72-2.83(m, 2H), 2. 56 (s, 2H), 2.36 (s, 3H), 1.14 (s, 3H), 0.99 (s, 3H), 0.87 (t, J=7.2Hz, 3H).

[0418] Example 79: 4-((4-aminocyclohexene)methyl)-3-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)-5-methylbenzonitrile

[0419]

[0420] The synthesis method of Example 79 is the same as that of Example 1. 1 H NMR (400MHz, CDCl3), 8.52-8.63 (m, 1H), 7.59 (s, 1H), 7.44-7.56 (m, 2H), 7.03-7.12 (m, 1H), 6.00 (s, 1H), 4.69-4.84 (m, 2H), 2. 94-3.05 (m, 1H), 2-38 (s, 2H), 2.28 (s, 3H), 2.15-2.25 (m, 1H), 1.82-2.10 (m, 4H), 1.36-1.80 (m, 3H), 1.21 (s, 3H), 1.09 (s, 3H).

[0421] Example 80: 3-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)-4-((4-(dimethylamino)cyclohexylene)methyl)-5-methylbenzonitrile

[0422]

[0423] The synthesis method of Example 80 is the same as that of Example 36. 1H NMR(400MHz, CDCl3), 8.56-8.70(m, 1H), 7.46-7.60(m, 3H), 6.93-7.11(m, 1H), 5.93-6.04(m, 1H), 4.76-4.85( m, 2H), 2.46-2.62 (m, 1H), 2.12-2.42 (m, 12H), 1.80-2.06 (m, 4H), 1.42-1.75 (m, 3H), 1.23 (s, 3H), 1.13 (s, 3H).

[0424] Example 81: 3-(2-((2,5-dioxopyrrolidone-1-yl)methyl)thieno[3,2-b]pyridin-7-yl)-5-methyl-4-(piperidin-4-ylenylmethyl)benzonitrile

[0425]

[0426] The synthesis method of Example 81 is the same as that of Example 26. 1 H NMR (400MHz, CD3OD), 8.65 (d, J=4.8Hz, 1H), 7.78 (s, 1H), 7.71 (s, 1H), 7.49 (s, 1H), 7.29 (d, J=5.2Hz, 1H), 6.41 (s, 1H), 4.94 (s, 2H), 3.02-3 .17(m,1H),2.76-2.93(m,1H),2.75(s,4H),2.48-2.61(m,1H),2.31- 2.46 (m, 4H), 2.14-2.28 (m, 1H), 1.89-2.10 (m, 2H), 1.64-1.84 (m, 2H).

[0427] Example 82: 1-((7-(5-chloro-3-methyl-2-(piperidin-4-ylenylmethyl)phenyl)thiopheno[3,2-b]pyridin-2-yl)methyl)-3,3,4,4-tetramethylpyrrolidine-2,5-dione trifluoroacetate)

[0428]

[0429] The synthesis method of Example 82 is the same as that of Example 26. 1H NMR (400MHz, DMSO-d6), 8.64 (d, J=4.8Hz, 1H), 8.22-8.50 (br, 2H), 7.50 (s, 1H), 7.47 (s, 1H), 7.39 (s, 1H), 7.22 (d, J=4.0Hz, 1H), 6.2 0 (s, 1H), 4.85 (s, 2H), 2.86-3.02 (m, 1H), 2.40-2.70 (m, 2H), 2.16-2.34 (m, 4H), 1.68-2.09 (m, 3H), 1.30-1.50 (m, 1H), 1.05 (s, 12H).

[0430] Bioactivity experiments:

[0431] 1. Assay for the in vitro enzyme activity of the compound inhibiting USP7

[0432] In this patent, the enzymatic activity of USP7 was detected using a rapid fluorescence method. Ubiquitin-Rhodamine 110 was used as an alternative substrate, and a high-throughput screening platform was optimized and established. The inhibitory activity of the compound against USP7 was detected on this platform. The specific method is as follows: The compound was serially diluted 5-fold with 100% DMSO starting from 1 mM (total of 7 concentrations). 2 μL of each concentration 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, catalog number 6007270, purchased from PerkinElmer), followed by 10 μL of His-USP7 (final concentration 0.05 nM). After incubating the 384-well plate at 23°C for 30 minutes, 5 μL of the substrate substitute Ubiquitin-Rhodamine 110 (catalog number U-555, purchased from Boston Biochem, final concentration 10 nM) was added to each well, and the reaction was continued at 23°C for 1.5 hours. The reaction was terminated by adding 5 μL of citric acid (catalog number 77-92-9, purchased from Sinopharm Group, final concentration 10 mM). Fluorescence values ​​were read using a BMG Lariostar Microplate Reader (excitation 485 nm / emission 535 nm). The IC50 value of this compound inhibiting the enzymatic activity of USP7 was calculated using GraphPad Prism software.

[0433] Table 1. Inhibitory effect of the compounds in the examples on USP7

[0434]

[0435]

[0436] 2. Assay of the compound's activity in inhibiting RS4;11 cell proliferation.

[0437] Human acute lymphoblastic leukemia cell line RS4;11 cells were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS, Biological Industries, BI) and 1% penicillin / streptomycin (P / S, Thermo Fisher Scientific) at 37°C and 5% CO2. RS4;11 cells were seeded at a concentration of 4000 cells / 195 μL / well in 96-well plates (catalog number #3917, CORNING). After 24 hours, the compound was serially diluted 3-fold with 100% DMSO, starting at 10 mM (totaling 10 concentrations). 4 μL of each concentration was then added to 96 μL of RPMI-1640 medium. 5 μL of each diluted compound was added to the seeded cell suspension, and the compound and cells were incubated together in a cell culture incubator for 72 hours (3 days). Afterwards, 35 μL of CellTiter was added. (Catalog number G7570, purchased from Promega) Reagent, reacted on a shaker at room temperature for 5-10 minutes. Chemiluminescence values ​​were read on a BMG Clariostar Microplate Reader, and the data were processed using GraphPad Prism software to calculate the IC50 value of the compound's inhibitory effect on cell proliferation.

[0438] Table 2. Inhibitory effects of compounds on RS4;11 cell lines

[0439] .

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in, Rings A and B are aromatic rings. L is -(CH2) n- , n is 1 or 2, Both X1 and X2 are CH. X3 and X4 are each independently selected from C or N. X6 is S, X5 is CH. Y 1、 Y2, Y3and Y4are each independently selected from CR3, R9is selected from H, halogen and C 1-6 alkyl, which alkyl can optionally be substituted with halogen, R1 and R2 are each independently selected from H and C. 1-6 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic alkyl groups, wherein the alkyl, cycloalkyl, and heterocyclic alkyl groups may optionally be converted by halogen, -CN, -OR. 10 -NR 10 R 11 Or C 1-6 Alkyl substitution, or R1 and R2 can be connected together to form C. 3-12 Cycloalkyl or 3-12-membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl may optionally be converted by halogen, -CN, -OR 10 -NR 10 R 11 Or C 1-6 Alkyl substitution, wherein the alkyl group may optionally be substituted with a halogen. R3 is independently selected from H, halogen, C. 1-6 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups, wherein the alkyl, cycloalkyl, and heterocyclic alkyl groups may optionally be converted to halogen, -CN, -OR 10 -NR 10 R 11 Or C 1-6 Alkyl substitution, R7 is a 3-12 membered cycloalkyl or a 3-12 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl may optionally be (=O) or C. 1-6 Alkyl substitution, wherein the alkyl group may optionally be halogenated, -CN, or -OR. 10 , or -NR 10 R 11 replace, R 10 and R 11 Each is independently selected from H and C. 1-6 Alkyl and C 3-8 Cycloalkyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R7 is a 3-12 membered cycloalkyl or a 3-12 membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl may optionally be (=O) or C. 1-6 Alkyl substitution.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y1, Y2, Y3 and Y4 are each independently selected from CR3, and R3 is each independently selected from H, halogen and C. 1-6 alkyl.

4. The following compounds or their pharmaceutically acceptable salts, 5. A pharmaceutical composition comprising a compound according to any one of claims 1-4 or a pharmaceutically acceptable salt thereof, and optionally comprising a pharmaceutically acceptable carrier.

6. Use of the compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 5, in the preparation of a medicament for treating diseases associated with USP7 activity.

7. The use according to claim 6, 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.

Images