Hpk1 inhibitors, methods of making, and uses thereof

Abstract

The present application relates to HPK1 inhibitors, preparation methods and uses thereof. Further, the present application belongs to the field of medicine, and specifically discloses a compound of formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and uses thereof in the preparation of a medicament for preventing and / or treating HPK1-mediated related diseases.

Description

Technical Field

[0001] This application pertains to the pharmaceutical field, and specifically relates to compounds of formula (I), methods for their preparation, pharmaceutical compositions containing the compounds, and their use in the preparation of medicaments for the prevention and / or treatment of HPK1-mediated diseases. Background Technology

[0002] HPK1 (Hematopoietic progenitor kinase 1), also known as MAP4K1, is a serine / threonine kinase belonging to the MAP4K family. It is expressed by hematopoietic cells and can activate the JNK / MAPK signaling pathway by binding to adaptor proteins such as SLP76, thereby negatively regulating the TCR (T cell receptor) pathway and playing an important role in immune regulation. HPK1 has also become a popular target for tumor immunology.

[0003] MAP4K3 (also known as GLK) is a serine / threonine kinase belonging to the mammalian Ste20-like kinase family and is a homolog of HPK1. In T cells, GLK directly interacts with and activates PKCθ by phosphorylating PKCθ at the Ser-538 residue, leading to IKK / NF-κB activation. Therefore, GLK-deficient mice exhibit impaired T cell-mediated immune responses and reduced inflammatory phenotypes in autoimmune disease models. The percentage of GLK-overexpressing T cells has consistently been increased in the peripheral blood of patients with autoimmune diseases.

[0004] Given the important role of HPK1 in the development and progression of tumors and immune-related diseases (solid tumors, hematologic malignancies, autoimmune diseases, inflammation, etc.), and the fact that there are currently no marketed drugs targeting this target, it is particularly important to develop HPK1 inhibitors with high activity, high selectivity, and good drugability. Summary of the Invention

[0005] One object of the present invention is to provide a class of HPK1 inhibitor compounds and a method for preparing the same; another object of the present invention is to provide the application of a class of HPK1 inhibitors in tumor immunotherapy; the compounds of the present invention have good HPK1 inhibitory activity and kinase selectivity, good drug-like properties, and can be used for the prevention and / or treatment of HPK1-mediated diseases.

[0006] This invention provides compounds of formula (I), or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs:

[0007]

[0008] in,

[0009] Z is CR C Or N;

[0010] U is CR C Or N;

[0011] W is CR C Or N;

[0012] V is CR C Or N;

[0013] Q is selected from covalent bonds, -O-, -S-, -NR'-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR'-, -OC(O)-, -OC(O)NR'-, -N(R')C(O)O-, -N(R')C(O)- and -N(R')S(O)2-; or Q is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -N(R')C(O)-, -C(O)N(R')-, -N(R')S(O)2-, -S(O)2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

[0014] R B Selected from H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-C6-C 10 Aryl, -L-3 to 14-membered carbocyclic, -L-3 to 14-membered heterocyclic and -L-5 to 14-membered heteroaryl;

[0015] R C Selected from H, halogen, -CN, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-C6-C 10 Aryl, -L-3 to 14-membered carbocyclic, -L-3 to 14-membered heterocyclic and -L-5 to 14-membered heteroaryl;

[0016] R D Selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C 10 aryl, 3- to 14-membered carbocyclic, 3- to 14-membered heterocyclic, and 5- to 14-membered heteroaryl, each optionally bounded by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 R groups. d Group substitution;

[0017] R ESelected from -L-C6-C 10 aryl, -L-3 to 14-membered carbocyclic, -L-3 to 14-membered heterocyclic and -L-5 to 14-membered heteroaryl, wherein C6-C 10 The aryl, 3- to 14-membered carbocyclic, 3- to 14-membered heterocyclic and 5- to 14-membered heteroaryl groups are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 Re groups;

[0018] Among them, R d Each is independently selected from H, halogens, -CN, -L'-S(O). 0-2 R', -L'-S(O)2NR'R", -L'-S(O)NR'R", -L'-OR', -L'-NR'R", -L'-C(O)NR'R", and -L'-C(O)NR'R", or R d Selected from C1-C8 alkyl, C 2- C8 alkenyl, C 2- C8 ynyl, C1-C8 haloalkyl-L'-C6-C 10 Aryl, -L'-3 to 14-membered carbocyclic, -L'-3 to 14-membered heterocyclic, and -L'-5 to 14-membered heteroaryl, each optionally bounded by 1, 2, 3, 4, or 5 R groups. dd replace;

[0019] Or two adjacent R d Together with the carbon atoms connected to them, they form 3- to 7-membered monocyclic heterocyclic groups, 6- to 10-membered bridged bicyclic heterocyclic groups, 6- to 10-membered spirobicyclic heterocyclic groups, and 6- to 10-membered fused bicyclic heterocyclic groups, wherein the 3- to 7-membered monocyclic heterocyclic groups, 6- to 10-membered bridged bicyclic heterocyclic groups, 6- to 10-membered spirobicyclic heterocyclic groups, and 6- to 10-membered fused bicyclic heterocyclic groups are optionally surrounded by 1, 2, 3, 4, or 5 R atoms. dd replace;

[0020] R dd Each is independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C 2- C8 alkenyl, C 2- C8 alkynyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-C(O)OR’, -L”-C(O)NR’R”, -L”-S(O) 0-2 R', -L”-S(O)2NR'R”, -L”-S(O)NR’R”, -L”-OC(O)R’, -L”-OC(O)NR’R”, -L”-NR’R”, -L”-C(O)NR’R”, -L”-C6-C 10 Aryl, -L”-3 to 14-membered carbocyclic, -L”-3 to 14-membered heterocyclic and -L”-5 to 14-membered heteroaryl;

[0021] R e Each is independently selected from H, halogen, -CN, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L'-OR', -L'-NR'R", -NO2, -L'-SR', -L'-C(O)OR', -L'-C(O)NR'R", -L'-S(O)2R', -L'-S(O)2NR'R", -L'-OC(O)R', -L'-OC(O)NR'R", -L'-C6-C 10 Aryl, -L'-3 to 14-membered carbocyclic, -L'-3 to 14-membered heterocyclic and -L'-5 to 14-membered heteroaryl;

[0022] L is selected from covalent bonds, -O-, -S-, -NR'-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR'-, -OC(O)-, -OC(O)NR'-, -N(R')C(O)O-, -N(R')C(O)- and -N(R')S(O)2-; or L is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -N(R')C(O)-, -C(O)N(R')-, -N(R')S(O)2-, -S(O)2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

[0023] L' is selected from covalent bonds, -O-, -S-, -NR'-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR'-, -OC(O)-, -OC(O)NR'-, -N(R')C(O)O-, -N(R')C(O)- and -N(R')S(O)2-; or L' is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -N(R')C(O)-, -C(O)N(R')-, -N(R')S(O)2-, -S(O)2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

[0024] R' is independently selected from H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, -L”-C6-C 10 Aryl, -L”-3 to 14-membered carbocyclic, -L”-3 to 14-membered heterocyclic and -L”-5 to 14-membered heteroaryl;

[0025] R” is independently selected from H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, -L”-C6-C 10 Aryl, -L”-3 to 14-membered carbocyclic, -L”-3 to 14-membered heterocyclic and -L”-5 to 14-membered heteroaryl;

[0026] Alternatively, R' and R” together with the N atoms they are attached to form 3 to 14-membered heterocyclic groups;

[0027] L” is selected from covalent bonds, -O- and -S-; or L” is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-.

[0028] Some embodiments of the present invention relate to salts of the above-mentioned compounds, preferably hydrochlorides.

[0029] In some embodiments, the present invention provides a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable carrier, adjuvant, or mediator.

[0030] In some embodiments, the present invention provides the use of the compounds of the present invention or pharmaceutical compositions thereof in the preparation of medicaments for the treatment and / or prevention of HPK1-mediated disorders, diseases or conditions.

[0031] In some embodiments, the present invention provides a method for treating and / or preventing HPK1-mediated disorders, diseases, or conditions using the compounds of the present invention or pharmaceutical compositions thereof, including administering the compounds of the present invention or pharmaceutical compositions thereof to a subject.

[0032] In some embodiments, the present invention provides compounds of the present invention or pharmaceutical compositions thereof for the treatment and / or prevention of HPK-mediated disorders, diseases or conditions.

[0033] In some embodiments, the present invention is used to treat and / or prevent proliferative disorders.

[0034] In some implementations, the proliferative impairment is associated with one or more activating mutations in HPK1.

[0035] In some implementations, the proliferative disorder is cancer.

[0036] In some implementations, the HPK1-mediated barrier, disease, or condition is a chronic viral infection.

[0037] In some embodiments, the present invention relates to the use of the compounds of the present invention or pharmaceutical compositions thereof in the preparation of medicaments for increasing the efficacy of vaccination.

[0038] In some embodiments, the present invention relates to the compounds of the present invention or pharmaceutical compositions thereof for increasing the efficacy of vaccination.

[0039] In some embodiments, the present invention relates to a method for increasing the efficacy of a vaccine by means of the compound or pharmaceutical composition thereof, comprising administering the compound or pharmaceutical composition to a subject.

[0040] Definitions and Explanations

[0041] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0042] definition

[0043] Chemical definition

[0044] The definitions of specific functional groups and chemical terms are described in more detail below.

[0045] When listing a range of values, it is assumed that each value and the subranges within that range are included. For example, "C 1-8 Alkyl groups include C1, C2, C3, C4, C5, C6, C7, C8, and C6. 1-8 C 1-7 C 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-8 C 2-7 C 2-6 C 2-5 C 2-4 C 2-3 C 3-8 C 3-7 C 3-6 C 3-5 C 3-4 C 4-8 C 4-7 C 4-6 C 4-5 C 5-8 C 5-7 C 5-6 C 6-8 C 6-7 and C 7-8 .

[0046] “C 1-8"Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 8 carbon atoms. In some embodiments, C 1-6 Alkyl, C 1-4 Alkyl and C 1-2 Alkyl groups are preferred. C 1-6 Examples of alkyl groups include: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term "C" is used in conjunction with the preceding text. 1-6 "Alkyl" also includes heteroalkyl, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Common alkyl abbreviations include: Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), i-Bu (-CH2CH(CH3)2), and t-Bu (-C(CH3)3).

[0047] “C 2-8 "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 8 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-6 alkenyl and C 2-4 Alkenyl groups are preferred. C 2-6 Examples of alkenyl groups include: vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and so on. The term "C" is used in conjunction with these groups. 2-6 "Alkenyl" also includes heteroalkenyl groups, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkenyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0048] “C 2-8 "Alkyne" refers to a straight-chain or branched hydrocarbon group having 2 to 8 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 The alkynyl group is preferred. C 2-6Examples of alkynyl groups include, but are not limited to: ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentyynyl (C5), hexynyl (C6), etc. The term "C" is used in conjunction with other alkynyl groups. 2-6 "Alkyne" also includes heteroyne, wherein one or more (e.g., 1, 2, 3 or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkynyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0049] “C 1-8 "Alkylene" refers to the removal of C 1-8 The alkyl group is a divalent group formed by another hydrogen atom, and can be substituted or unsubstituted. In some embodiments, C 1-6 Alkylene, C 1-4 Alkylene, C 2-4 Alkylene and C 1-3 Alkylenes are preferred. Unsubstituted alkylenes include, but are not limited to: methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and so on. Exemplary substituted alkylenes, for example, those substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylidenes (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc.

[0050] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0051] “C 1-8 "Halogenated alkyl" refers to the above "C 1-8 "alkyl" is substituted with one or more halogen groups. In some embodiments, C 1-6 Haloalkyl, C 1-4 Halogenated alkyl groups and C 1-2Halogenated alkyl groups are particularly preferred. Exemplary halogenated alkyl groups include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc. The halogenated alkyl group can be substituted at any available connection point, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0052] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 shared π electrons arranged in a ring) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). Aryl also includes a ring system in which the above-mentioned aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the connection point is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. The aryl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0053] "3 to 14-membered carbocyclic or cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 14 ring carbon atoms and zero heteroatoms, including monocyclic carbocyclic, bridged carbocyclic, spirocyclic, and fused carbocyclic groups. More specifically, it includes any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic, or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic. In some embodiments, C 3-7 cycloalkyl and C 3-6 Cycloalkyl groups are particularly preferred, and C10 is more preferred. 5-6 Cycloalkyl. Cycloalkyl also includes ring systems in which the aforementioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the bonding point is on the cycloalkyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Examples of the carbon ring include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl (C6), cycloheptyl, cycloheptenyl, cycloheptadienyl (C7), cycloheptanetrienyl (C7), adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[4.4.0]decane, bicyclo[2.2.2]octane, fluorenyl, indanyl, adamantyl, and tetrahydronaphthyl. The cycloalkyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0054] "3- to 14-membered heterocyclic groups" refer to groups having a cyclic carbon atom and 1 to 5 cyclic heteroatoms, comprising a 3- to 14-membered non-aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. Optionally, the nitrogen atom is oxidized to form an N-oxide; the sulfur atom is oxidized to form a sulfone or sulfoxide. 3- to 14-membered heterocyclic groups include monocyclic heterocyclic groups, bridged heterocyclic groups, spirocyclic heterocyclic groups, and fused heterocyclic groups. More specifically, they include any stable 3, 4, 5, 6, 7, or 8-membered monocyclic or bicyclic, or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic. More preferably, they include 3- to 8-membered monocyclic heterocyclic groups and 6- to 10-membered groups, including 6- to 10-membered bridged bicyclic heterocyclic groups, 6- to 10-membered spirobicyclic heterocyclic groups, and 6- to 10-membered fused bicyclic heterocyclic groups. In heterocyclic groups containing one or more nitrogen atoms, the linkage can be a carbon or nitrogen atom, provided the valence allows. In some embodiments, 4-12 membered heterocyclic groups are preferred, which are 4-12 membered non-aromatic ring systems having a cyclic carbon atom and 1 to 5 cyclic heteroatoms selected from N, O, and S; in some embodiments, 3-10 membered heterocyclic groups are preferred, which are 3-10 membered non-aromatic ring systems having a cyclic carbon atom and 1 to 5 cyclic heteroatoms selected from N, O, and S; in some embodiments, 3-8 or 3-7 membered heterocyclic groups are preferred, which are 3-8 or 3-7 membered non-aromatic ring systems having a cyclic carbon atom and 1 to 4 cyclic heteroatoms selected from N, O, and S; 3-6 membered heterocyclic groups are preferred, which are 3-6 membered heterocyclic groups having a cyclic carbon atom and 1 to 3 cyclic heteroatoms selected from N, O, and S. 3- to 6-membered non-aromatic ring systems with cyclic heteroatoms of O and S; preferably 4- to 8-membered heterocyclic groups, which are 4- to 8-membered non-aromatic ring systems having a cyclic carbon atom and 1 to 3 cyclic heteroatoms selected from N, O and S; more preferably 4- to 6-membered heterocyclic groups, which are 4- to 6-membered non-aromatic ring systems having a cyclic carbon atom and 1 to 3 cyclic heteroatoms selected from N, O and S; more preferably 5- to 6-membered heterocyclic groups, which are 5- to 6-membered non-aromatic ring systems having a cyclic carbon atom and 1 to 3 cyclic heteroatoms selected from N, O and S; more preferably 4- to 5-membered heterocyclic groups, which are 4- to 5-membered non-aromatic ring systems having a cyclic carbon atom and 1 to 2 cyclic heteroatoms selected from N, O and S. Heterocyclic groups also include ring systems in which the aforementioned heterocyclic ring is fused with one or more cycloalkyl groups, wherein the linking point is on the cycloalkyl ring, or ring systems in which the aforementioned heterocyclic ring is fused with one or more aryl or heteroaryl groups, wherein the linking point is on the heterocyclic ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclic ring system. Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirropropyl, oxetane, and thioheteropropyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirrobutyl, oxetane, and thioheterobutyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolidinyl, and pyrrolidin-2,5-dione.Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: dioxacyclopentyl, oxothiocyclopentyl, dithiocyclopentyl, oxazolidinyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thiocyclohexyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazine, morpholinyl, dithiocyclohexyl, and dioxalyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazineyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirheptanyl, oxacycloheptanyl, thiocycloheptanyl-nitrogen, heterocycloheptrienyl, oxacycloheptrienyl, and thiocycloheptrienyl. Exemplary 7-membered heterocyclic groups containing two heteroatoms include, but are not limited to: nitrogen-nitroheptanyl, oxythioheptanyl, and thionitroheptanyl-nitrogen. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to: dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinoneyl, etc. Exemplary 6-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclic groups) include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc. The heterocyclic group may be optionally substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0055] "5- to 14-membered heteroaryl" refers to a 4n+2 aromatic ring system of a 5- to 14-membered monocyclic or bicyclic ring (e.g., having 6, 10, or 14 shared π electrons arranged in a ring), wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, provided the valence allows. A heteroaryl bicyclic system may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the bonding point is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5- to 10-membered heteroaryl is preferred, which is a 4n+2 aromatic ring system of a 5- to 10-membered monocyclic or bicyclic ring having a cyclic carbon atom and 1-4 ring heteroatoms. In other embodiments, 5- to 6-membered heteroaryl groups are particularly preferred, which are 4n+2 aromatic ring systems of 5- to 6-membered monocyclic or bicyclic rings having a cyclic carbon atom and 1-4 cyclic heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrole, furanyl, and thiophene. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl), and thiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to: triazinyl and tetraazinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazole, benzotriazolyl, benzothiopheneyl, isobenzothiopheneyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinel. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to: naphridinyl, pteridinyl, quinolinyl, isoquinolinyl, zolinyl, quinoxolinyl, phthalazinyl, and quinazolinyl. The heteroaryl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0056] "Pyridinopyrazinyl" refers to a group formed by the fusion of pyridine and pyrrol, followed by the fusion of pyrrol and pyrazine, wherein the attachment to other groups is located on any of the three rings, namely pyridine, pyrrol, and pyrazine. Similar groups include tetrahydropyridinopyrazinyl, pyridinoimidazopyrazinyl, tetrahydropyridinoimidazopyrazinyl, pyridinopyrazinyl, dihydropyridinopyrazinyl, tetrahydropyridinopyrazinyl, pyridinoimidazopyrazinyl, dihydropyridinopyrazinyl, pyridinopyrazinyl, hexahydropyridinopyrazinyl, pyrazinophthaloyl, tetrahydropyrazinophthalophthaloyl, hexahydropyridinopyrazinyl, oxazinophthalophthaloyl, tetrahydrooxazinophthalophthalophthaloyl, and hexahydrooxazinophthal ...

[0057] "Oxytochemical" means =O.

[0058] "Alkoxy" refers to -OR, where R is an alkyl group as defined above. Preferably, it is -OC. 1-8 Alkyl, -OC 1-6 Alkyl, -OC 1-4 Alkyl or -OC 1-3 alkyl.

[0059] The divalent groups formed by removing one hydrogen atom from the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups defined above are collectively referred to as "subunits". Cyclic groups such as cycloalkyl, heterocyclic, aryl, and heteroaryl are collectively referred to as "cyclogroups".

[0060] The alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups defined in this article are optional substituted groups.

[0061] Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa -ON(R) bb )2、-N(R bb )2、-N(R bb )3 + X - -N(OR) cc )R bb -SH, -SR aa -SSR cc -C(=O)R aa -CO2H, -CHO, -C(OR) cc )2、-CO2R aa -OC(=O)R aa -OCO2R aa -C(=O)N(R) bb )2、-OC(=O)N(R bb)2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NRbb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(R cc )3、-B(R aa 2. -B(OR) cc )2、-BR aa (OR cc ), alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0062] Or the two hydrogen-bearing groups on the carbon atom: =O, =S, =NN(R) bb )2、=NNR bb C(=O)R aa =NNR bb C(=O)OR aa =NNR bb S(=O)2R aa =NR bb or = NOR cc replace;

[0063] R aa Each of them is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R aa Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0064] R bb Each is independently selected from: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) cc OR aa -C(=NR) cc )N(Rcc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, or two R bb Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0065] R cc Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R cc Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0066] R dd Each is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee -ON(R) ff )2、-N(R ff )2,、-N(R ff )3 + X - -N(OR) ee )R ff -SH, -SR ee -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee -OCO2R ee -C(=O)N(R) ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee -NRff CO2R ee -NR ff C(=O)N(R ff )2、-C(=NR ff OR ee -OC(=NR) ff )R ee -OC(=NR) ff OR ee -C(=NR) ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee -SO2N(R) ff )2、-SO2R ee -SO2OR ee -OSO2R ee -S(=O)R ee 、-Si(R ee )3、-OSi(R ee 3. -C(=S)N(R) ff )2、-C(=O)SR ee -C(=S)SR ee -SC(=S)SR ee -P(=O)2R ee -P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee 2. Alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently marked by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two geminal radicals dd Substituents can combine to form =O or =S;

[0067] R ee Each is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently surrounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0068] R ffEach is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R ff The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0069] R gg Each of these is independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C) 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - -NH(C 1-6 Alkyl)2 + X - -NH2(C 1-6 alkyl) + X - -NH3 + X - -N(OC) 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl groups, -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl group, -CO2H, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl groups, -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2、-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 Alkyl)2、-NHC(=O)NH(C 1-6 Alkyl groups, -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl), -OC (=NH)(C 1-6 Alkyl group), -OC (=NH)OC 1-6Alkyl group, -C(=NH)N(C 1-6 Alkyl)2、-C(=NH)NH(C 1-6 Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2、-OC(NH)NH(C 1-6 Alkyl groups, -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2、-SO2NH(C 1-6 Alkyl groups, -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C) 1-6 Alkyl)3、-OSi(C 1-6 Alkyl)3, -C(=S)N(C 1-6 Alkyl)2、C(=S)NH(C 1-6 Alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1-6 Alkyl, -SC (=S)SC 1-6 Alkyl group, -P(=O)2(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl)2、-OP(=O)(C 1-6 Alkyl)2、-OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 cycloalkyl, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two ethryl groups gg Substituents can combine to form =O or =S; where X - It is a counterion.

[0070] Exemplary substituents on the nitrogen atom include, but are not limited to: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) bb)R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R atoms attached to a nitrogen atom. cc The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, wherein R aa R bb R cc and R dd As stated above.

[0071] Other definitions

[0072] As used herein, the term "pharmaceutically acceptable salt" refers to carboxylates and amino acid addition salts of the compounds of the present invention that are suitable for contact with patient tissues within the limits of reliable medical judgment, without producing undue toxicity, irritation, allergic reactions, etc., and are effective for their intended use in proportion to a reasonable benefit / risk ratio, including (where possible) zwitterionic forms of the compounds of the present invention.

[0073] Pharmaceutically acceptable base addition salts are those formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, and calcium. Suitable amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucosamine, and procaine.

[0074] The base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the required base in a conventional manner to form a salt. The free acid can be regenerated by contacting the salt form with an acid in a conventional manner and then separating the free acid. The free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents; however, for the purposes of this invention, the salts are equivalent to their respective free acids.

[0075] Salts can be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, and iodides prepared from inorganic acids, such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphoric acid. Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthate, methanesulfonate, gluconate, lactobionate, laurylsulfonate, and hydroxyethanesulfonate. Salts can also be prepared from organic acids, such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkyl acids, hydroxyalkyl acids, alkyl diacids, aromatic acids, and aliphatic and aromatic sulfonic acids. Representative salts include acetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, octanoates, sebacic acid salts, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, naphthates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleates, tartrates, and methanesulfonates. Pharmaceutically acceptable salts may include alkali metal and alkaline earth metal-based cations, such as sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. It also covers salts of amino acids, such as arginine salts, gluconates, galacturons, etc. (see, for example, Berge S. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, incorporated herein by reference).

[0076] The term "subject" in the administration includes, but is not limited to: humans (i.e., men or women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0077] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0078] Unless otherwise stated, the term “treatment” as used herein includes effects that occur when a subject has a specific disease, disorder, or condition, which reduce the severity of the disease, disorder, or condition, or delay or slow the development of the disease, disorder, or condition (“therapeutic treatment”), and also includes effects that occur before a subject begins to have a specific disease, disorder, or condition (“preventive treatment”).

[0079] Unless otherwise stated, the term "therapeuticly effective amount" of a compound as used herein is an amount sufficient to provide therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. Therapeuticly effective amount of a compound refers to the amount of a therapeutic agent, used alone or in combination with other therapies, that provides therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeuticly effective amount" may include amounts that improve overall treatment, reduce or prevent symptoms or causes of a disease or condition, or enhance the therapeutic effects of other therapeutic agents.

[0080] Unless otherwise stated, the “preventively effective amount” of a compound as used herein is an amount sufficient to prevent a disease, disorder, or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or an amount sufficient to prevent recurrence of a disease, disorder, or condition. The preventively effective amount of a compound refers to the amount of a therapeutic agent, used alone or in combination with other agents, that provides preventive benefit in the prevention of a disease, disorder, or condition. The term “preventively effective amount” may include amounts that improve overall prevention or enhance the preventive effect of other preventive agents.

[0081] The term "combination" and related terms refer to the simultaneous or sequential administration of the compounds of the present invention and other therapeutic agents. For example, the compounds of the present invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or simultaneously with other therapeutic agents in a single unit dosage form.

[0082] The compounds of this invention may include one or more asymmetric centers and therefore may exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of this invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. The isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0083] The compounds of this invention can exist as tautomers. Tautomers are functional group isomers that arise from the rapid movement of an atom between two positions in a molecule. Tautomers are a special type of functional group isomer. A pair of tautomers can interconvert, but usually the more stable isomer is the dominant form. The most important examples are enol and keto tautomers.

[0084] The term "solvent" refers to a compound or its salt that is bound to a solvent and formed by a solvent decomposition reaction. This physical association may include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be separable, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvent" includes solvates in solution and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0085] The term "hydrate" refers to a compound that is bound to water. Typically, it is determined by the ratio of the number of water molecules contained in the hydrate to the number of molecules of the compound in the hydrate. Therefore, a hydrate of a compound can be represented, for example, by the general formula R·xH₂O, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, e.g., hemihydrates (R·0.5H₂O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R·2H₂O) and hexahydrates (R·6H₂O)).

[0086] The term "metabolite" refers to the product produced in vivo by the metabolism of a substance, including the compounds of the present invention, including intermediate metabolites and final metabolites.

[0087] The compounds of this invention can be in amorphous or crystalline form (polymorphs). Furthermore, the compounds of this invention can exist in one or more crystalline forms. Therefore, this invention encompasses all amorphous or crystalline forms of the compounds of this invention within its scope. The term "polymorph" refers to the crystalline form of a compound (or its salts, hydrates, or solvates) with a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, photoelectric properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can lead to the dominance of one crystalline form. Various polymorphs of the compounds can be prepared by crystallization under different conditions.

[0088] The present invention also includes isotopically labeled compounds (isotopic variants) that are equivalent to those described in formula (I), but in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, for example... 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Other isotopes of the present invention containing the aforementioned isotopes and / or other atoms, their prodrugs, and pharmaceutically acceptable salts of said compounds or said prodrugs are all within the scope of this invention. Certain isotope-labeled compounds of the present invention, for example, those incorporating radioactive isotopes (e.g.,...) 3 H and 14 Those in category C) can be used for drug and / or substrate tissue distribution determination. Tritium, i.e. 3 H and carbon-14, i.e. 14 Carbon isotopes are particularly preferred because they are easy to prepare and detect. Subsequently, they are replaced by heavier isotopes, such as deuterium, i.e., 2 H, because higher metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, may be preferred in some cases. Isotope-labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by using readily available isotope-labeled reagents instead of non-isotope-labeled reagents when performing the processes described below and / or the techniques disclosed in the examples and preparation examples.

[0089] Furthermore, prodrugs are also included in the context of this invention. As used herein, the term "prodrug" refers to a compound which is converted in vivo, for example, by hydrolysis in the blood, into its active form having a medical effect. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACSSymposium Series, Vol. 14; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; and D. Fleisher, S. Ramon, and H. Barbra, "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs," Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each of which is incorporated herein by reference.

[0090] A prodrug is any covalently bonded compound of the present invention that, when administered to a patient, releases the parent compound in vivo. Prodrugs are typically prepared by modifying functional groups in a manner that allows the modification to produce the parent compound through conventional operation or in vivo cleavage. Prodrugs include, for example, compounds of the present invention in which a hydroxyl, amino, or thiol group is bonded to any group, which, when administered to a patient, can cleave to form a hydroxyl, amino, or thiol group. Thus, representative examples of prodrugs include (but are not limited to) acetate / amide, formate / amide, and benzoate / amide derivatives of formula (I) with hydroxyl, thiol, and amino functional groups. Additionally, in the case of carboxylic acids (-COOH), esters, such as methyl esters, ethyl esters, etc., can be used. The ester itself may be active and / or hydrolyzable under in vivo conditions. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those groups that readily decompose in the body to release the parent acid or its salt.

[0091] The present invention also provides pharmaceutical formulations comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, or excipient thereof. All such forms are subject to the present invention. Detailed Implementation

[0092] The present invention relates to the following aspects.

[0093] In one embodiment, the present invention relates to a compound of formula (I), or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug:

[0094]

[0095] in,

[0096] Z is CR C Or N;

[0097] U is CR C Or N;

[0098] W is CR C Or N;

[0099] V is CR C Or N;

[0100] Q is selected from covalent bonds, -O-, -S-, -NR'-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR'-, -OC(O)-, -OC(O)NR'-, -N(R')C(O)O-, -N(R')C(O)- and -N(R')S(O)2-; or Q is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -N(R')C(O)-, -C(O)N(R')-, -N(R')S(O)2-, -S(O)2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

[0101] R B Selected from H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-C6-C 10 Aryl, -L-3 to 14-membered carbocyclic, -L-3 to 14-membered heterocyclic and -L-5 to 14-membered heteroaryl;

[0102] R C Selected from H, halogen, -CN, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-C6-C 10 Aryl, -L-3 to 14-membered carbocyclic, -L-3 to 14-membered heterocyclic and -L-5 to 14-membered heteroaryl;

[0103] R DSelected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C 10 aryl, 3- to 14-membered carbocyclic, 3- to 14-membered heterocyclic, and 5- to 14-membered heteroaryl, each optionally bounded by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 R groups. d Group substitution;

[0104] R E Selected from -L-C6-C 10 aryl, -L-3 to 14-membered carbocyclic, -L-3 to 14-membered heterocyclic and -L-5 to 14-membered heteroaryl, wherein C6-C 10 The aryl, 3- to 14-membered carbocyclic, 3- to 14-membered heterocyclic and 5- to 14-membered heteroaryl groups are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 Re groups;

[0105] Among them, R d Each is independently selected from H, halogens, -CN, -L'-S(O). 0-2 R', -L'-S(O)2NR'R", -L'-S(O)NR'R", -L'-OR', -L'-NR'R", -L'-C(O)NR'R", and -L'-C(O)NR'R", or R d Selected from C1-C8 alkyl, C 2- C8 alkenyl, C 2- C8 ynyl, C1-C8 haloalkyl-L'-C6-C 10 Aryl, -L'-3 to 14-membered carbocyclic, -L'-3 to 14-membered heterocyclic, and -L'-5 to 14-membered heteroaryl, each optionally bounded by 1, 2, 3, 4, or 5 R groups. dd replace;

[0106] Or two adjacent R d Together with the carbon atoms connected to them, they form 3- to 7-membered monocyclic heterocyclic groups, 6- to 10-membered bridged bicyclic heterocyclic groups, 6- to 10-membered spirobicyclic heterocyclic groups, and 6- to 10-membered fused bicyclic heterocyclic groups, wherein the 3- to 7-membered monocyclic heterocyclic groups, 6- to 10-membered bridged bicyclic heterocyclic groups, 6- to 10-membered spirobicyclic heterocyclic groups, and 6- to 10-membered fused bicyclic heterocyclic groups are optionally surrounded by 1, 2, 3, 4, or 5 R atoms. dd replace;

[0107] R dd Each is independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C 2- C8 alkenyl, C 2- C8 alkynyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-C(O)OR’, -L”-C(O)NR’R”, -L”-S(O) 0-2R', -L”-S(O)2NR'R”, -L”-S(O)NR’R”, -L”-OC(O)R’, -L”-OC(O)NR’R”, -L”-NR’R”, -L”-C(O)NR’R”, -L”-C6-C 10 Aryl, -L”-3 to 14-membered carbocyclic, -L”-3 to 14-membered heterocyclic and -L”-5 to 14-membered heteroaryl;

[0108] R e Each is independently selected from H, halogen, -CN, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L'-OR', -L'-NR'R", -NO2, -L'-SR', -L'-C(O)OR', -L'-C(O)NR'R", -L'-S(O)2R', -L'-S(O)2NR'R", -L'-OC(O)R', -L'-OC(O)NR'R", -L'-C6-C 10 Aryl, -L'-3 to 14-membered carbocyclic, -L'-3 to 14-membered heterocyclic and -L'-5 to 14-membered heteroaryl;

[0109] L is selected from covalent bonds, -O-, -S-, -NR'-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR'-, -OC(O)-, -OC(O)NR'-, -N(R')C(O)O-, -N(R')C(O)- and -N(R')S(O)2-; or L is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -N(R')C(O)-, -C(O)N(R')-, -N(R')S(O)2-, -S(O)2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

[0110] L' is selected from covalent bonds, -O-, -S-, -NR'-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR'-, -OC(O)-, -OC(O)NR'-, -N(R')C(O)O-, -N(R')C(O)- and -N(R')S(O)2-; or L' is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -N(R')C(O)-, -C(O)N(R')-, -N(R')S(O)2-, -S(O)2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

[0111] R' is independently selected from H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, -L”-C6-C 10 Aryl, -L”-3 to 14-membered carbocyclic, -L”-3 to 14-membered heterocyclic and -L”-5 to 14-membered heteroaryl;

[0112] R” is independently selected from H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, -L”-C6-C 10 Aryl, -L”-3 to 14-membered carbocyclic, -L”-3 to 14-membered heterocyclic and -L”-5 to 14-membered heteroaryl;

[0113] Alternatively, R' and R” together with the N atoms they are attached to form 3 to 14-membered heterocyclic groups;

[0114] L” is selected from covalent bonds, -O- and -S-; or L” is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-.

[0115] In a further embodiment, the present invention relates to compounds of formula (I) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs, wherein the compound of formula (I) is one of the following formulas:

[0116]

[0117]

[0118] In a further embodiment, the present invention relates to compounds of formula (I) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs: wherein R D Selected from phenyl, furanyl, furazanyl, imidazoalkyl, imidazolinyl, imidazolyl, isothiazolyl, isoxazolyl, morpholinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolyl, oxazolyl, oxazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, oxazolidinyl, oxazolidinyl, pyrimidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl Pyrazolyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrroliyl, 2H-pyrroliyl, pyrroliyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthonyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and hexahydropyrazinoquinolinyl.

[0119] In a further embodiment, the present invention relates to compounds of formula (I) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs:

[0120] Among them, R D Selected from Where f is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0121] In a further embodiment, the present invention relates to compounds of formula (I) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs:

[0122] Among them, R d Selected from H, F, -OH, -OCH3,

[0123]

[0124] In a further embodiment, the present invention relates to compounds of formula (I) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs: wherein R D Together with its substituent R d for:

[0125]

[0126]

[0127]

[0128]

[0129] In a further embodiment, the present invention relates to compounds of formula (I) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs: wherein R ESelected from phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrroloyl, pyrazolyl, imidazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyridinyl, pyrazololopyridinyl, pyrazololopyrimidinyl, pyrazololopyrimidinyl, pyridinolpyridinyl, dihydropyridinoloxazinyl, indolyl, triazololopyridinyl. Tetrahydroimidazopyrazinyl, dihydropyrrolopyridyl, thienopyridyl, benzimidazolyl, dihydroimidazooxazinyl, tetrahydropyrazopyridyl, dihydropyrrolopyridyl, dihydropyrroloimidazoyl, oxazolpyridyl, pyrazolozaheptanyl, pyrazolozaheptanyl, imidazozaheptanyl, imidazozaheptanyl, pyrazolodiazaheptanyl, pyrazolodiazaheptanyl, and thienopyridyl.

[0130] In a further embodiment, the present invention relates to compounds of formula (I) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs:

[0131] Among them, R E Selected from Where g is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0132] In a further embodiment, the present invention relates to compounds of formula (I) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs: wherein R E Together with its substituent R e for:

[0133]

[0134] In one embodiment, the present invention relates to compounds of formula (II), or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs:

[0135]

[0136] in,

[0137] Z is CR C Or N;

[0138] U is CR C Or N;

[0139] W is CR C Or N;

[0140] V is CRC Or N;

[0141] X is C(R) d1 ) or N;

[0142] Y is C(R) d2 ) or N;

[0143] R C Selected from H, halogen, -CN, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-C6-C 10 Aryl, -L-3 to 14-membered carbocyclic, -L-3 to 14-membered heterocyclic and -L-5 to 14-membered heteroaryl;

[0144] R e1 Selected from H, C1-C8 alkyl, C1-C8 haloalkyl, -L'-OR', -L'-NR'R", -L'-SR', -L'-C(O)OR', -L'-C(O)NR'R", -L'-S(O)2R', -L'-S(O)2NR'R", -L'-OC(O)R', -L'-OC(O)NR'R", -L'-C6-C 10 Aryl, -L'-3 to 14-membered carbocyclic, -L'-3 to 14-membered heterocyclic and -L'-5 to 14-membered heteroaryl;

[0145] R e2 Selected from H, halogen, -CN, C1-C8 alkyl, C1-C8 haloalkyl, -L'-OR', -L'-NR'R", -NO2, -L'-SR', -L'-C(O)OR', -L'-C(O)NR'R", -L'-S(O)2R', -L'-S(O)2NR'R", -L'-OC(O)R', -L'-OC(O)NR'R", -L'-C6-C 10 Aryl, -L'-3 to 14-membered carbocyclic, -L'-3 to 14-membered heterocyclic and -L'-5 to 14-membered heteroaryl;

[0146] R e3 Selected from H, halogens, -CN, C1-C8 alkyl, C1-C8 haloalkyl, -L'-OR', -L'-NR'R", -NO2, -L'-SR', -L'-C(O)OR', -L'-C(O)NR'R", -L'-S(O)2R', -L'-S(O)2NR'R", -L'-OC(O)R', -L'-OC(O)NR'R", -L'-C6-C 10 Aryl, -L'-3 to 14-membered carbocyclic, -L'-3 to 14-membered heterocyclic and -L'-5 to 14-membered heteroaryl;

[0147] R e4 Selected from H, halogens, -CN, C1-C8 alkyl, C1-C8 haloalkyl, -L'-OR', -L'-NR'R", -NO2, -L'-SR', -L'-C(O)OR', -L'-C(O)NR'R", -L'-S(O)2R', -L'-S(O)2NR'R", -L'-OC(O)R', -L'-OC(O)NR'R", -L'-C6-C 10 Aryl, -L'-3 to 14-membered carbocyclic, -L'-3 to 14-membered heterocyclic and -L'-5 to 14-membered heteroaryl;

[0148] R e5 Selected from H, halogen, -CN, C1-C8 alkyl, C1-C8 haloalkyl, -L'-OR', -L'-NR'R", -NO2, -L'-SR', -L'-C(O)OR', -L'-C(O)NR'R", -L'-S(O)2R', -L'-S(O)2NR'R", -L'-OC(O)R', -L'-OC(O)NR'R", -L'-C6-C 10 Aryl, -L'-3 to 14-membered carbocyclic, -L'-3 to 14-membered heterocyclic and -L'-5 to 14-membered heteroaryl;

[0149] R d1 Selected from H, halogens, -CN, -L'-S(O) 0-2 R', -L'-S(O)2NR'R", -L'-S(O)NR'R", -L'-OR', -L'-NR'R", -L'-C(O)NR'R", and -L'-C(O)NR'R", or R d1 Selected from C 1-8 Alkyl, C 2- C8 alkenyl, C 2- C8 ynyl group, C 1-8 Haloalkyl-L'-C6-C 10 Aryl, -L'-3 to 14-membered carbocyclic, -L'-3 to 14-membered heterocyclic, and -L'-5 to 14-membered heteroaryl, each optionally bounded by 1, 2, 3, 4, or 5 R groups. dd replace;

[0150] R d2 Selected from H, halogens, -CN, -L'-S(O) 0-2 R', -L'-S(O)2NR'R", -L'-S(O)NR'R", -L'-OR', -L'-NR'R", -L'-C(O)NR'R", and -L'-C(O)NR'R", or R d2 Selected from C1-8 Alkyl, C 2- C8 alkenyl, C 2- C8 ynyl group, C 1-8 Haloalkyl, -L'-C6-C 10 Aryl, -L'-3 to 14-membered carbocyclic, -L'-3 to 14-membered heterocyclic, and -L'-5 to 14-membered heteroaryl, each optionally bounded by 1, 2, 3, 4, or 5 R groups. dd replace;

[0151] R d3 Selected from H, halogens, -CN, -L'-S(O) 0-2 R', -L'-S(O)2NR'R", -L'-S(O)NR'R", -L'-OR', -L'-NR'R", -L'-C(O)NR'R", and -L'-C(O)NR'R", or R d3 Selected from C 1-8 Alkyl, C 2- C8 alkenyl, C 2- C8 ynyl group, C 1-8 Haloalkyl, -L'-C6-C 10 Aryl, -L'-3 to 14-membered carbocyclic, -L'-3 to 14-membered heterocyclic, and -L'-5 to 14-membered heteroaryl, each optionally bounded by 1, 2, 3, 4, or 5 R groups. dd replace;

[0152] R d4 Selected from H, halogens, -CN, -L'-S(O) 0-2 R', -L'-S(O)2NR'R", -L'-S(O)NR'R", -L'-OR', -L'-NR'R", -L'-C(O)NR'R", and -L'-C(O)NR'R", or R d4 Selected from C 1-8 Alkyl, C 2- C8 alkenyl, C 2- C8 ynyl group, C 1-8 Haloalkyl, -L'-C6-C 10 Aryl, -L'-3 to 14-membered carbocyclic, -L'-3 to 14-membered heterocyclic, and -L'-5 to 14-membered heteroaryl, each optionally bounded by 1, 2, 3, 4, or 5 R groups. dd replace;

[0153] R d5 Selected from H, halogens, -CN, -L'-S(O) 0-2 R', -L'-S(O)2NR'R", -L'-S(O)NR'R", -L'-OR', -L'-NR'R", -L'-C(O)NR'R", and -L'-C(O)NR'R", or Rd5 Selected from C 1-8 Alkyl, C 2- C8 alkenyl, C 2- C8 ynyl group, C 1-8 Haloalkyl-L'-C6-C 10 Aryl, -L'-3 to 14-membered carbocyclic, -L'-3 to 14-membered heterocyclic, and -L'-5 to 14-membered heteroaryl, each optionally bounded by 1, 2, 3, 4, or 5 R groups. dd replace;

[0154] Or when Y is C(R) d2 When R d2 and R d3 Together with the carbon atoms connected to them, they form 3- to 7-membered monocyclic heterocyclic groups, 6- to 10-membered bridged bicyclic heterocyclic groups, 6- to 10-membered spirobicyclic heterocyclic groups, and 6- to 10-membered fused bicyclic heterocyclic groups, wherein the 3- to 7-membered monocyclic heterocyclic groups, 6- to 10-membered bridged bicyclic heterocyclic groups, 6- to 10-membered spirobicyclic heterocyclic groups, and 6- to 10-membered fused bicyclic heterocyclic groups are optionally surrounded by 1, 2, 3, 4, or 5 R atoms. dd replace;

[0155] R dd Each is independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C 2- C8 alkenyl, C 2- C8 alkynyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-C(O)OR’, -L”-C(O)NR’R”, -L”-S(O) 0-2 R', -L”-S(O)2NR'R”, -L”-S(O)NR’R”, -L”-OC(O)R’, -L”-OC(O)NR’R”, -L”-NR’R”, -L”-C(O)NR’R”, -L”-C6-C 10 Aryl, -L”-3 to 14-membered carbocyclic, -L”-3 to 14-membered heterocyclic and -L”-5 to 14-membered heteroaryl;

[0156] L is selected from covalent bonds, -O-, -S-, -NR'-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR'-, -OC(O)-, -OC(O)NR'-, -N(R')C(O)O-, -N(R')C(O)- and -N(R')S(O)2-; or L is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -N(R')C(O)-, -C(O)N(R')-, -N(R')S(O)2-, -S(O)2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

[0157] L' is selected from covalent bonds, -O-, -S-, -NR'-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR'-, -OC(O)-, -OC(O)NR'-, -N(R')C(O)O-, -N(R')C(O)- and -N(R')S(O)2-; or L' is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -N(R')C(O)-, -C(O)N(R')-, -N(R')S(O)2-, -S(O)2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

[0158] R' is selected from H and C. 1-8 Alkyl, C1-C8 haloalkyl, -L”-C6-C 10 Aryl, -L”-3 to 14-membered carbocyclic, -L”-3 to 14-membered heterocyclic and -L”-5 to 14-membered heteroaryl;

[0159] "R" is selected from H and C. 1-8 Alkyl, C1-C8 haloalkyl, -L”-C6-C 10 Aryl, -L”-3 to 14-membered carbocyclic, -L”-3 to 14-membered heterocyclic and -L”-5 to 14-membered heteroaryl;

[0160] Alternatively, R' and R” together with the N atoms they are attached to form 3 to 14-membered heterocyclic groups;

[0161] L” is selected from covalent bonds, -O- or -S-; or L” is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-.

[0162] In one embodiment, the present invention relates to compounds of formula (II) as described above, or stereoisomers thereof, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs having formula (III),

[0163]

[0164] in,

[0165] R e1 R e2 R e3 R e4 and R e5 As defined in this application;

[0166] R d2 and R d3 Together with the carbon atoms attached to them, they form 6- to 10-membered fused bicyclic heterocyclic groups, which are optionally bounded by one or two R atoms. dd replace;

[0167] R dd Selected from C 1-6 Alkyl groups and -L”-OR';

[0168] R' is H or C 1-6 alkyl;

[0169] "L" represents a covalent bond or C 1-6 Alkylene.

[0170] In one embodiment, the present invention relates to compounds of formula (III) as described above, or stereoisomers thereof, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs, wherein R e1 R e2 R e3 R e4 and R e5 Both are H; R d2 and R d3 Together with the carbon atoms attached to them, they form a diazadecahydronaphthyl group, which is optionally surrounded by one or two R atoms. dd replace;

[0171] R dd C 1-6 alkyl.

[0172] In one embodiment, the present invention relates to compounds of formula (III) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs.

[0173] in,

[0174] Re1 R e2 R e3 R e4 and R e5 All are H;

[0175] R d2 It is a 6- to 10-membered fused bicyclic heterocyclic group, optionally surrounded by 1 or 2 R groups. dd replace;

[0176] R d3 For H;

[0177] R dd Selected from H, C 1-6 Alkyl groups and -L”-OR';

[0178] R' is H or C 1-6 alkyl;

[0179] "L" represents a covalent bond or C 1-6 Alkylene.

[0180] In one embodiment, the present invention relates to compounds of formula (III) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs.

[0181] in,

[0182] R e1 R e2 R e3 R e4 and R e5 All are H;

[0183] R d2 It is a pyrrolidine-pyrrolyl group;

[0184] R d3 For H.

[0185] In one embodiment, the present invention relates to compounds of formula (III) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs.

[0186] in,

[0187] R e1 R e2 R e3 R e4 and R e5 All are H;

[0188] R d2 C 1-6 Alkyl groups, optionally marked with one or two R groups ddreplace;

[0189] R d3 It is a -L'-3 to 7-membered heterocyclic group;

[0190] R dd For -L”-NR'R”;

[0191] R' is selected from H and C. 1-4 alkyl;

[0192] "R" is selected from H and C. 1-4 alkyl;

[0193] Or R' and R” form 3 to 6-membered heterocyclic alkyl groups;

[0194] L' is O or C 1-6 Alkylene;

[0195] "L" represents a covalent bond.

[0196] In one embodiment, the present invention relates to compounds of formula (III) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs.

[0197] in,

[0198] R d2 C 1-6 Alkyl groups, optionally marked with one or two R groups dd replace;

[0199] R d3 It is -L'-tetrahydrofuranyl;

[0200] R dd For -L”-NR'R”;

[0201] R' is selected from H and C. 1-4 alkyl;

[0202] "R" is selected from H and C. 1-4 alkyl;

[0203] L' is O;

[0204] "L" represents a covalent bond.

[0205] In one embodiment, the present invention relates to compounds of formula (II) as described above, or stereoisomers thereof, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs having formula (IV):

[0206]

[0207] Among them, Z, U, W, V, X, Y, Re1 R e2 R e3 R e4 and R e5 As defined in this application;

[0208] x1 is C(R) dd ) or N;

[0209] x2 is C(R) dd (R) dd ), N(R dd ), O or S (=O) 0-2 ;

[0210] R dd Each is independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C 2- C8 alkenyl, C 2- C8 alkynyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-C(O)OR’, -L”-C(O)NR’R”, -L”-S(O) 0-2 R', -L”-S(O)2NR'R”, -L”-S(O)NR’R”, -L”-OC(O)R’, -L”-OC(O)NR’R”, -L”-NR’R”, -L”-C(O)NR’R”, -L”-C6-C 10 Aryl, -L”-3 to 14-membered carbocyclic, -L”-3 to 14-membered heterocyclic and -L”-5 to 14-membered heteroaryl;

[0211] Or two Rs attached to the same carbon atom dd Together with the attached carbon, a 3- to 8-membered heterocyclic group is formed, wherein the 3- to 8-membered heterocyclic group is optionally selected from one or more halogens, C 1-6 Alkyl, C 1-6 Haloalkyl and -L”-OR' substituents;

[0212] L”, R' and R” are as defined in this application;

[0213] m is 0, 1, or 2;

[0214] n is 0, 1, or 2;

[0215] o can be 0, 1, or 2;

[0216] p is 0, 1, or 2;

[0217] q can be 0, 1, 2, or 3;

[0218] s can be 0, 1, 2, 3, 4 or 5.

[0219] In one embodiment, the present invention relates to compounds of formula (IV) or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs having formula (V):

[0220]

[0221] in,

[0222] Z is CR C Or N;

[0223] U is CR C Or N;

[0224] W is CR C Or N;

[0225] V is CR C Or N;

[0226] X is C(R) d1 ) or N;

[0227] Y is C(R) d2 ) or N;

[0228] R C Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0229] R e1 For H;

[0230] R e2 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0231] R e3 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0232] R e4 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0233] R e5 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0234] R d1 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0235] Rd2 Selected from H, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, -L'-OR' and -L'-3 to 6-membered heterocyclic groups, wherein the C 1-6 Alkyl groups and 3 to 6-membered heterocyclic groups are optionally surrounded by 1 or 2 R groups. dd replace;

[0236] R dd Selected from H, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, -L”-OR’ and -L”-NR’R”;

[0237] R' is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclic groups;

[0238] "R" is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclic groups;

[0239] Or R' and R” form 3 to 6-membered heterocyclic alkyl groups;

[0240] L' is selected from covalent bonds, -O-, and C. 1-6 Alkylene;

[0241] "L" is selected from covalent bonds and C 1-6 Alkylene;

[0242] m is 0, 1, or 2;

[0243] n is 0, 1, or 2;

[0244] o can be 0, 1, or 2;

[0245] p is 0, 1, or 2;

[0246] q is 0, 1, or 2;

[0247] s can be 0, 1, 2, 3, 4 or 5.

[0248] In one embodiment, the present invention relates to compounds of formula (V) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs.

[0249] in,

[0250] Z is CR C ;

[0251] U is N;

[0252] W is CR C ;

[0253] V is CR C ;

[0254] X is C(R) d1 );

[0255] Y is C(R) d2 );

[0256] R C For H;

[0257] R e1 Selected from H, halogens and C 1-6 alkyl;

[0258] R e2 Selected from H, halogens and C 1-6 alkyl;

[0259] R e3 Selected from H, halogens and C 1-6 alkyl;

[0260] R e4 Selected from H, halogens and C 1-6 alkyl;

[0261] R e5 Selected from H, halogens and C 1-6 alkyl;

[0262] R d1 Selected from H, halogens and C 1-6 alkyl;

[0263] R d2 Selected from H, C 1-6 Alkyl groups and -L'-3 to 6-membered heterocyclic groups, wherein the C 1-6 Alkyl groups and 3 to 6-membered heterocyclic groups are optionally surrounded by 1 or 2 R groups. dd replace;

[0264] R dd Selected from H, halogens, C 1-6 Alkyl groups, -L”-OR’ and -L”-NR’R”;

[0265] R' is selected from H and C. 1-6 Alkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclic groups;

[0266] "R" is selected from H and C. 1-6 Alkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclic groups;

[0267] Or R' and R” form 3 to 6-membered heterocyclic alkyl groups;

[0268] L' is selected from covalent bonds, -O-, and C. 1-6 Alkylene;

[0269] "L" is selected from covalent bonds and C 1-6 Alkylene;

[0270] m is 0 or 1;

[0271] n is 0 or 1;

[0272] o is 0 or 1;

[0273] p is 0 or 1;

[0274] q is 0 or 1;

[0275] s can be 0, 1, or 2.

[0276] In one embodiment, the present invention relates to compounds of formula (V) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs.

[0277] in,

[0278] Z is CR C ;

[0279] U is N;

[0280] W is CR C ;

[0281] V is CR C ;

[0282] X is C(R) d1 );

[0283] Y is C(R) d2 );

[0284] R C For H;

[0285] R e1 For H;

[0286] R e2 For H;

[0287] R e3 For H;

[0288] R e4 For H;

[0289] R e5 For H;

[0290] R d1 For H;

[0291] R d2 C 1-4Alkyl groups, which are substituted with substituents selected from H and -L”-NR'R”;

[0292] R dd Selected from H, C 1-4 Alkyl groups and -L”-OR';

[0293] R' is selected from H and C. 1-4 alkyl;

[0294] "R" is selected from H and C. 1-4 alkyl;

[0295] Or R' and R” form a 4- to 5-membered heterocyclic alkyl group;

[0296] "L" represents a covalent bond or C 1-4 Alkylene;

[0297] m is 0, 1, or 2;

[0298] n is 0, 1, or 2;

[0299] o can be 0, 1, or 2;

[0300] p is 0, 1, or 2;

[0301] q is 0;

[0302] s can be 0, 1, or 2.

[0303] In one embodiment, the present invention relates to the stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs of the formula (IV) as described above, having the formula (VI):

[0304]

[0305] in,

[0306] Z is CR C Or N;

[0307] U is CR C Or N;

[0308] W is CR C Or N;

[0309] V is CR C Or N;

[0310] X is C(R) d1 ) or N;

[0311] Y is C(R) d2 ) or N;

[0312] R C Selected from H, halogens, C 1-6Alkyl and C 1-6 Halogenated alkyl groups;

[0313] R e1 For H;

[0314] R e2 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0315] R e3 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0316] R e4 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0317] R e5 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0318] R d1 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0319] R d2 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -L'-3 to 6-membered heterocyclic groups, wherein the C 1-6 Alkyl groups and 3 to 6-membered heterocyclic groups are optionally surrounded by 1 or 2 R groups. dd replace;

[0320] R dd Selected from H, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, -L”-OR’ and -L”-NR’R”;

[0321] R' is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclic groups;

[0322] "R" is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclic groups;

[0323] Or R' and R” form 3 to 6-membered heterocyclic alkyl groups;

[0324] L' is selected from covalent bonds, -O-, and C. 1-6 Alkylene;

[0325] "L" is selected from covalent bonds and C 1-6 Alkylene;

[0326] m is 0, 1, or 2;

[0327] n is 0, 1, or 2;

[0328] o can be 0, 1, or 2;

[0329] p is 0, 1, or 2;

[0330] q is 0, 1, or 2;

[0331] s can be 0, 1, 2, 3, 4 or 5.

[0332] In one embodiment, the present invention relates to compounds of formula (VI) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs.

[0333] in,

[0334] Z is CR C ;

[0335] U is N;

[0336] W is CR C ;

[0337] V is CR C ;

[0338] X is C(R) d1 );

[0339] Y is C(R) d2 );

[0340] R C For H;

[0341] R e1 Selected from H, halogens and C 1-6 alkyl;

[0342] R e2 Selected from H, halogens and C 1-6 alkyl;

[0343] R e3 Selected from H, halogens and C 1-6 alkyl;

[0344] R e4 Selected from H, halogens and C 1-6 alkyl;

[0345] R e5 Selected from H, halogens and C 1-6 alkyl;

[0346] R d1 Selected from H, halogens and C 1-6 alkyl;

[0347] R d2 Selected from H, C 1-6 Alkyl groups and -L'-3 to 6-membered heterocyclic groups, wherein the C 1-6 Alkyl groups and 3 to 6-membered heterocyclic groups are optionally surrounded by 1 or 2 R groups. dd replace;

[0348] R dd Selected from H, C 1-6 Alkyl groups, -L”-OR’ and -L”-NR’R”;

[0349] R' is selected from H and C. 1-6 Alkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclic groups;

[0350] "R" is selected from H and C. 1-6 Alkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclic groups;

[0351] Or R' and R” form 3 to 6-membered heterocyclic alkyl groups;

[0352] L' is selected from covalent bonds, -O-, and C. 1-6 Alkylene;

[0353] "L" is selected from covalent bonds and C 1-6 Alkylene;

[0354] m is 0 or 1;

[0355] n is 0 or 1;

[0356] o is 0 or 1;

[0357] p is 0 or 1;

[0358] q is 0 or 1;

[0359] s can be 0, 1, or 2.

[0360] In one embodiment, the present invention relates to compounds of formula (VI) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs.

[0361] in,

[0362] Z is CR C ;

[0363] U is N;

[0364] W is CR C ;

[0365] V is CR C ;

[0366] X is C(R) d1 );

[0367] Y is C(R) d2 );

[0368] R C For H;

[0369] R e1 For H;

[0370] R e2 For H;

[0371] R e3 H, halogen (preferably F) or C 1-4 alkyl;

[0372] R e4 It is H or a halogen (preferably F);

[0373] R e5 For H;

[0374] R d1 For H;

[0375] R d2 Selected from H and C 1-4 Alkyl, the C 1-4 Alkyl groups are optionally enclosed by one or two Rs. dd replace;

[0376] R dd Selected from H and -L"-NR'R";

[0377] R' is selected from H and C. 1-4 alkyl;

[0378] "R" is selected from H and C. 1-4 alkyl;

[0379] Or R' and R” form a 4- to 5-membered heterocyclic alkyl group;

[0380] "L" represents a covalent bond;

[0381] m is 0 or 1;

[0382] n is 1;

[0383] o is 1;

[0384] p is 1;

[0385] q is 0;

[0386] s is 0.

[0387] In one embodiment, the present invention relates to compounds of formula (IV) as described above, or stereoisomers thereof, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs having formula (VII),

[0388]

[0389] in,

[0390] Z is CR C Or N;

[0391] U is CR C Or N;

[0392] W is CR C Or N;

[0393] V is CR C Or N;

[0394] X is C(R) d1 ) or N;

[0395] Y is C(R) d2 ) or N;

[0396] x1 is C(R) dd ) or N;

[0397] R C Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0398] R e1 For H;

[0399] R e2 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0400] R e3 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0401] R e4 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0402] R e5 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0403] R d1 Selected from H, halogens, C 1-6 Alkyl and C1-6 Halogenated alkyl groups;

[0404] R d2 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl, the C 1-6 Alkyl groups are optionally enclosed by one or two Rs. dd replace;

[0405] R dd Selected from H, oxo, C 1-6 Alkyl groups, -L”-NR'R” and -L”-OR';

[0406] R' is selected from H and C. 1-4 alkyl;

[0407] "R" is selected from H and C. 1-4 alkyl;

[0408] Or R' and R” form 3 to 6-membered heterocyclic alkyl groups;

[0409] "L" represents a covalent bond or C 1-6 alkyl;

[0410] m is 0, 1, or 2;

[0411] n is 0, 1, or 2;

[0412] o can be 0, 1, or 2;

[0413] p is 0, 1, or 2;

[0414] q is 0, 1, or 2;

[0415] s can be 0, 1, 2, 3, 4 or 5.

[0416] In one embodiment, the present invention relates to compounds of formula (VII) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs.

[0417] in,

[0418] Z is CR C ;

[0419] U is CR C Or N;

[0420] W is CR C ;

[0421] V is CR C ;

[0422] X is C(R) d1 ) or N;

[0423] Y is C(R) d2 );

[0424] x1 is C(R) dd ) or N;

[0425] R C For H;

[0426] R e1 For H;

[0427] R e2 Selected from H, halogen or C 1-6 alkyl;

[0428] R e3 Selected from H, halogen or C 1-6 alkyl;

[0429] R e4 Selected from H, halogen or C 1-6 alkyl;

[0430] R e5 Selected from H, halogen or C 1-6 alkyl;

[0431] R d1 For H;

[0432] R d2 Selected from H, halogen or C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally enclosed by one or two Rs. dd replace;

[0433] R dd Selected from H, halogen, oxo, C 1-6 Alkyl groups, -L”-NR'R” and -L”-OR';

[0434] R' is selected from H and C. 1-4 alkyl;

[0435] "R" is selected from H and C. 1-4 alkyl;

[0436] Or R' and R” form a 4- to 5-membered heterocyclic alkyl group;

[0437] "L" represents a covalent bond or C 1-4 alkyl;

[0438] m is 0, 1, or 2;

[0439] n is 0, 1, or 2;

[0440] o can be 0, 1, or 2;

[0441] p is 0, 1, or 2;

[0442] q is 0, 1, or 2;

[0443] s can be 0, 1, or 2.

[0444] In one embodiment, the present invention relates to compounds of formula (VII) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs.

[0445] in,

[0446] Z is CR C ;

[0447] U is CR C Or N;

[0448] W is CR C ;

[0449] V is CR C ;

[0450] X is C(R) d1 ) or N;

[0451] Y is C(R) d2 );

[0452] x1 is C(R) dd ) or N;

[0453] R C For H;

[0454] R e1 For H;

[0455] R e2 For H;

[0456] R e3 For H;

[0457] R e4 For H;

[0458] R e5 For H;

[0459] R d1 For H;

[0460] R d2 H, halogen or C 1-4 Alkyl, the C 1-4 Alkyl groups are optionally enclosed by one or two Rs. dd replace;

[0461] R dd For H, C 1-4 Alkyl or -L”-NR'R”;

[0462] R' is selected from H and C.1-4 alkyl;

[0463] "R" is selected from H and C. 1-4 alkyl;

[0464] m is 0 or 1;

[0465] n is 0 or 1;

[0466] o is 0 or 1;

[0467] p is 0 or 1;

[0468] q is 0 or 2;

[0469] s is 0 or 1.

[0470] In one embodiment, the present invention relates to compounds of formula (IV) or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs having formula (VIII), as described above.

[0471]

[0472] in,

[0473] Z is CR C Or N;

[0474] U is CR C Or N;

[0475] W is CR C Or N;

[0476] V is CR C Or N;

[0477] X is C(R) d1 ) or N;

[0478] Y is C(R) d2 ) or N;

[0479] x1 is C(R) dd ) or N;

[0480] R C Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0481] R e1 For H;

[0482] R e2 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0483] Re3 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0484] R e4 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0485] R e5 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0486] R d1 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0487] R d2 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl, the C 1-6 Alkyl groups are optionally enclosed by one or two Rs. dd replace;

[0488] R dd Selected from H, halogen, oxo, C 1-6 Alkyl groups, -L”-NR'R”, -L”-NR'R”, and -L”-OR'; or two Rs attached to the same carbon atom. dd Together with the attached carbon, a 3- to 8-membered heterocyclic group is formed, wherein the 3- to 8-membered heterocyclic group is optionally selected from halogens, C 1-6 Alkyl, C 1-6 Substitution with haloalkyl groups and -L”-OR' groups;

[0489] R' is selected from H and C. 1-4 alkyl;

[0490] "R" is selected from H and C. 1-4 alkyl;

[0491] Or R' and R” form 3 to 6-membered heterocyclic alkyl groups;

[0492] "L" represents a covalent bond or C 1-6 Alkylene;

[0493] m is 0, 1, or 2;

[0494] n is 0, 1, or 2;

[0495] o can be 0, 1, or 2;

[0496] p is 0, 1, or 2;

[0497] q is 0, 1, or 2;

[0498] s can be 0, 1, 2, 3, 4 or 5.

[0499] In one embodiment, the present invention relates to compounds of formula (VIII) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs.

[0500] in,

[0501] Z is CR C ;

[0502] U is N;

[0503] W is CR C ;

[0504] V is CR C ;

[0505] X is C(R) d1 );

[0506] Y is C(R) d2 );

[0507] x1 is N;

[0508] R C For H;

[0509] R e1 For H;

[0510] R e2 Selected from H, halogens and C 1-6 alkyl;

[0511] R e3 Selected from H, halogens and C 1-6 alkyl;

[0512] R e4 Selected from H, halogens and C 1-6 alkyl;

[0513] R e5 Selected from H, halogens and C 1-6 alkyl;

[0514] R d1 For H;

[0515] R d2 Selected from halogens and C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally enclosed by one or two Rs. dd replace;

[0516] R dd Selected from H, halogens, C 1-6Alkyl groups, -L”-NR'R” and -L”-OR';

[0517] R' is selected from H and C. 1-4 alkyl;

[0518] "R" is selected from H and C. 1-4 alkyl;

[0519] "L" represents a covalent bond or C 1-4 alkyl;

[0520] m is 0 or 1;

[0521] n is 0 or 1;

[0522] o is 0 or 1;

[0523] p is 0 or 1;

[0524] q is 0;

[0525] s can be 0, 1, or 2.

[0526] In one embodiment, the present invention relates to formula (VIII) or its stereoisomers as described above, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs.

[0527] in,

[0528] Z is CR C ;

[0529] U is N;

[0530] W is CR C ;

[0531] V is CR C ;

[0532] X is C(R) d1 );

[0533] Y is C(R) d2 );

[0534] x1 is N;

[0535] R C For H;

[0536] R e1 For H;

[0537] R e2 For H;

[0538] R e3 For H;

[0539] R e4 For H;

[0540] R e5 For H;

[0541] R d1 For H;

[0542] R d2 Selected from halogens and C 1-4 Alkyl, the C 1-4 Alkyl groups are optionally enclosed by one or two Rs. dd replace;

[0543] R dd Selected from H, halogens, C 1-4 Alkyl groups, -L”-NR'R” and -L”-OR';

[0544] R' is selected from H and C. 1-4 alkyl;

[0545] "R" is selected from H and C. 1-4 alkyl;

[0546] "L" represents a covalent bond or C 1-4 alkyl;

[0547] m is 0 or 1;

[0548] n is 1;

[0549] o is 1;

[0550] p is 1;

[0551] q is 0;

[0552] s is 1 or 2.

[0553] In one embodiment, the present invention relates to a compound of formula (IX), or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug:

[0554]

[0555] in,

[0556] X is C(R) d1 ) or N;

[0557] Y is C(R) d2 ) or N;

[0558] R e1 Selected from H, C 1-6 Alkyl and Halogenated C 1-6 alkyl;

[0559] R e2 Selected from H, halogens, C 1-6 Alkyl and Halogenated C1-6 alkyl;

[0560] R e3 Selected from H, halogens, C 1-6 Alkyl and Halogenated C 1-6 alkyl;

[0561] R e6 Selected from H, halogen, -CN, oxo, C 1-6 Alkyl and Halogenated C 1-6 alkyl;

[0562] R e7 Selected from H, halogen, -CN, oxo, C 1-6 Alkyl and Halogenated C 1-6 alkyl;

[0563] R d1 Selected from H, halogens, C 1-6 Alkyl and Halogenated C 1-6 alkyl;

[0564] R d2 Selected from H, halogens, C 1-6 Alkyl and Halogenated C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by one or two Rs. dd replace;

[0565] R d3 It is a -L'-3 to 7-membered heterocyclic group, which is optionally surrounded by 1 or 2 R groups. dd replace;

[0566] Or, R d2 and R d3 Together with the carbon atoms attached to them, they form 5- to 7-membered heterocyclic groups, which optionally have 1 or 2 R atoms. dd replace;

[0567] R dd Selected from H, halogens, C 1-6 Alkyl groups, -L”-NR'R” and -L”-OR';

[0568] R' is H or C 1-6 alkyl;

[0569] R" represents H or C 1-6 alkyl;

[0570] L' represents a covalent bond, -O-, or C. 1-6 Alkylene;

[0571] "L" represents a covalent bond or C 1-6 Alkylene.

[0572] In one embodiment, the present invention relates to compounds of formula (IX) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs.

[0573] in,

[0574] X is C(R) d1 );

[0575] Y is C(R) d2 );

[0576] R d1 For H;

[0577] R e1 For H;

[0578] R e2 Selected from H and C 1-4 alkyl;

[0579] R e3 For H;

[0580] R e6 For H;

[0581] R e7 For H;

[0582] R d2 and R d3 Together with the carbon atoms attached to them, they form 5- to 6-membered heterocyclic groups, which are optionally bounded by 1 or 2 R atoms. dd replace;

[0583] R dd C 1-4 alkyl.

[0584] In one embodiment, the present invention relates to compounds of formula (IX) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs.

[0585] in,

[0586] X is C(R) d1 );

[0587] Y is C(R) d2 );

[0588] R e1 For H;

[0589] R e2 Selected from H and C 1-6 alkyl;

[0590] R e3 For H;

[0591] R e6 For H;

[0592] R e7 For H;

[0593] R d1 For H;

[0594] R d2 C 1-6 Alkyl groups, optionally marked with one or two R groups dd replace;

[0595] R d3 It is a -L'-4 to 6-membered heterocyclic group;

[0596] R dd For -L”-NR'R”;

[0597] R' is selected from H and C. 1-4 alkyl;

[0598] "R" is selected from H and C. 1-4 alkyl;

[0599] "L" represents a covalent bond.

[0600] In one embodiment, the present invention relates to a compound of formula (X), or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug:

[0601]

[0602] in,

[0603] X is C(R) d1 ) or N;

[0604] Y is C(R) d2 ) or N;

[0605] R e1 C 1-6 alkyl;

[0606] R e2 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0607] R e3 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0608] R e4 Selected from H, halogens, C 1-6 Alkyl and C1-6 Halogenated alkyl groups;

[0609] R e5 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0610] R d1 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0611] R d2 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl, the C 1-6 Alkyl groups are optionally surrounded by one or two Rs. dd replace;

[0612] R d3 It is a -L'-3 to 7-membered heterocyclic group;

[0613] Or, R d2 and R d3 Together with the carbon atoms attached to them, they form 5- to 7-membered heterocyclic groups, which are optionally bounded by 1 or 2 R atoms. dd replace;

[0614] R dd Selected from H, halogens, C 1-6 Alkyl groups, -L”-NR'R” and -L”-OR';

[0615] R' is H or C 1-6 alkyl;

[0616] R" represents H or C 1-6 alkyl;

[0617] L' represents a covalent bond, -O-, or C. 1-6 Alkylene;

[0618] "L" represents a covalent bond or C 1-6 Alkylene.

[0619] In one embodiment, the present invention relates to compounds of formula (X) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs.

[0620] in,

[0621] X is C(R) d1 );

[0622] Y is C(R) d2 );

[0623] Rd1 For H;

[0624] R e1 C 1-4 alkyl;

[0625] R e2 For H;

[0626] R e3 For H;

[0627] R e4 For H;

[0628] R e5 For H;

[0629] R d2 and R d3 Together with the carbon atoms attached to them, they form 5- to 6-membered heterocyclic groups, which are optionally bounded by 1 or 2 R atoms. dd replace;

[0630] R dd C 1-4 alkyl.

[0631] In one embodiment, the present invention relates to compounds of formula (X) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs.

[0632] in,

[0633] X is C(R) d1 );

[0634] Y is N;

[0635] R e1 C 1-4 alkyl;

[0636] R e2 For H;

[0637] R e3 For H;

[0638] R e4 For H;

[0639] R e5 For H;

[0640] R d1 For H;

[0641] R d3 It is a -L'-4 to 6-membered heterocyclic group, which is optionally surrounded by 1 or 2 R groups. dd replace;

[0642] R dd C1-4 alkyl;

[0643] L' represents a covalent bond.

[0644] In one embodiment, the present invention relates to compounds of formula (XI), or stereoisomers thereof, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs:

[0645]

[0646] in,

[0647] X is C(R) d1 ) or N;

[0648] Y is C(R) d2 ) or N;

[0649] R e2 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0650] R e3 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0651] R e4 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0652] R e5 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0653] R e8 Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0654] R d1 Selected from H, halogens and C 1-6 alkyl;

[0655] R d2 Selected from halogens and C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally enclosed by one or two Rs. dd replace;

[0656] R d3 It is a -L'-4 to 6-membered heterocyclic group, which is optionally surrounded by 1 or 2 R groups. dd replace;

[0657] Rdd Selected from C 1-6 Alkyl groups, -L”-NR'R” and -L”-OR';

[0658] R' is H or C 1-6 alkyl;

[0659] R" represents H or C 1-6 alkyl;

[0660] L' represents a covalent bond, -O-, or C. 1-6 Alkylene

[0661] "L" represents a covalent bond or C 1-6 Alkylene.

[0662] In one embodiment, the present invention relates to compounds of formula (XI) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs.

[0663] in,

[0664] X is C(R) d1 );

[0665] Y is C(R) d2 );

[0666] R e2 For H;

[0667] R e3 For H;

[0668] R e4 For H;

[0669] R e5 Selected from halogens and C 1-4 alkyl;

[0670] R e8 Selected from H and halogens;

[0671] R d1 For H;

[0672] R d2 Selected from halogens and C 1-4 Alkyl, the C 1-4 Alkyl groups can be selected from 1 or 2 Rdd replace;

[0673] R d3 It is a -L'-4 to 6-membered heterocyclic group, which is optionally surrounded by 1 or 2 R groups. dd replace;

[0674] R dd Selected from C 1-4Alkyl groups, -L”-NR'R” and -L”-OR';

[0675] R' is H or C 1-4 alkyl;

[0676] R" represents H or C 1-4 alkyl;

[0677] L' is a covalent bond;

[0678] "L" represents a covalent bond or C 1-4 Alkylene.

[0679] This invention relates to specific compounds, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs, selected from:

[0680]

[0681]

[0682]

[0683]

[0684] In one embodiment, the present invention relates to a pharmaceutical composition comprising the compound of the present invention or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs, and pharmaceutically acceptable carriers, adjuvants, or mediators.

[0685] In one embodiment, the present invention relates to the use of the compound of the invention or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs or pharmaceutical compositions comprising the thereof in the preparation of a medicament for the prevention and / or treatment of HPK1-mediated disorders, diseases or conditions.

[0686] In one embodiment, the present invention relates to the compounds described herein or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs, or pharmaceutical compositions comprising thereof, for the prevention and / or treatment of HPK1-mediated disorders, diseases, or conditions.

[0687] In one embodiment, the present invention relates to a method for preventing and / or treating HPK1-mediated disorders, diseases, or conditions, comprising administering to a subject a compound of the present invention or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs, or pharmaceutical compositions comprising the present invention.

[0688] Furthermore, the disorder, disease, or symptom mentioned therein is a proliferative disorder.

[0689] Furthermore, the proliferative disorder mentioned above is cancer.

[0690] Furthermore, the proliferative impairment is associated with one or more activating mutations in HPK1.

[0691] In one implementation, the obstacle, disease, or symptom is a chronic viral infection.

[0692] In one embodiment, the present invention relates to the use of the compounds of the present invention or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs, or pharmaceutical compositions comprising the thereof in the preparation of a medicament for increasing the efficacy of a vaccine.

[0693] In one embodiment, the present invention relates to a compound or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug, or pharmaceutical composition comprising the thereof, for increasing the efficacy of a vaccine.

[0694] In one embodiment, the present invention relates to a method for increasing the efficacy of a vaccine, comprising administering to a subject a compound of the present invention or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs, or pharmaceutical compositions comprising the present invention.

[0695] Furthermore, this application relates to the following implementation scheme:

[0696] In one embodiment, the present invention relates to compounds of formula (1), or stereoisomers thereof, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs.

[0697]

[0698] in:

[0699] A is CR o Or N;

[0700] D is CR o Or N;

[0701] H is CR o Or N;

[0702] E is CR o Or N;

[0703] J is selected from covalent bonds, -O-, -S-, -NR'-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR'-, -OC(O)-, -OC(O)NR'-, -N(R')C(O)O-, -N(R')C(O)- and -N(R')S(O)2-; or J is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -N(R')C(O)-, -C(O)N(R')-, -N(R')S(O)2-, -S(O)2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

[0704] R o Selected from H, halogen, -CN, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, -L-OR', -L-NR'R", -LC(O)NR'R", -L-C6-C 10 Aryl, -L-3 to 14-membered carbocyclic, -L-3 to 14-membered heterocyclic and -L-5 to 14-membered heteroaryl;

[0705] R G Selected from H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C 10 Aryl, 3 to 14-membered carbocyclic, 3 to 14-membered heterocyclic and 5 to 14-membered heteroaryl, each of which may be optionally substituted by g Rg groups;

[0706] R F Selected from -L-C6-C 10 aryl, -L-3 to 14-membered carbocyclic, -L-3 to 14-membered heterocyclic and -L-5 to 14-membered heteroaryl, wherein C6-C 10 Aryl, 3- to 14-membered carbocyclic, 3- to 14-membered heterocyclic, and 5- to 14-membered heteroaryl are each optionally replaced by f R f Group substitution;

[0707] Among them, R g Each is independently selected from H, halogens, -CN, -L'-S(O). 0-2 R', -L'-S(O)2NR'R", -L'-S(O)NR'R", -L'-OR', -L'-NR'R", -L'-C(O)OR' and -L'-C(O)NR'R", or R g Selected from C1-C8 alkyl, C 2- C8 alkenyl, C 2- C8 ynyl, C1-C8 haloalkyl and Each of them is randomly assigned to h R.gg replace;

[0708] The ring in question can be either an aromatic ring or a non-aromatic ring;

[0709] w1 is selected from (CR) w1 R w1 ') r1 NR w1 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[0710] w2 is selected from (CR) w2 R w2 ') r2 NR w2 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[0711] w3 is selected from (CR) w3 R w3 ') r3 NR w3 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[0712] w4 is selected from (CR) w4 R w4 ') r4 and N;

[0713] w5 is selected from (CR) w5 R w5 ') r5 NR w5 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[0714] w6 is selected from (CR) w6 R w6 ') r6 NR w6 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[0715] and / or

[0716] Among w1, w2, w3, w4, w5, and w6, the two non-adjacent variables can be arbitrarily chosen from -(CH2). t -Bridge, where -(CH2) t One or more methylene groups in - are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; and / or

[0717] In w1, w2, w3, w4, w5, and w6, if a substituent is present on a single atom, it forms a 3-7 membered carbon ring or a 3-7 membered heterocycle together with that atom, thereby forming a spirocyclic group as a whole; and / or

[0718] If substituents on adjacent atoms are present, they may, together with the atoms, optionally form 3-7 membered carbon rings or 3-7 membered heterocycles, thereby forming a fused ring group as a whole.

[0719] R w1 R w1 '、R w2 R w2 '、R w3 R w3 '、R w4 R w4 '、R w5 R w5 '、R w6 R w6 Each element is independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C 2- C8 alkenyl, C 2- C8 alkynyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-C(O)OR’, -L”-C(O)NR’R”, -L”-S(O) 0-2 R', -L”-S(O)2NR'R”, -L”-S(O)NR’R”, -L”-OC(O)R’, -L”-OC(O)NR’R”, -L”-NR’R”, -L”-OC(O)NR’R”, -L”-C6-C 10 Aryl, -L”-3 to 14-membered carbocyclic, -L”-3 to 14-membered heterocyclic, and -L”-5 to 14-membered heteroaryl; wherein the aryl, carbocyclic, heterocyclic, and heteroaryl are optionally surrounded by k R ggg replace;

[0720] R gg Independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C 2- C8 alkenyl, C 2- C8 alkynyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-C(O)OR’, -L”-C(O)NR’R”, -L”-S(O) 0-2 R', -L”-S(O)2NR'R”, -L”-S(O)NR’R”, -L”-OC(O)R’, -L”-OC(O)NR’R”, -L”-NR’R”, -L”-C(O)NR’R”, -L”-C6-C 10 Aryl, -L”-3 to 14-membered carbocyclic, -L”-3 to 14-membered heterocyclic, and -L”-5 to 14-membered heteroaryl; wherein the aryl, carbocyclic, heterocyclic, and heteroaryl are optionally surrounded by k Rggg replace;

[0721] R ggg Each is independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C 2- C8 alkenyl, C 2- C8 alkynyl, C1-C8 haloalkyl, -L”'-OR', -L”'-NR'R”, -L”'-C(O)OR', -L”'-C(O)NR'R”, -L”'-S(O) 0-2 R', -L"'-S(O)2NR'R", -L"'-S(O)NR'R", -L"'-OC(O)R', -L"'-OC(O)NR'R", -L"'-NR'R", -L"'-OC(O)NR'R", -L"'-C6-C 10 Aryl, -L”'-3 to 14-membered carbocyclic, -L”'-3 to 14-membered heterocyclic and -L”'-5 to 14-membered heteroaryl;

[0722] R f Each is independently selected from H, halogen, -CN, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L'-OR', -L'-NR'R", -NO2, -L'-SR', -L'-C(O)OR', -L'-C(O)NR'R", -L'-S(O)2R', -L'-S(O)2NR'R", -L'-OC(O)R', -L'-OC(O)NR'R", -L'-C6-C 10 Aryl, -L'-3 to 14-membered carbocyclic, -L'-3 to 14-membered heterocyclic and -L'-5 to 14-membered heteroaryl;

[0723] R' is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-NR”'R””, -L”-C6-C 10 Aryl, -L”-3 to 14-membered carbocyclic, -L”-3 to 14-membered heterocyclic and -L”-5 to 14-membered heteroaryl;

[0724] R” is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-NR”'R””, -L”-C6-C 10 Aryl, -L”-3 to 14-membered carbocyclic, -L”-3 to 14-membered heterocyclic and -L”-5 to 14-membered heteroaryl;

[0725] Alternatively, R' and R” together with the N atoms they are attached to form 3 to 14-membered heterocyclic groups;

[0726] R”' and R”” are each independently selected from H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, -L”'-C6-C 10 Aryl, -L”'-3 to 14-membered carbocyclic, -L”'-3 to 14-membered heterocyclic and -L”'-5 to 14-membered heteroaryl; or R”' and R”” together with the N atom to which they are attached to form 3 to 14-membered heterocyclic groups;

[0727] L is selected from covalent bonds, -O-, -S-, -NR'-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR'-, -OC(O)-, -OC(O)NR'-, -N(R')C(O)O-, -N(R')C(O)- and -N(R')S(O)2-; or L is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -N(R')C(O)-, -C(O)N(R')-, -N(R')S(O)2-, -S(O)2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

[0728] L' is selected from covalent bonds, -O-, -S-, -NR'-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR'-, -OC(O)-, -OC(O)NR'-, -N(R')C(O)O-, -N(R')C(O)- and -N(R')S(O)2-; or L' is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -N(R')C(O)-, -C(O)N(R')-, -N(R')S(O)2-, -S(O)2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

[0729] L” is selected from covalent bonds, -O- and -S-; or L” is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-.

[0730] L”' is selected from covalent bonds, -O- and -S-; or L”' is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

[0731] r1, r2, r3, r4, r5, and r6 are each independently 0, 1, or 2;

[0732] f is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0733] g is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0734] h can be 1, 2, 3, 4, or 5;

[0735] k is 1, 2, 3, 4 or 5;

[0736] t can be 0, 1, 2 or 3.

[0737] In one embodiment, the present invention relates to compounds of formula (1) as described above, which are one of the following formulas:

[0738]

[0739] In one embodiment, the present invention relates to compounds of formula (1) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs:

[0740] Among them, R G for

[0741] The ring in question can be either an aromatic ring or a non-aromatic ring;

[0742] S is C(R) x1 R x1’ ) or NR x1 ;

[0743] T is C(R) x2 R x2’ ) or NR x2 ;

[0744] N is C(R) x4 R x4’ ) or NR x4 ;

[0745] M is C(R) x5 R x5’ ) or NR x5 ;

[0746] K is C(R) x6 R x6’ ) or N;

[0747] The condition is that one or two of S, T, M, and N are absent;

[0748] R x1R x1’ R x2 and R x2’ Each is independently absent or selected from H, halogen, oxo, -CN, -L'-OR' and -L'-NR'R", or R x1 and R x2 Each is independently selected from C 1-8 Alkyl, C 1-8 Haloalkyl-, L'-phenyl, -L'-3 to 6-membered carbocyclic, -L'-3 to 10-membered heterocyclic and -L'-5 to 6-membered heteroaryl, each optionally dominated by h R gg replace;

[0749] R x4 R x4’ R x5 R x5’ R x6 and R x6’ Each is independently absent or selected from H, halogens, -L'-OR' and -L'-NR'R", or R x4 and R x5 Each is independently selected from C 1-8 Alkyl, C 1-8 Haloalkyl, -L'-phenyl, -L'-3 to 6-membered carbocyclic, -L'-3 to 6-membered heterocyclic and -L'-5 to 6-membered heteroaryl, each optionally dominated by h R gg replace.

[0750] In one embodiment, the present invention relates to compounds of formula (1) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs:

[0751] Among them, R G Selected from C6-C 10 Aryl, 3- to 7-membered monocyclic carbocyclic, 3- to 7-membered monocyclic heterocyclic, 5- to 6-membered monocyclic heteroaryl, 6- to 10-membered bicyclic groups containing 0-4 heteroatoms selected from N, O and S, and 11- to 14-membered tricyclic groups containing 0-4 heteroatoms selected from N, O and S.

[0752] In one embodiment, the present invention relates to compounds of formula (1) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs:

[0753] Among them, R g Selected from -L'-S(O) 0-2 R', -L'-NR'R" and

[0754] In one embodiment, the present invention relates to compounds of formula (1) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs:

[0755] Among them, R G Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziridine, oxacyclopentyl, oxacyclohexyl, phenyl, furanyl, furazanyl, imidazoalkyl, imidazolinyl, imidazolyl, isothiazolyl, isoxazolyl, morpholinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolyl, oxazolyl, pyrimidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyrazolyl, pyrazolyl, pyridinyl, pyridinyl, pyrrolylyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolyl, thiophene, triazinyl, 1,2,3-triazolyl, 1,2,4-triazole 1,2,5-triazolyl, 1,3,4-triazolyl, xanthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, hexahydropyrazinoquinolinyl, hexahydrooxazinodianaphthyl, hexahydropyrazinodianaphthyl, pyridinopyrrolopyrazinyl, tetrahydropyridinopyrrolopyrazinyl, pyridinoimidazopyrazinyl, tetrahydropyridinoimidazopyrazinyl, pyridinopyrrolooxazinyl, di Hydropyridinopyrroloxazinyl, tetrahydropyridinopyrroloxazinyl, pyridinoimidazoxazinyl, dihydropyridinoimidazoxazinyl, pyridinopyrrolopyrazinyl, hexahydropyridinopyrrolopyrazinyl, pyrazinodiazanaphthyl, tetrahydropyrazinodiazanaphthyl, hexahydropyrazinodiazanaphthyl, oxazinodiazanaphthyl, tetrahydrooxazinodiazanaphthyl and hexahydrooxazinodiazanaphthyl.

[0756] In one embodiment, the present invention relates to compounds of formula (1) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs:

[0757] Among them, R G Selected from

[0758]

[0759] In one embodiment, the present invention relates to compounds of formula (1) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs:

[0760] Among them, R g Selected from F, CH3, -OCH3, CN, -C(O)-,

[0761]

[0762]

[0763]

[0764] In one embodiment, the present invention relates to compounds of formula (1) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs:

[0765] Among them, R G Rather than replacing base R g Together they form groups selected from the following:

[0766]

[0767]

[0768]

[0769]

[0770]

[0771]

[0772]

[0773] In one embodiment, the present invention relates to compounds of formula (1) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs:

[0774] Among them, R FSelected from phenyl, -L-phenyl, -L-cyclopentyl, pyridyl, pyrimidinyl, pyrazinyl, pyrroloyl, pyrazolyl, imidazoleyl, pyrrolopyridyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridinyl, imidazoleolopyridinyl, imidazoleolopyrimidinyl, imidazoleolopyridinyl, dihydrocyclopentadienylpyridinyl, tetrahydroimidazopyridinyl, tetrahydropyrazolopyridinyl, benzimidazoleyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridinyl, pyridinolpyridinyl, pyridinolpyridinyl, dihydropyridinyl Andoxazinyl, indolyl, dihydroindolyl, triazolylpyridinyl, tetrahydroimidazopyrazinyl, dihydropyrrolopyridinyl, thienopyridinyl, benzimidazolyl, dihydropyridinoxazinyl, dihydroimidazopyrazinyl, tetrahydropyrazolylpyridinyl, dihydropyrazolyloxazinyl, dihydropyrroloimidazoyl, oxazolylpyridinyl, pyrazolozaheptanyl, pyrazolozaheptanyl, imidazozaheptanyl, imidazozaheptanyl, pyrazolodiazaheptanyl, pyrazolodiazaheptanyl and thienopyridinyl.

[0775] In one embodiment, the present invention relates to compounds of formula (1) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs:

[0776] Among them, R F Selected from

[0777] Where f is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0778] In one embodiment, the present invention relates to compounds of formula (1) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs:

[0779] Among them, R f Selected from H, -CH3, -CH2CH3, -CF3, -CHF2, -OCH3, -OCF3, -OCHF2, -OCH2CH3, -CN, -NH2, -C(O)-, OH, F, Cl, -CHF2 and cyclopropyl.

[0780] In one embodiment, the present invention relates to compounds of formula (1) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs:

[0781] Among them, R F Together with its substituent R f Selected from:

[0782]

[0783]

[0784] In one embodiment, the present invention relates to a compound of formula (1) as described above, or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug, wherein said compound is represented by one of the following formulas:

[0785]

[0786]

[0787]

[0788] in,

[0789] The ring in question can be either an aromatic ring or a non-aromatic ring;

[0790] Each can be a double bond or a single bond independently;

[0791] S is C(R) x1 ) or N;

[0792] T is C(R) x2 ) or N;

[0793] w1 is selected from (CR) w1 R w1 ') r1 NR w1 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[0794] w2 is selected from (CR) w2 R w2 ') r2 NR w2 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[0795] w3 is selected from (CR) w3 R w3 ') r3 NR w3 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[0796] w4 is selected from (CR) w4 R w4 ') r4 and N;

[0797] w5 is selected from (CR)w5 R w5 ') r5 NR w5 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[0798] w6 is selected from (CR) w6 R w6 ') r6 NR w6 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[0799] and / or

[0800] Among w1, w2, w3, w4, w5, and w6, the two non-adjacent variables can be arbitrarily chosen from -(CH2). t -Bridge, where -(CH2) t One or more methylene groups in - are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; and / or

[0801] In w1, w2, w3, w4, w5, and w6, if a substituent is present on a single atom, it forms a 3-7 membered carbon ring or a 3-7 membered heterocycle together with that atom, thereby forming a spirocyclic group as a whole; and / or

[0802] If substituents on adjacent atoms are present, they may, together with the atoms, optionally form 3-7 membered carbon rings or 3-7 membered heterocycles, thereby forming a fused ring group as a whole.

[0803] R o Selected from H, CN, halogens, C1-C8 alkyl, C1-C8 haloalkyl, -L-OR' and -L-NR'R";

[0804] R v1 -R v5 R f1 -R f5 R g1 -R g5 R h1 -R h4 R j1 -R j4 R k1 -R k4 R m1 -R m4 R n1 -R n5 R p1 -R p4 R q1 -R q5 R s1-R s5 R t1 -R t6 R u1 -R u5 Each is independently selected from H, CN, halogen, C1-C8 alkyl, C1-C8 haloalkyl, -L'-OR', -L'-NR'R", -L'-SR', -L'-3 to 6-membered carbon cycloyl, -L'-4 to 6-membered heterocyclic and -L'-5 to 6-membered heteroaryl;

[0805] R x1 and R x2 Each is independently selected from H, halogen, -CN, -L'-OR' and -L'-NR'R", or R x1 and R x2 Each is independently selected from C 1-8 Alkyl, C 1-8 Haloalkyl-, L'-phenyl, -L'-3 to 6-membered carbocyclic, -L'-3 to 6-membered heterocyclic and -L'-5 to 6-membered heteroaryl, each optionally dominated by h R gg replace;

[0806] R x4 and R x5 Each is independently selected from H, halogen, -L'-OR' and -L'-NR'R", or R x4 and R x5 Each is independently selected from C 1-8 Alkyl, C 1-8 Haloalkyl, -L'-phenyl, -L'-3 to 6-membered carbocyclic, -L'-3 to 6-membered heterocyclic and -L'-5 to 6-membered heteroaryl, each optionally dominated by h R gg replace;

[0807] R w1 R w1 '、R w2 R w2 '、R w3 R w3 '、R w4 R w4 '、R w5 R w5 '、R w6 R w6 Each element is independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C 2- C8 alkenyl, C 2- C8 alkynyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-C(O)OR’, -L”-C(O)NR’R”, -L”-S(O) 0-2R', -L”-S(O)2NR'R”, -L”-S(O)NR’R”, -L”-OC(O)R’, -L”-OC(O)NR’R”, -L”-NR’R”, -L”-OC(O)NR’R”, -L”-C6-C 10 Aryl, -L”-3 to 14-membered carbocyclic, -L”-3 to 14-membered heterocyclic, and -L”-5 to 14-membered heteroaryl; wherein the aryl, carbocyclic, heterocyclic, and heteroaryl are optionally surrounded by k R ggg replace;

[0808] R gg Independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C 2- C8 alkenyl, C 2- C8 alkynyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-C(O)OR’, -L”-C(O)NR’R”, -L”-S(O) 0-2 R', -L”-S(O)2NR'R”, -L”-S(O)NR’R”, -L”-OC(O)R’, -L”-OC(O)NR’R”, -L”-NR’R”, -L”-C(O)NR’R”, -L”-C6-C 10 Aryl, -L”-3 to 14-membered carbocyclic, -L”-3 to 14-membered heterocyclic, and -L”-5 to 14-membered heteroaryl; wherein the aryl, carbocyclic, heterocyclic, and heteroaryl are optionally surrounded by k R ggg replace;

[0809] R ggg Each is independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C 2- C8 alkenyl, C 2- C8 alkynyl, C1-C8 haloalkyl, -L”'-OR', -L”'-NR'R”, -L”'-C(O)OR', -L”'-C(O)NR'R”, -L”'-S(O) 0-2 R', -L"'-S(O)2NR'R", -L"'-S(O)NR'R", -L"'-OC(O)R', -L"'-OC(O)NR'R", -L"'-NR'R", -L"'-OC(O)NR'R", -L"'-C6-C 10 Aryl, -L”'-3 to 14-membered carbocyclic, -L”'-3 to 14-membered heterocyclic and -L”'-5 to 14-membered heteroaryl;

[0810] L is selected from covalent bonds, -O-, -S-, -NR'-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR'-, -OC(O)-, -OC(O)NR'-, -N(R')C(O)O-, -N(R')C(O)- and -N(R')S(O)2-; or L is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -N(R')C(O)-, -C(O)N(R')-, -N(R')S(O)2-, -S(O)2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

[0811] L' is selected from covalent bonds, -O-, -S-, -NR'-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR'-, -OC(O)-, -OC(O)NR'-, -N(R')C(O)O-, -N(R')C(O)- and -N(R')S(O)2-; or L' is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -N(R')C(O)-, -C(O)N(R')-, -N(R')S(O)2-, -S(O)2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

[0812] L” is selected from covalent bonds, -O- and -S-; or L” is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-.

[0813] L”' is selected from covalent bonds, -O-, and -S-; or L”' is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-.

[0814] R' is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-NR”'R””, -L”-C6-C 10 Aryl, -L”-3 to 14-membered carbocyclic, -L”-3 to 14-membered heterocyclic and -L”-5 to 14-membered heteroaryl;

[0815] R” is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-NR”'R””, -L”-C6-C 10 Aryl, -L”-3 to 14-membered carbocyclic, -L”-3 to 14-membered heterocyclic and -L”-5 to 14-membered heteroaryl;

[0816] Alternatively, R' and R” together with the N atoms they are attached to form 3 to 14-membered heterocyclic groups;

[0817] R”' and R”” are each independently selected from H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, -L”'-C6-C 10 Aryl, -L”'-3 to 14-membered carbocyclic, -L”'-3 to 14-membered heterocyclic and -L”'-5 to 14-membered heteroaryl; or R”' and R”” together with the N atom to which they are attached to form 3 to 14-membered heterocyclic groups;

[0818] r1, r2, r3, r4, r5, and r6 are each independently 0, 1, or 2;

[0819] h can be 1, 2, 3, 4, or 5;

[0820] k is 1, 2, 3, 4 or 5;

[0821] t can be 0, 1, or 2.

[0822] In one embodiment, the present invention relates to compounds of formula (2) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs:

[0823]

[0824] in,

[0825] The ring in question is a non-aromatic ring;

[0826] R o Selected from H, C1-C8 alkyl, and C1-C8 haloalkyl;

[0827] S is C(R) x1 ) or N;

[0828] T is C(R) x2 ) or N;

[0829] R x1 Selected from H, C 1-8 Alkyl and C 1-8 Halogenated alkyl groups;

[0830] R x2Selected from H, halogen, -L'-OR' and -L'-NR'R", or R x2 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl, -L'-phenyl, -L'-3 to 6-membered carbocyclic, -L'-4 to 6-membered heterocyclic and -L'-5 to 6-membered heteroaryl, each optionally dominated by h R gg replace;

[0831] w1 is selected from (CR) w1 R w1 ') r1 NR w1 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[0832] w2 is (CR) w2 R w2 ') r2 ;

[0833] w3 is (CR) w3 R w3 ') r3 ;

[0834] w4 is selected from (CR) w4 R w4 ') r4 and N;

[0835] w5 is (CR) w5 R w5 ') r5 ;

[0836] w6 is (CR) w6 R w6 ') r6 ;

[0837] R w1 R w1 '、R w2 R w2 '、R w3 R w3 '、R w4 R w4 '、R w5 R w5 '、R w6 R w6 Each is independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-phenyl, -L”-3 to 6 carbon cycloyl, -L”-4 to 6 heterocyclic and -L”-5 to 6 heteroaryl;

[0838] R ggIndependently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L”-OR', -L”-NR'R”, -L”-phenyl, -L”-3 to 6 carbon cycloyl, -L”-4 to 6 heterocyclic and -L”-5 to 6 heteroaryl;

[0839] R v1 -R v5 Each is independently selected from H, CN, halogen, C1-C8 alkyl, C1-C8 haloalkyl, -L'-OR', -L'-NR'R", -L'-SR', -L'-3 to 6-membered carbon cycloyl, -L'-4 to 6-membered heterocyclic and -L'-5 to 6-membered heteroaryl;

[0840] L' is a covalent bond or a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -O-, -C(O)-, -S-, -S(O)- or -S(O)2-;

[0841] L” is selected from covalent bonds, -O- and -S-; or L” is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-.

[0842] R' is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-phenyl, -L”-3 to 6-membered carbon cycloyl, -L”-3 to 6-membered heterocycloyl and -L”-5 to 6-membered heteroaryl;

[0843] R” is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-phenyl, -L”-3 to 6-membered carbon cycloyl, -L”-3 to 6-membered heterocycloyl and -L”-5 to 6-membered heteroaryl;

[0844] R”' is independently selected from H, C1-C8 alkyl, C1-C8 alkoxy and C1-C8 haloalkyl;

[0845] h can be 0, 1, 2, or 3;

[0846] r1, r2, r3, r4, r5, and r6 are each independently 0, 1, or 2.

[0847] In one embodiment, the present invention relates to compounds of formula (2) as described above, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs.

[0848] S is C(R) x1 );

[0849] T is C(R) x2 );

[0850] R x1 For H;

[0851] R x2 Selected from H, halogen, -L'-OR' and -L'-NR'R", or R x2 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl groups and -L'-4 to 6-membered heterocyclic groups, each optionally surrounded by h R groups gg replace;

[0852] w1 is selected from (CR) w1 R w1 ') r1 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[0853] w2 is (CR) w2 R w2 ') r2 ;

[0854] w3 is (CR) w3 R w3 ') r3 ;

[0855] w4 is selected from (CR) w4 R w4 ') r4 and N;

[0856] w5 is (CR) w5 R w5 ') r5 ;

[0857] w6 is (CR) w6 R w6 ') r6 ;

[0858] R w1 R w1 '、R w2 R w2 '、R w3 R w3 '、R w4 R w4 '、R w5 R w5 '、R w6 R w6 Each is independently selected from H, halogen, C1-C8 alkyl, oxo, -L”-OR’, -L”-NR’R” and -L”-4 to 6-membered heterocyclic groups;

[0859] Preferably, the groups composed of w1 to w6 are selected from...

[0860]

[0861] R gg Independently selected from H, halogen, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-3 to 6 carbon cycloalkanes and -L”-4 to 6 heterocyclic groups;

[0862] R' is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-3 to 6-membered carbon cycloyl and -L”-3 to 6-membered heterocyclic;

[0863] R” is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-3 to 6-membered carbon cycloyl and -L”-3 to 6-membered heterocyclic;

[0864] R”' is independently selected from H and C1-C8 alkyl groups;

[0865] L' is a covalent bond or a C1-C8 alkylene group;

[0866] L” is a covalent bond or a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -S-, -S(O)- or -S(O)2-.

[0867] r1, r2, r3, r4, r5, and r6 are each independently 0, 1, or 2;

[0868] h is 0, 1, or 2;

[0869] t can be 0, 1, 2 or 3.

[0870] In one embodiment, the present invention relates to a compound of formula (3) as described above, or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug, wherein said compound is represented by the following formula:

[0871]

[0872] The ring in question is a non-aromatic ring;

[0873] Each can be a double bond or a single bond independently;

[0874] w1 is selected from (CR) w1 R w1 ')r1 NR w1 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[0875] w2 is (CR) w2 R w2 ') r2 ;

[0876] w3 is (CR) w3 R w3 ') r3 ;

[0877] w4 is selected from (CR) w4 R w4 ') r4 and N;

[0878] w5 is (CR) w5 R w5 ') r5 ;

[0879] w6 is (CR) w6 R w6 ') r6 ;

[0880] R f1 -R f5 Each is independently selected from H, CN, halogen, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L'-OR', -L'-NR'R", -L'-SR', -L'-3 to 6-membered carbon cycloyl, -L'-4 to 6-membered heterocyclic and -L'-5 to 6-membered heteroaryl;

[0881] R x2 Selected from H, halogen, oxo, -CN, -L'-OR' and -L'-NR'R", or R x2 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl-, L'-phenyl, -L'-3 to 6-membered carbocyclic, -L'-3 to 10-membered heterocyclic and -L'-5 to 6-membered heteroaryl, each optionally dominated by h R gg replace;

[0882] R w1 R w1 '、R w2 R w2 '、R w3 R w3 '、R w4 R w4 '、R w5 R w5 '、R w6 R w6Each is independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-phenyl, -L”-3 to 6 carbon cycloyl, -L”-4 to 6 heterocyclic and -L”-5 to 6 heteroaryl;

[0883] R gg Independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L”-OR', -L”-NR'R”, -L”-phenyl, -L”-3 to 6 carbon cycloyl, -L”-4 to 6 heterocyclic and -L”-5 to 6 heteroaryl;

[0884] L' is a covalent bond or a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -O-, -C(O)-, -S-, -S(O)- or -S(O)2-;

[0885] L” is selected from covalent bonds, -O- and -S-; or L” is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-.

[0886] R' is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-phenyl, -L”-3 to 6-membered carbon cycloyl, -L”-3 to 6-membered heterocycloyl and -L”-5 to 6-membered heteroaryl;

[0887] R” is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-phenyl, -L”-3 to 6-membered carbon cycloyl, -L”-3 to 6-membered heterocycloyl and -L”-5 to 6-membered heteroaryl;

[0888] R”' is independently selected from H, C1-C8 alkyl, C1-C8 alkoxy and C1-C8 haloalkyl;

[0889] h can be 0, 1, 2, or 3;

[0890] r1, r2, r3, r4, r5, and r6 are each independently 0, 1, or 2.

[0891] In one embodiment, the present invention relates to a compound of formula (3-1) as described above, or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug, wherein:

[0892] All are double bonds;

[0893] R x2 Selected from H, halogen, -L'-OR' and -L'-NR'R", or R x2 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl groups and -L'-4 to 6-membered heterocyclic groups, each optionally surrounded by h R groups gg replace;

[0894] w1 is selected from (CR) w1 R w1 ') r1 and O;

[0895] w2 is (CR) w2 R w2 ') r2 ;

[0896] w3 is (CR) w3 R w3 ') r3 ;

[0897] w4 is selected from (CR) w4 R w4 ') r4 and N;

[0898] w5 is (CR) w5 R w5 ') r5 ;

[0899] w6 is (CR) w6 R w6 ') r6 ;

[0900] R w1 R w1 '、R w2 R w2 '、R w3 R w3 '、R w4 R w4 '、R w5 R w5 '、R w6 R w6 Each is independently selected from H, halogen, C1-C8 alkyl, oxo, -L”-OR’ and -L”-NR’R”;

[0901] R f1 -R f5 Each is independently selected from H, halogen, CN, C1-C8 alkyl, C1-C8 haloalkyl and -L'-OR';

[0902] R ggIndependently selected from H, halogen, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-3 to 6 carbon cycloalkanes and -L”-4 to 6 heterocyclic groups;

[0903] R' is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-3 to 6-membered carbon cycloyl and -L”-3 to 6-membered heterocyclic;

[0904] R” is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-3 to 6-membered carbon cycloyl and -L”-3 to 6-membered heterocyclic;

[0905] R”' is independently selected from H and C1-C8 alkyl groups;

[0906] L' is a covalent bond or a C1-C8 alkylene group;

[0907] "L" represents a covalent bond or a C1-C8 alkylene group;

[0908] h is 0, 1, or 2;

[0909] r1, r2, r3, r4, r5, and r6 are each independently 0, 1, or 2.

[0910] In one embodiment, the present invention relates to a compound of formula (3-1) as described above, or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug, wherein:

[0911] All are double bonds;

[0912] R x2 For H;

[0913] w1 is 0;

[0914] w2 is (CR) w2 R w2 ') r2 ;

[0915] w3 is (CR) w3 R w3 ') r3 ;

[0916] w4 is N;

[0917] w5 is (CR) w5 R w5 ') r5 ;

[0918] w6 is (CR) w6 R w6') r6 ;

[0919] R w2 R w2 '、R w3 R w3 '、R w5 R w5 '、R w6 R w6 Each is independently H;

[0920] R f1 For -L'-OR';

[0921] R f2 -R f5 Each is independently selected from H;

[0922] R' is selected from C1-C8 alkyl and C1-C8 haloalkyl;

[0923] L' is a covalent bond

[0924] r2, r3, r5 and r6 are each independently 1.

[0925] In one embodiment, the present invention relates to a compound of formula (4) as described above, or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug, wherein said compound is of the following formula:

[0926]

[0927] in,

[0928] The ring in question is a non-aromatic ring;

[0929] Each can be a double bond or a single bond independently;

[0930] w1 is selected from (CR) w1 R w1 ') r1 NR w1 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[0931] w2 is (CR) w2 R w2 ') r2 ;

[0932] w3 is (CR) w3 R w3 ') r3 ;

[0933] w4 is selected from (CR) w4 Rw4 ') r4 and N;

[0934] w5 is (CR) w5 R w5 ') r5 ;

[0935] w6 is (CR) w6 R w6 ') r6 ;

[0936] R g1 -R g5 Each is independently selected from H, CN, halogen, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L'-OR', -L'-NR'R", -L'-SR', -L'-3 to 6-membered carbon cycloyl, -L'-4 to 6-membered heterocyclic and -L'-5 to 6-membered heteroaryl;

[0937] R x2 Selected from H, halogen, oxo, -CN, -L'-OR' and -L'-NR'R", or R x2 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl-, L'-phenyl, -L'-3 to 6-membered carbocyclic, -L'-3 to 10-membered heterocyclic and -L'-5 to 6-membered heteroaryl, each optionally dominated by h R gg replace;

[0938] R w1 R w1 '、R w2 R w2 '、R w3 R w3 '、R w4 R w4 '、R w5 R w5 '、R w6 R w6 Each is independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-phenyl, -L”-3 to 6 carbon cycloyl, -L”-4 to 6 heterocyclic and -L”-5 to 6 heteroaryl;

[0939] R gg Independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L”-OR', -L”-NR'R”, -L”-phenyl, -L”-3 to 6 carbon cycloyl, -L”-4 to 6 heterocyclic and -L”-5 to 6 heteroaryl;

[0940] L' is a covalent bond or a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -O-, -C(O)-, -S-, -S(O)- or -S(O)2-;

[0941] L” is selected from covalent bonds, -O- and -S-; or L” is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-.

[0942] R' is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-phenyl, -L”-3 to 6-membered carbon cycloyl, -L”-3 to 6-membered heterocycloyl and -L”-5 to 6-membered heteroaryl;

[0943] R” is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-phenyl, -L”-3 to 6-membered carbon cycloyl, -L”-3 to 6-membered heterocycloyl and -L”-5 to 6-membered heteroaryl;

[0944] R”' is independently selected from H, C1-C8 alkyl, C1-C8 alkoxy and C1-C8 haloalkyl;

[0945] h can be 0, 1, 2, or 3;

[0946] r1, r2, r3, r4, r5, and r6 are each independently 0, 1, or 2.

[0947] In one embodiment, the present invention relates to a compound of formula (4-1) as described above, or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug, wherein:

[0948] All are double bonds;

[0949] R x2 Selected from H, halogen, -L'-OR' and -L'-NR'R", or R x2 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl groups and -L'-4 to 6-membered heterocyclic groups, each optionally surrounded by h R groups gg replace;

[0950] w1 is selected from (CR) w1 R w1 ') r1 and O;

[0951] w2 is (CR) w2 R w2 ') r2 ;

[0952] w3 is (CR) w3 R w3 ') r3 ;

[0953] w4 is selected from (CR) w4 R w4 ') r4 and N;

[0954] w5 is (CR) w5 R w5 ') r5 ;

[0955] w6 is (CR) w6 R w6 ') r6 ;

[0956] R w1 R w1 '、R w2 R w2 '、R w3 R w3 '、R w4 R w4 '、R w5 R w5 '、R w6 R w6 Each is independently selected from H, halogen, C1-C8 alkyl, oxo, -L”-OR’ and -L”-NR’R”;

[0957] R g1 -R g5 Each is independently selected from H, halogen, CN, C1-C8 alkyl, C1-C8 haloalkyl and -L'-OR';

[0958] R gg Independently selected from H, halogen, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-3 to 6 carbon cycloalkanes and -L”-4 to 6 heterocyclic groups;

[0959] R' is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-3 to 6-membered carbon cycloyl and -L”-3 to 6-membered heterocyclic;

[0960] R” is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-3 to 6-membered carbon cycloyl and -L”-3 to 6-membered heterocyclic;

[0961] R”' is independently selected from H and C1-C8 alkyl groups;

[0962] L' is a covalent bond or a C1-C8 alkylene group;

[0963] "L" represents a covalent bond or a C1-C8 alkylene group;

[0964] h is 0, 1, or 2;

[0965] r1, r2, r3, r4, r5, and r6 are each independently 0, 1, or 2.

[0966] In one embodiment, the present invention relates to a compound of formula (4-1) as described above, or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug, wherein:

[0967] All are double bonds;

[0968] R x2 For H;

[0969] w1 is 0;

[0970] w2 is (CR) w2 R w2 ') r2 ;

[0971] w3 is (CR) w3 R w3 ') r3 ;

[0972] w4 is N;

[0973] w5 is (CR) w5 R w5 ') r5 ;

[0974] w6 is (CR) w6 R w6 ') r6 ;

[0975] R w2 R w2 '、R w3 R w3 '、R w5 R w5 '、R w6 R w6 Each is independently H;

[0976] R f1 For -L'-OR';

[0977] R f2-R f5 Each is independently selected from H;

[0978] R' is selected from C1-C8 alkyl and C1-C8 haloalkyl;

[0979] L' is a covalent bond;

[0980] r2, r3, r5 and r6 are each independently 1.

[0981] In one embodiment, the present invention relates to a compound of formula (5) as described above, or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug, wherein said compound is of the following formula:

[0982]

[0983] The ring in question is a non-aromatic ring;

[0984] w1 is selected from (CR) w1 R w1 ') r1 NR w1 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[0985] w2 is (CR) w2 R w2 ') r2 ;

[0986] w3 is (CR) w3 R w3 ') r3 ;

[0987] w4 is selected from (CR) w4 R w4 ') r4 and N;

[0988] w5 is (CR) w5 R w5 ') r5 ;

[0989] w6 is (CR) w6 R w6 ') r6 ;

[0990] R h1 -R h4 Each is independently selected from H, CN, halogen, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L'-OR', -L'-NR'R", -L'-SR', -L'-3 to 6-membered carbon cycloyl, -L'-4 to 6-membered heterocyclic and -L'-5 to 6-membered heteroaryl;

[0991] R x2 Selected from H, halogen, oxo, -CN, -L'-OR' and -L'-NR'R", or R x2 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl-, L'-phenyl, -L'-3 to 6-membered carbocyclic, -L'-3 to 10-membered heterocyclic and -L'-5 to 6-membered heteroaryl, each optionally dominated by h R gg replace;

[0992] R w1 R w1 '、R w2 R w2 '、R w3 R w3 '、R w4 R w4 '、R w5 R w5 '、R w6 R w6 Each is independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-phenyl, -L”-3 to 6 carbon cycloyl, -L”-4 to 6 heterocyclic and -L”-5 to 6 heteroaryl;

[0993] R gg Independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L”-OR', -L”-NR'R”, -L”-phenyl, -L”-3 to 6 carbon cycloyl, -L”-4 to 6 heterocyclic and -L”-5 to 6 heteroaryl;

[0994] L' is a covalent bond or a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -O-, -C(O)-, -S-, -S(O)- or -S(O)2-;

[0995] L” is selected from covalent bonds, -O- and -S-; or L” is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-.

[0996] R' is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-phenyl, -L”-3 to 6-membered carbon cycloyl, -L”-3 to 6-membered heterocycloyl and -L”-5 to 6-membered heteroaryl;

[0997] R” is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-phenyl, -L”-3 to 6-membered carbon cycloyl, -L”-3 to 6-membered heterocycloyl and -L”-5 to 6-membered heteroaryl;

[0998] R”' is independently selected from H, C1-C8 alkyl, C1-C8 alkoxy and C1-C8 haloalkyl;

[0999] h can be 0, 1, 2, or 3;

[1000] r1, r2, r3, r4, r5, and r6 are each independently 0, 1, or 2.

[1001] In one embodiment, the present invention relates to a compound of formula (5-1) as described above, or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug, wherein:

[1002] R x2 Selected from H, halogen, -L'-OR' and -L'-NR'R", or R x2 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl groups and -L'-4 to 6-membered heterocyclic groups, each optionally surrounded by h R groups gg replace;

[1003] w1 is selected from (CR) w1 R w1 ') r1 and O;

[1004] w2 is (CR) w2 R w2 ') r2 ;

[1005] w3 is (CR) w3 R w3 ') r3 ;

[1006] w4 is selected from (CR) w4 R w4 ') r4 and N;

[1007] w5 is (CR) w5 R w5 ') r5 ;

[1008] w6 is (CR) w6 R w6 ') r6 ;

[1009] R w1 Rw1 '、R w2 R w2 '、R w3 R w3 '、R w4 R w4 '、R w5 R w5 '、R w6 R w6 Each is independently selected from H, halogen, C1-C8 alkyl, oxo, -L”-OR’ and -L”-NR’R”;

[1010] R h1 -R h4 Each is independently selected from H, halogen, CN, C1-C8 alkyl, C1-C8 haloalkyl and -L'-OR';

[1011] R gg Independently selected from H, halogen, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-3 to 6 carbon cycloalkanes and -L”-4 to 6 heterocyclic groups;

[1012] R' is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-3 to 6-membered carbon cycloyl and -L”-3 to 6-membered heterocyclic;

[1013] R” is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-3 to 6-membered carbon cycloyl and -L”-3 to 6-membered heterocyclic;

[1014] R”' is independently selected from H and C1-C8 alkyl groups;

[1015] L' is a covalent bond or a C1-C8 alkylene group;

[1016] "L" represents a covalent bond or a C1-C8 alkylene group;

[1017] h is 0, 1, or 2;

[1018] r1, r2, r3, r4, r5, and r6 are each independently 0, 1, or 2.

[1019] In one embodiment, the present invention relates to a compound of formula (5-1) as described above, or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug, wherein:

[1020] All are double bonds;

[1021] R x2 For H;

[1022] w1 is 0;

[1023] w2 is (CR) w2 R w2 ') r2 ;

[1024] w3 is (CR) w3 R w3 ') r3 ;

[1025] w4 is N;

[1026] w5 is (CR) w5 R w5 ') r5 ;

[1027] w6 is (CR) w6 R w6 ') r6 ;

[1028] R w2 and R w2 Each is independently selected from H and -L"-OR";

[1029] R w3 R w3 '、R w5 R w5 '、R w6 R w6 Each is independently H;

[1030] R h1 Selected from H and -L'-OR'; R h2 -R f4 Each is independently selected from H;

[1031] R' is independently selected from H, C1-C8 alkyl, and C1-C8 haloalkyl;

[1032] L' is a covalent bond;

[1033] L” represents a C1-C8 alkylene group;

[1034] r2, r3, r5 and r6 are each independently 1.

[1035] In one embodiment, the present invention relates to a compound of formula (6) as described above, or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug, wherein:

[1036]

[1037] The ring in question is a non-aromatic ring;

[1038] w1 is selected from (CR) w1 R w1 ') r1 NR w1 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[1039] w2 is (CR) w2 R w2 ') r2 ;

[1040] w3 is (CR) w3 R w3 ') r3 ;

[1041] w4 is selected from (CR) w4 R w4 ') r4 and N;

[1042] w5 is (CR) w5 R w5 ') r5 ;

[1043] w6 is (CR) w6 R w6 ') r6 ;

[1044] R j1 -R j4 Each is independently selected from H, CN, halogen, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L'-OR', -L'-NR'R", -L'-SR', -L'-3 to 6-membered carbon cycloyl, -L'-4 to 6-membered heterocyclic and -L'-5 to 6-membered heteroaryl;

[1045] R x2 Selected from H, halogen, oxo, -CN, -L'-OR' and -L'-NR'R", or R x2 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl-, L'-phenyl, -L'-3 to 6-membered carbocyclic, -L'-3 to 10-membered heterocyclic and -L'-5 to 6-membered heteroaryl, each optionally dominated by h R gg replace;

[1046] R w1 R w1 '、R w2 R w2 '、R w3 R w3 '、R w4 R w4 '、Rw5 R w5 '、R w6 R w6 Each is independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-phenyl, -L”-3 to 6 carbon cycloyl, -L”-4 to 6 heterocyclic and -L”-5 to 6 heteroaryl;

[1047] R gg Independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L”-OR', -L”-NR'R”, -L”-phenyl, -L”-3 to 6 carbon cycloyl, -L”-4 to 6 heterocyclic and -L”-5 to 6 heteroaryl;

[1048] L' is a covalent bond or a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -O-, -C(O)-, -S-, -S(O)- or -S(O)2-;

[1049] L” is selected from covalent bonds, -O- and -S-; or L” is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-.

[1050] R' is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-phenyl, -L”-3 to 6-membered carbon cycloyl, -L”-3 to 6-membered heterocycloyl and -L”-5 to 6-membered heteroaryl;

[1051] R” is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-phenyl, -L”-3 to 6-membered carbon cycloyl, -L”-3 to 6-membered heterocycloyl and -L”-5 to 6-membered heteroaryl;

[1052] R”' is independently selected from H, C1-C8 alkyl, C1-C8 alkoxy and C1-C8 haloalkyl;

[1053] h can be 0, 1, 2, or 3;

[1054] r1, r2, r3, r4, r5, and r6 are each independently 0, 1, or 2.

[1055] In one embodiment, the present invention relates to a compound of formula (6-1) as described above, or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug, wherein:

[1056] R x2 Selected from H, halogen, -L'-OR' and -L'-NR'R", or R x2 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl groups and -L'-4 to 6-membered heterocyclic groups, each optionally surrounded by h R groups gg replace;

[1057] w1 is selected from (CR) w1 R w1 ') r1 and O;

[1058] w2 is (CR) w2 R w2 ') r2 ;

[1059] w3 is (CR) w3 R w3 ') r3 ;

[1060] w4 is selected from (CR) w4 R w4 ') r4 and N;

[1061] w5 is (CR) w5 R w5 ') r5 ;

[1062] w6 is (CR) w6 R w6 ') r6 ;

[1063] R w1 R w1 '、R w2 R w2 '、R w3 R w3 '、R w4 R w4 '、R w5 R w5 '、R w6 R w6 Each is independently selected from H, halogen, C1-C8 alkyl, oxo, -L”-OR’ and -L”-NR’R”;

[1064] R j1 -R j4Each is independently selected from H, halogen, CN, C1-C8 alkyl, C1-C8 haloalkyl and -L'-OR';

[1065] R gg Independently selected from H, halogen, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-3 to 6 carbon cycloalkanes and -L”-4 to 6 heterocyclic groups;

[1066] R' is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-3 to 6-membered carbon cycloyl and -L”-3 to 6-membered heterocyclic;

[1067] R” is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-3 to 6-membered carbon cycloyl and -L”-3 to 6-membered heterocyclic;

[1068] R”' is independently selected from H and C1-C8 alkyl groups;

[1069] L' is a covalent bond or a C1-C8 alkylene group;

[1070] "L" represents a covalent bond or a C1-C8 alkylene group;

[1071] h is 0, 1, or 2;

[1072] r1, r2, r3, r4, r5, and r6 are each independently 0, 1, or 2.

[1073] In one embodiment, the present invention relates to a compound of formula (6-1) as described above, or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug, wherein:

[1074] All are double bonds;

[1075] R x2 For H;

[1076] w1 is 0;

[1077] w2 is (CR) w2 R w2 ') r2 ;

[1078] w3 is (CR) w3 R w3 ') r3 ;

[1079] w4 is N;

[1080] w5 is (CR) w5 Rw5 ') r5 ;

[1081] w6 is (CR) w6 R w6 ') r6 ;

[1082] R w2 and R w2 Each is independently selected from H and -L"-OR";

[1083] R w3 R w3 '、R w5 R w5 '、R w6 R w6 Each is independently H;

[1084] R j1 Selected from H, and -L'-OR'; R j2 -R j4 Each is independently selected from H;

[1085] R' is independently selected from H, C1-C8 alkyl, and C1-C8 haloalkyl;

[1086] L' is a covalent bond;

[1087] L” represents a C1-C8 alkylene group; r2, r3, r5 and r6 are each independently 1.

[1088] In one embodiment, the present invention relates to a compound of formula (7) as described above, or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug, wherein:

[1089]

[1090] The ring in question is a non-aromatic ring;

[1091] w1 is selected from (CR) w1 R w1 ') r1 NR w1 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[1092] w2 is (CR) w2 R w2 ') r2 ;

[1093] w3 is (CR) w3 R w3 ') r3 ;

[1094] w4 is selected from (CR) w4 R w4 ') r4 and N;

[1095] w5 is (CR) w5 R w5 ') r5 ;

[1096] w6 is (CR) w6 R w6 ') r6 ;

[1097] R k1 -R k4 Each is independently selected from H, CN, halogen, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L'-OR', -L'-NR'R", -L'-SR', -L'-3 to 6-membered carbon cycloyl, -L'-4 to 6-membered heterocyclic and -L'-5 to 6-membered heteroaryl;

[1098] R x2 Selected from H, halogen, oxo, -CN, -L'-OR' and -L'-NR'R", or R x2 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl-, L'-phenyl, -L'-3 to 6-membered carbocyclic, -L'-3 to 10-membered heterocyclic and -L'-5 to 6-membered heteroaryl, each optionally dominated by h R gg replace;

[1099] R w1 R w1 '、R w2 R w2 '、R w3 R w3 '、R w4 R w4 '、R w5 R w5 '、R w6 R w6 Each is independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-phenyl, -L”-3 to 6 carbon cycloyl, -L”-4 to 6 heterocyclic and -L”-5 to 6 heteroaryl;

[1100] R ggIndependently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L”-OR', -L”-NR'R”, -L”-phenyl, -L”-3 to 6 carbon cycloyl, -L”-4 to 6 heterocyclic and -L”-5 to 6 heteroaryl;

[1101] L' is a covalent bond or a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -O-, -C(O)-, -S-, -S(O)- or -S(O)2-;

[1102] L” is selected from covalent bonds, -O- and -S-; or L” is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-.

[1103] R' is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-phenyl, -L”-3 to 6-membered carbon cycloyl, -L”-3 to 6-membered heterocycloyl and -L”-5 to 6-membered heteroaryl;

[1104] R” is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-phenyl, -L”-3 to 6-membered carbon cycloyl, -L”-3 to 6-membered heterocycloyl and -L”-5 to 6-membered heteroaryl;

[1105] R”' is independently selected from H, C1-C8 alkyl, C1-C8 alkoxy and C1-C8 haloalkyl;

[1106] h can be 0, 1, 2, or 3;

[1107] r1, r2, r3, r4, r5, and r6 are each independently 0, 1, or 2.

[1108] In one embodiment, the present invention relates to a compound of formula (7-1) as described above, or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug, wherein:

[1109] R x2 Selected from H, halogen, -L'-OR' and -L'-NR'R", or R x2 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl groups and -L'-4 to 6-membered heterocyclic groups, each optionally surrounded by h R groups gg replace;

[1110] w1 is selected from (CR)w1 R w1 ') r1 and O;

[1111] w2 is (CR) w2 R w2 ') r2 ;

[1112] w3 is (CR) w3 R w3 ') r3 ;

[1113] w4 is selected from (CR) w4 R w4 ') r4 and N;

[1114] w5 is (CR) w5 R w5 ') r5 ;

[1115] w6 is (CR) w6 R w6 ') r6 ;

[1116] R w1 R w1 '、R w2 R w2 '、R w3 R w3 '、R w4 R w4 '、R w5 R w5 '、R w6 R w6 Each is independently selected from H, halogen, C1-C8 alkyl, oxo, -L”-OR’ and -L”-NR’R”;

[1117] R k1 -R k4 Each is independently selected from H, halogen, CN, C1-C8 alkyl, C1-C8 haloalkyl and -L'-OR';

[1118] R gg Independently selected from H, halogen, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-3 to 6 carbon cycloalkanes and -L”-4 to 6 heterocyclic groups;

[1119] R' is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-3 to 6-membered carbon cycloyl and -L”-3 to 6-membered heterocyclic;

[1120] R” is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-3 to 6-membered carbon cycloyl and -L”-3 to 6-membered heterocyclic;

[1121] R”' is independently selected from H and C1-C8 alkyl groups;

[1122] L' is a covalent bond or a C1-C8 alkylene group;

[1123] "L" represents a covalent bond or a C1-C8 alkylene group;

[1124] h is 0, 1, or 2;

[1125] r1, r2, r3, r4, r5, and r6 are each independently 0, 1, or 2.

[1126] In one embodiment, the present invention relates to a compound of formula (7-1) as described above, or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug, wherein:

[1127] All are double bonds;

[1128] R x2 For H;

[1129] w1 is 0;

[1130] w2 is (CR) w2 R w2 ') r2 ;

[1131] w3 is (CR) w3 R w3 ') r3 ;

[1132] w4 is N;

[1133] w5 is (CR) w5 R w5 ') r5 ;

[1134] w6 is (CR) w6 R w6 ') r6 ;

[1135] R w2 and R w2 Each is independently selected from H and -L"-OR";

[1136] R w3 R w3 '、R w5 R w5 '、Rw6 R w6 Each is independently H;

[1137] R k1 The preferred halogen is Cl;

[1138] R k2 -R k4 Each is independently selected from H;

[1139] R' is independently selected from H, C1-C8 alkyl, and C1-C8 haloalkyl; L” is a C1-C8 alkylene;

[1140] r2, r3, r5 and r6 are each independently 1.

[1141] In one embodiment, the present invention relates to a compound of formula (2) as described above, or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug, wherein:

[1142] Among w1, w2, w3, w4, w5, and w6, the two non-adjacent variables can be arbitrarily chosen from -(CH2). t -Bridge, where -(CH2) t One or more methylene groups in the ring are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-, wherein the ring is optionally substituted with h R- gg replace;

[1143] R gg Independently selected from H, halogen, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-3 to 6 carbon cycloalkanes and -L”-4 to 6 heterocyclic groups;

[1144] h is 0, 1, or 2;

[1145] t can be 0, 1, or 2.

[1146] In one embodiment, the present invention relates to a compound of formula (2) as described above, or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug, wherein:

[1147] In w1, w2, w3, w4, w5, and w6, if a substituent is present on a single atom, it forms a 3-7 membered carbon ring or a 3-7 membered heterocycle together with that atom, thereby forming a spirocyclic group as a whole. The 3-7 membered carbon ring or 3-7 membered heterocycle may optionally undergo h R... gg replace;

[1148] R ggIndependently selected from H, halogen, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-3 to 6 carbon cycloalkanes and -L”-4 to 6 heterocyclic groups;

[1149] h can be 0, 1, or 2.

[1150] In one embodiment, the present invention relates to a compound of formula (2) as described above, or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug, wherein:

[1151] In w1, w2, w3, w4, w5, and w6, substituents on adjacent atoms, if present, may optionally form a 3-7 membered carbon ring or a 3-7 membered heterocycle together with the atoms, thereby forming a fused ring group; the 3-7 membered carbon ring or 3-7 membered heterocycle may optionally undergo h R... gg replace;

[1152] R gg Independently selected from H, halogen, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-3 to 6 carbon cycloalkanes and -L”-4 to 6 heterocyclic groups;

[1153] h can be 0, 1, or 2.

[1154] In one embodiment, the present invention relates to a compound of formula (1) as described above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein said compound is one of the following formulas:

[1155]

[1156]

[1157]

[1158] in,

[1159] This indicates that the ring can be either aromatic or non-aromatic.

[1160] Each can be a double bond or a single bond independently;

[1161] S is C(R) x1 ) or NR x1 ;

[1162] T is C(R) x2 ) or NR x2 ;

[1163] N is C(R) x4 ) or NR x4 ;

[1164] M is C(R) x5 ) or NR x5 ;

[1165] K is C(R) x6 ) or N;

[1166] The condition is that one or two of S, T, M, and N are absent;

[1167] w1 is selected from (CR) w1 R w1 ') r1 NR w1 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[1168] w2 is selected from (CR) w2 R w2 ') r2 NR w2 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[1169] w3 is selected from (CR) w3 R w3 ') r3 NR w3 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[1170] w4 is selected from (CR) w4 R w4 ') r4 and N;

[1171] w5 is selected from (CR) w5 R w5 ') r5 NR w5 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[1172] w6 is selected from (CR) w6 R w6 ') r6 NR w6 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[1173] and / or

[1174] Among w1, w2, w3, w4, w5, and w6, the two non-adjacent variables can be arbitrarily chosen from -(CH2). t -Bridge, where -(CH2) tOne or more methylene groups in - are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; and / or

[1175] In w1, w2, w3, w4, w5, and w6, if a substituent is present on a single atom, it forms a 3-7 membered carbon ring or a 3-7 membered heterocycle together with that atom, thereby forming a spirocyclic group as a whole; and / or

[1176] If substituents on adjacent atoms are present, they may, together with the atoms, optionally form 3-7 membered carbon rings or 3-7 membered heterocycles, thereby forming a fused ring group as a whole.

[1177] R v1 -R v5 R f1 -R f5 R g1 -R g5 R h1 -R h4 R j1 -R j4 R k1 -R k4 R p1 -R p4 R s1 -R s5 R y1 -R y4 R z1 -R z4 R a1 -R a3 Each is independently selected from H, CN, halogen, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L'-OR', -L'-NR'R", -L'-SR', -L'-3 to 6-membered carbon cycloyl, -L'-4 to 6-membered heterocyclic and -L'-5 to 6-membered heteroaryl;

[1178] R x1 and R x2 Each is independently selected from H, halogen, oxo, -CN, -L'-OR' and -L'-NR'R", or R x1 and R x2 Each is independently selected from C 1-8 Alkyl, C 1-8 Haloalkyl-, L'-phenyl, -L'-3 to 6-membered carbocyclic, -L'-3 to 10-membered heterocyclic and -L'-5 to 6-membered heteroaryl, each optionally dominated by h R gg replace;

[1179] R x4 Rx5 and R x6 Each is independently selected from H, halogen, -L'-OR' and -L'-NR'R", or R x4 and R x5 Each is independently selected from C 1-8 Alkyl, C 1-8 Haloalkyl, -L'-phenyl, -L'-3 to 6-membered carbocyclic, -L'-3 to 6-membered heterocyclic and -L'-5 to 6-membered heteroaryl, each optionally dominated by h R gg replace;

[1180] R w1 R w1 '、R w2 R w2 '、R w3 R w3 '、R w4 R w4 '、R w5 R w5 '、R w6 R w6 Each element is independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C 2- C8 alkenyl, C 2- C8 alkynyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-C(O)OR’, -L”-C(O)NR’R”, -L”-S(O) 0-2 R', -L”-S(O)2NR'R”, -L”-S(O)NR’R”, -L”-OC(O)R’, -L”-OC(O)NR’R”, -L”-NR’R”, -L”-OC(O)NR’R”, -L”-C6-C 10 Aryl, -L”-3 to 14-membered carbocyclic, -L”-3 to 14-membered heterocyclic, and -L”-5 to 14-membered heteroaryl; wherein the aryl, carbocyclic, heterocyclic, and heteroaryl are optionally surrounded by k R ggg replace;

[1181] R gg Independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C 2- C8 alkenyl, C 2- C8 alkynyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-C(O)OR’, -L”-C(O)NR’R”, -L”-S(O) 0-2R', -L”-S(O)2NR'R”, -L”-S(O)NR’R”, -L”-OC(O)R’, -L”-OC(O)NR’R”, -L”-NR’R”, -L”-C(O)NR’R”, -L”-C6-C 10 Aryl, -L”-3 to 14-membered carbocyclic, -L”-3 to 14-membered heterocyclic, and -L”-5 to 14-membered heteroaryl; wherein the aryl, carbocyclic, heterocyclic, and heteroaryl are optionally surrounded by k R ggg replace;

[1182] R ggg Each is independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C 2- C8 alkenyl, C 2- C8 alkynyl, C1-C8 haloalkyl, -L”'-OR', -L”'-NR'R”, -L”'-C(O)OR', -L”'-C(O)NR'R”, -L”'-S(O) 0-2 R', -L"'-S(O)2NR'R", -L"'-S(O)NR'R", -L"'-OC(O)R', -L"'-OC(O)NR'R", -L"'-NR'R", -L"'-OC(O)NR'R", -L"'-C6-C 10 Aryl, -L”'-3 to 14-membered carbocyclic, -L”'-3 to 14-membered heterocyclic and -L”'-5 to 14-membered heteroaryl;

[1183] L' is selected from covalent bonds, -O-, -S-, -NR'-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR'-, -OC(O)-, -OC(O)NR'-, -N(R')C(O)O-, -N(R')C(O)- and -N(R')S(O)2-; or L' is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -N(R')C(O)-, -C(O)N(R')-, -N(R')S(O)2-, -S(O)2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

[1184] L” is selected from covalent bonds, -O- and -S-; or L” is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-.

[1185] L”' is selected from covalent bonds, -O-, and -S-; or L”' is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-.

[1186] R' is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-NR”'R””, -L”-C6-C 10 Aryl, -L”-3 to 14-membered carbocyclic, -L”-3 to 14-membered heterocyclic and -L”-5 to 14-membered heteroaryl;

[1187] R” is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-NR”'R””, -L”-C6-C 10 Aryl, -L”-3 to 14-membered carbocyclic, -L”-3 to 14-membered heterocyclic and -L”-5 to 14-membered heteroaryl;

[1188] Alternatively, R' and R” together with the N atoms they are attached to form 3 to 14-membered heterocyclic groups;

[1189] R”' and R”” are each independently selected from H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, -L”'-C6-C 10 Aryl, -L”'-3 to 14-membered carbocyclic, -L”'-3 to 14-membered heterocyclic and -L”'-5 to 14-membered heteroaryl; or R”' and R”” together with the N atom to which they are attached to form 3 to 14-membered heterocyclic groups;

[1190] h can be 1, 2, 3, 4, or 5;

[1191] k is 1, 2, 3, 4 or 5;

[1192] r1, r2, r3, r4, r5, and r6 are each independently 0, 1, or 2;

[1193] t can be 0, 1, or 2.

[1194] In one embodiment, the present invention relates to a compound of formula (9) as described above, or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug, wherein said compound is of the following formula:

[1195]

[1196] in,

[1197] This indicates that the ring in question is a non-aromatic ring;

[1198] Each can be a double bond or a single bond independently;

[1199] w1 is selected from (CR) w1 R w1 ') r1 NR w1 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[1200] w2 is (CR) w2 R w2 ') r2 ;

[1201] w3 is (CR) w3 R w3 ') r3 ;

[1202] w4 is selected from (CR) w4 R w4 ') r4 and N;

[1203] w5 is (CR) w5 R w5 ') r5 ;

[1204] w6 is (CR) w6 R w6 ') r6 ;

[1205] R f1 -R f5 Each is independently selected from H, CN, halogen, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L'-OR', -L'-NR'R", -L'-SR', -L'-3 to 6-membered carbon cycloyl, -L'-4 to 6-membered heterocyclic and -L'-5 to 6-membered heteroaryl;

[1206] R x2 Selected from H, halogen, oxo, -CN, -L'-OR' and -L'-NR'R", or R x2 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl-, L'-phenyl, -L'-3 to 6-membered carbocyclic, -L'-3 to 10-membered heterocyclic and -L'-5 to 6-membered heteroaryl, each optionally dominated by h R gg replace;

[1207] R w1 R w1 '、R w2 R w2 '、R w3 R w3'、R w4 R w4 '、R w5 R w5 '、R w6 R w6 Each is independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-phenyl, -L”-3 to 6 carbon cycloyl, -L”-4 to 6 heterocyclic and -L”-5 to 6 heteroaryl;

[1208] R gg Independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L”-OR', -L”-NR'R”, -L”-phenyl, -L”-3 to 6 carbon cycloyl, -L”-4 to 6 heterocyclic and -L”-5 to 6 heteroaryl;

[1209] L' is a covalent bond or a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -O-, -C(O)-, -S-, -S(O)- or -S(O)2-;

[1210] L” is selected from covalent bonds, -O- and -S-; or L” is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-.

[1211] R' is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-phenyl, -L”-3 to 6-membered carbon cycloyl, -L”-3 to 6-membered heterocycloyl and -L”-5 to 6-membered heteroaryl;

[1212] R” is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-phenyl, -L”-3 to 6-membered carbon cycloyl, -L”-3 to 6-membered heterocycloyl and -L”-5 to 6-membered heteroaryl;

[1213] R”' is independently selected from H, C1-C8 alkyl, C1-C8 alkoxy and C1-C8 haloalkyl;

[1214] h can be 0, 1, 2, or 3;

[1215] r1, r2, r3, r4, r5, and r6 are each independently 0, 1, or 2.

[1216] In one embodiment, the present invention relates to a compound of formula (9-1) as described above, or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug, wherein:

[1217] All are double bonds;

[1218] R x2 Selected from H, halogen, -L'-OR' and -L'-NR'R", or R x2 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl groups and -L'-4 to 6-membered heterocyclic groups, each optionally surrounded by h R groups gg replace;

[1219] w1 is selected from (CR) w1 R w1 ') r1 and O;

[1220] w2 is (CR) w2 R w2 ') r2 ;

[1221] w3 is (CR) w3 R w3 ') r3 ;

[1222] w4 is selected from (CR) w4 R w4 ') r4 and N;

[1223] w5 is (CR) w5 R w5 ') r5 ;

[1224] w6 is (CR) w6 R w6 ') r6 ;

[1225] R w1 R w1 '、R w2 R w2 '、R w3 R w3 '、R w4 R w4 '、R w5 R w5 '、R w6 R w6 Each is independently selected from H, halogen, C1-C8 alkyl, oxo, -L”-OR’ and -L”-NR’R”;

[1226] R f1 -R f5 Each is independently selected from H, halogen, CN, C1-C8 alkyl, C1-C8 haloalkyl and -L'-OR';

[1227] R gg Independently selected from H, halogen, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-3 to 6 carbon cycloalkanes and -L”-4 to 6 heterocyclic groups;

[1228] R' is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-3 to 6-membered carbon cycloyl and -L”-3 to 6-membered heterocyclic;

[1229] R” is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-3 to 6-membered carbon cycloyl and -L”-3 to 6-membered heterocyclic;

[1230] R”' is independently selected from H and C1-C8 alkyl groups;

[1231] L' is a covalent bond or a C1-C8 alkylene group;

[1232] "L" represents a covalent bond or a C1-C8 alkylene group;

[1233] h is 0, 1, or 2;

[1234] r1, r2, r3, r4, r5, and r6 are each independently 0, 1, or 2.

[1235] In one embodiment, the present invention relates to a compound of formula (9-1) as described above, or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug, wherein:

[1236] All are double bonds;

[1237] R x2 For H, or R x2 It is a -L'-4 to 6-membered heterocyclic group, which is arbitrarily divided by h R gg replace;

[1238] w1 is 0;

[1239] w2 is (CR) w2 R w2 ') r2 ;

[1240] w3 is (CR) w3 R w3 ')r3 ;

[1241] w4 is selected from (CR) w4 R w4 ') r4 and N;

[1242] w5 is (CR) w5 R w5 ') r5 ;

[1243] w6 is (CR) w6 R w6 ') r6 ;

[1244] R w2 and R w2 Each is independently selected from H and -L"-OR";

[1245] R w3 R w3 '、R w4 R w4 '、R w5 R w5 '、R w6 R w6 Each is independently H;

[1246] Preferably, the groups composed of w1 to w6 are selected from...

[1247] R f1 Selected from H, CN, and -L'-OR';

[1248] R f2 -R f5 Each is independently represented by H;

[1249] R' is independently selected from H, C1-C8 alkyl, and C1-C8 haloalkyl;

[1250] R gg Independently selected from H and halogens;

[1251] L' is a covalent bond;

[1252] L” represents a C1-C8 alkylene group;

[1253] h is 0 or 1;

[1254] r2, r3, r4, r5 and r6 are each independently 1.

[1255] In one embodiment, the present invention relates to a compound of formula (10) as described above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein said compound is of the following formula:

[1256]

[1257] in,

[1258] The ring in question is a non-aromatic ring;

[1259] Each can be a double bond or a single bond independently;

[1260] w1 is selected from (CR) w1 R w1 ') r1 NR w1 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[1261] w2 is (CR) w2 R w2 ') r2 ;

[1262] w3 is (CR) w3 R w3 ') r3 ;

[1263] w4 is selected from (CR) w4 R w4 ') r4 and N;

[1264] w5 is (CR) w5 R w5 ') r5 ;

[1265] w6 is (CR) w6 R w6 ') r6 ;

[1266] R g1 -R g5 Each is independently selected from H, CN, halogen, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L'-OR', -L'-NR'R", -L'-SR', -L'-3 to 6-membered carbon cycloyl, -L'-4 to 6-membered heterocyclic and -L'-5 to 6-membered heteroaryl;

[1267] R x2 Selected from H, halogen, oxo, -CN, -L'-OR' and -L'-NR'R", or R x2 Selected from C 1-8Alkyl, C 1-8 Haloalkyl-, L'-phenyl, -L'-3 to 6-membered carbocyclic, -L'-3 to 10-membered heterocyclic and -L'-5 to 6-membered heteroaryl, each optionally dominated by h R gg replace;

[1268] R w1 R w1 '、R w2 R w2 '、R w3 R w3 '、R w4 R w4 '、R w5 R w5 '、R w6 R w6 Each is independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-phenyl, -L”-3 to 6 carbon cycloyl, -L”-4 to 6 heterocyclic and -L”-5 to 6 heteroaryl;

[1269] R gg Independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L”-OR', -L”-NR'R”, -L”-phenyl, -L”-3 to 6 carbon cycloyl, -L”-4 to 6 heterocyclic and -L”-5 to 6 heteroaryl;

[1270] L' is a covalent bond or a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -O-, -C(O)-, -S-, -S(O)- or -S(O)2-;

[1271] L” is selected from covalent bonds, -O- and -S-; or L” is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-.

[1272] R' is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-phenyl, -L”-3 to 6-membered carbon cycloyl, -L”-3 to 6-membered heterocycloyl and -L”-5 to 6-membered heteroaryl;

[1273] R” is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-phenyl, -L”-3 to 6-membered carbon cycloyl, -L”-3 to 6-membered heterocycloyl and -L”-5 to 6-membered heteroaryl;

[1274] R”' is independently selected from H, C1-C8 alkyl, C1-C8 alkoxy and C1-C8 haloalkyl;

[1275] h can be 0, 1, 2, or 3;

[1276] r1, r2, r3, r4, r5, and r6 are each independently 0, 1, or 2.

[1277] In one embodiment, the present invention relates to a compound of formula (10-1) as described above, or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug, wherein:

[1278] All are double bonds;

[1279] R x2 Selected from H, halogen, -L'-OR' and -L'-NR'R", or R x2 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl groups and -L'-4 to 6-membered heterocyclic groups, each optionally surrounded by h R groups gg replace;

[1280] w1 is selected from (CR) w1 R w1 ') r1 and O;

[1281] w2 is (CR) w2 R w2 ') r2 ;

[1282] w3 is (CR) w3 R w3 ') r3 ;

[1283] w4 is selected from (CR) w4 R w4 ') r4 and N;

[1284] w5 is (CR) w5 R w5 ') r5 ;

[1285] w6 is (CR) w6 R w6 ') r6 ;

[1286] R w1 R w1 '、R w2 R w2'、R w3 R w3 '、R w4 R w4 '、R w5 R w5 '、R w6 R w6 Each is independently selected from H, halogen, C1-C8 alkyl, oxo, -L”-OR’ and -L”-NR’R”;

[1287] R g1 -R g5 Each is independently selected from H, halogen, CN, C1-C8 alkyl, C1-C8 haloalkyl and -L'-OR';

[1288] R gg Independently selected from H, halogen, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-3 to 6 carbon cycloalkanes and -L”-4 to 6 heterocyclic groups;

[1289] R' is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-3 to 6-membered carbon cycloyl and -L”-3 to 6-membered heterocyclic;

[1290] R” is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-3 to 6-membered carbon cycloyl and -L”-3 to 6-membered heterocyclic;

[1291] R”' is independently selected from H and C1-C8 alkyl groups;

[1292] L' is a covalent bond or a C1-C8 alkylene group;

[1293] "L" represents a covalent bond or a C1-C8 alkylene group;

[1294] h is 0, 1, or 2;

[1295] r1, r2, r3, r4, r5, and r6 are each independently 0, 1, or 2.

[1296] In one embodiment, the present invention relates to a compound of formula (10-1) as described above, or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug, wherein:

[1297] All are double bonds;

[1298] R x2 For H;

[1299] w1 is 0;

[1300] w2 is (CR) w2 R w2 ') r2 ;

[1301] w3 is (CR) w3 R w3 ') r3 ;

[1302] w4 is selected as N;

[1303] w5 is (CR) w5 R w5 ') r5 ;

[1304] w6 is (CR) w6 R w6 ') r6 ;

[1305] R w2 and R w2 'Each is independently -L"-OR';

[1306] R w3 R w3 '、R w5 R w5 '、R w6 R w6 Each is independently H;

[1307] Preferably, the groups composed of w1 to w6 are

[1308] R g1 Selected from CN and -L'-OR';

[1309] R g2 -R g5 Each is independently represented by H;

[1310] R' is independently selected from H, C1-C8 alkyl, and C1-C8 haloalkyl;

[1311] L' is a covalent bond;

[1312] L” represents a C1-C8 alkylene group;

[1313] r2, r3, r5 and r6 are each independently 1.

[1314] In one embodiment, the present invention relates to a compound of formula (11) as described above, or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug, wherein said compound is of the following formula:

[1315]

[1316] The ring in question is a non-aromatic ring;

[1317] w1 is selected from (CR) w1 R w1 ') r1 NR w1 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[1318] w2 is (CR) w2 R w2 ') r2 ;

[1319] w3 is (CR) w3 R w3 ') r3 ;

[1320] w4 is selected from (CR) w4 R w4 ') r4 and N;

[1321] w5 is (CR) w5 R w5 ') r5 ;

[1322] w6 is (CR) w6 R w6 ') r6 ;

[1323] R h1 -R h4 Each is independently selected from H, CN, halogen, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L'-OR', -L'-NR'R", -L'-SR', -L'-3 to 6-membered carbon cycloyl, -L'-4 to 6-membered heterocyclic and -L'-5 to 6-membered heteroaryl;

[1324] R x2 Selected from H, halogen, oxo, -CN, -L'-OR' and -L'-NR'R", or R x2 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl-, L'-phenyl, -L'-3 to 6-membered carbocyclic, -L'-3 to 10-membered heterocyclic and -L'-5 to 6-membered heteroaryl, each optionally dominated by h R gg replace;

[1325] R w1 R w1 '、R w2 R w2 '、Rw3 R w3 '、R w4 R w4 '、R w5 R w5 '、R w6 R w6 Each is independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-phenyl, -L”-3 to 6 carbon cycloyl, -L”-4 to 6 heterocyclic and -L”-5 to 6 heteroaryl;

[1326] R gg Independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L”-OR', -L”-NR'R”, -L”-phenyl, -L”-3 to 6 carbon cycloyl, -L”-4 to 6 heterocyclic and -L”-5 to 6 heteroaryl;

[1327] L' is a covalent bond or a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -O-, -C(O)-, -S-, -S(O)- or -S(O)2-;

[1328] L” is selected from covalent bonds, -O- and -S-; or L” is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-.

[1329] R' is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-phenyl, -L”-3 to 6-membered carbon cycloyl, -L”-3 to 6-membered heterocycloyl and -L”-5 to 6-membered heteroaryl;

[1330] R” is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-phenyl, -L”-3 to 6-membered carbon cycloyl, -L”-3 to 6-membered heterocycloyl and -L”-5 to 6-membered heteroaryl;

[1331] R”' is independently selected from H, C1-C8 alkyl, C1-C8 alkoxy and C1-C8 haloalkyl;

[1332] h can be 0, 1, 2, or 3;

[1333] r1, r2, r3, r4, r5, and r6 are each independently 0, 1, or 2.

[1334] In one embodiment, the present invention relates to a compound of formula (11-1) as described above, or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug, wherein:

[1335] R x2 Selected from H, halogen, -L'-OR' and -L'-NR'R", or R x2 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl groups and -L'-4 to 6-membered heterocyclic groups, each optionally surrounded by h R groups gg replace;

[1336] w1 is selected from (CR) w1 R w1 ') r1 and O;

[1337] w2 is (CR) w2 R w2 ') r2 ;

[1338] w3 is (CR) w3 R w3 ') r3 ;

[1339] w4 is selected from (CR) w4 R w4 ') r4 and N;

[1340] w5 is (CR) w5 R w5 ') r5 ;

[1341] w6 is (CR) w6 R w6 ') r6 ;

[1342] R w1 R w1 '、R w2 R w2 '、R w3 R w3 '、R w4 R w4 '、R w5 R w5 '、R w6 R w6 Each is independently selected from H, halogen, C1-C8 alkyl, oxo, -L”-OR’ and -L”-NR’R”;

[1343] R h1 -R h4Each is independently selected from H, halogen, CN, C1-C8 alkyl, C1-C8 haloalkyl and -L'-OR';

[1344] R gg Independently selected from H, halogen, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-3 to 6 carbon cycloalkanes and -L”-4 to 6 heterocyclic groups;

[1345] R' is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-3 to 6-membered carbon cycloyl and -L”-3 to 6-membered heterocyclic;

[1346] R” is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-3 to 6-membered carbon cycloyl and -L”-3 to 6-membered heterocyclic;

[1347] R”' is independently selected from H and C1-C8 alkyl groups;

[1348] L' is a covalent bond or a C1-C8 alkylene group;

[1349] "L" represents a covalent bond or a C1-C8 alkylene group;

[1350] h is 0, 1, or 2;

[1351] r1, r2, r3, r4, r5, and r6 are each independently 0, 1, or 2.

[1352] In one embodiment, the present invention relates to a compound of formula (11-1) as described above, or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug, wherein:

[1353] R x2 "-L'-NR'R", or R x2 It is a -L'-4 to 6-membered heterocyclic group, which is arbitrarily divided by h R gg replace;

[1354] w1 is 0;

[1355] w2 is (CR) w2 R w2 ') r2 ;

[1356] w3 is (CR) w3 R w3 ') r3 ;

[1357] w4 is (CR) w4 R w4 ')r4 ;

[1358] w5 is (CR) w5 R w5 ') r5 ;

[1359] w6 is (CR) w6 R w6 ') r6 ;

[1360] R w2 R w2 '、R w3 R w3 '、R w4 R w4 '、R w5 R w5 '、R w6 R w6 Each is independently H;

[1361] R h1 -R h4 Each is independently represented by H;

[1362] R' is independently selected from H, C1-C8 alkyl, and C1-C8 haloalkyl;

[1363] R” is independently selected from H, C1-C8 alkyl and C1-C8 haloalkyl;

[1364] R gg H is independent;

[1365] L' is a covalent bond or a C1-C8 alkylene group;

[1366] h is 0 or 1;

[1367] r2, r3, r4, r5 and r6 are each independently 1.

[1368] In one embodiment, the present invention relates to a compound of formula (1) as described above, or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug, wherein said compound is represented by one of the following formulas:

[1369]

[1370] in,

[1371] The ring in which it is located can be either aromatic or non-aromatic;

[1372] Each can be a double bond or a single bond independently;

[1373] S is C(R) x1 ) or NR x1 ;

[1374] T is C(R) x2 ) or NR x2 ;

[1375] N is C(R) x4 ) or NR x4 ;

[1376] M is C(R) x5 ) or NR x5 ;

[1377] K is C(R) x6 ) or N;

[1378] The condition is that one or two of S, T, M, and N are absent;

[1379] w1 is selected from (CR) w1 R w1 ') r1 NR w1 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[1380] w2 is selected from (CR) w2 R w2 ') r2 NR w2 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[1381] w3 is selected from (CR) w3 R w3 ') r3 NR w3 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[1382] w4 is selected from (CR) w4 R w4 ') r4 and N;

[1383] w5 is selected from (CR) w5 R w5 ') r5 NR w5 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[1384] w6 is selected from (CR) w6 R w6 ') r6 NR w6 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[1385] and / or

[1386] Among w1, w2, w3, w4, w5, and w6, the two non-adjacent variables can be arbitrarily chosen from -(CH2). t -Bridge, where -(CH2) t One or more methylene groups in - are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; and / or

[1387] In w1, w2, w3, w4, w5, and w6, if a substituent is present on a single atom, it forms a 3-7 membered carbon ring or a 3-7 membered heterocycle together with that atom, thereby forming a spirocyclic group as a whole; and / or

[1388] If substituents on adjacent atoms are present, they may, together with the atoms, optionally form 3-7 membered carbon rings or 3-7 membered heterocycles, thereby forming a fused ring group as a whole.

[1389] R f1 -R f5 R g1 -R g5 Each is independently selected from H, CN, halogen, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L'-OR', -L'-NR'R", -L'-SR', -L'-3 to 6-membered carbon cycloyl, -L'-4 to 6-membered heterocyclic and -L'-5 to 6-membered heteroaryl;

[1390] R x1 and R x2 Each is independently selected from H, halogen, oxo, -CN, -L'-OR' and -L'-NR'R", or R x1 and R x2 Each is independently selected from C 1-8 Alkyl, C 1-8 Haloalkyl-, L'-phenyl, -L'-3 to 6-membered carbocyclic, -L'-3 to 10-membered heterocyclic and -L'-5 to 6-membered heteroaryl, each optionally dominated by h R gg replace;

[1391] R x4 R x5 and R x6 Each is independently selected from H, halogen, -L'-OR' and -L'-NR'R", or R x4 and R x5 Each is independently selected from C 1-8 Alkyl, C 1-8 Haloalkyl, -L'-phenyl, -L'-3 to 6-membered carbocyclic, -L'-3 to 6-membered heterocyclic and -L'-5 to 6-membered heteroaryl, each optionally dominated by h Rgg replace;

[1392] R w1 R w1 '、R w2 R w2 '、R w3 R w3 '、R w4 R w4 '、R w5 R w5 '、R w6 R w6 Each element is independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C 2- C8 alkenyl, C 2- C8 alkynyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-C(O)OR’, -L”-C(O)NR’R”, -L”-S(O) 0-2 R', -L”-S(O)2NR'R”, -L”-S(O)NR’R”, -L”-OC(O)R’, -L”-OC(O)NR’R”, -L”-NR’R”, -L”-OC(O)NR’R”, -L”-C6-C 10 Aryl, -L”-3 to 14-membered carbocyclic, -L”-3 to 14-membered heterocyclic, and -L”-5 to 14-membered heteroaryl; wherein the aryl, carbocyclic, heterocyclic, and heteroaryl are optionally surrounded by k R ggg replace;

[1393] R gg Independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C 2- C8 alkenyl, C 2- C8 alkynyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-C(O)OR’, -L”-C(O)NR’R”, -L”-S(O) 0-2 R', -L”-S(O)2NR'R”, -L”-S(O)NR’R”, -L”-OC(O)R’, -L”-OC(O)NR’R”, -L”-NR’R”, -L”-C(O)NR’R”, -L”-C6-C 10 Aryl, -L”-3 to 14-membered carbocyclic, -L”-3 to 14-membered heterocyclic, and -L”-5 to 14-membered heteroaryl; wherein the aryl, carbocyclic, heterocyclic, and heteroaryl are optionally surrounded by k R ggg replace;

[1394] R ggg Each is independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C2- C8 alkenyl, C 2- C8 alkynyl, C1-C8 haloalkyl, -L”'-OR', -L”'-NR'R”, -L”'-C(O)OR', -L”'-C(O)NR'R”, -L”'-S(O) 0-2 R', -L"'-S(O)2NR'R", -L"'-S(O)NR'R", -L"'-OC(O)R', -L"'-OC(O)NR'R", -L"'-NR'R", -L"'-OC(O)NR'R", -L"'-C6-C 10 Aryl, -L”'-3 to 14-membered carbocyclic, -L”'-3 to 14-membered heterocyclic and -L”'-5 to 14-membered heteroaryl;

[1395] L' is selected from covalent bonds, -O-, -S-, -NR'-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR'-, -OC(O)-, -OC(O)NR'-, -N(R')C(O)O-, -N(R')C(O)- and -N(R')S(O)2-; or L' is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -N(R')C(O)-, -C(O)N(R')-, -N(R')S(O)2-, -S(O)2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

[1396] L” is selected from covalent bonds, -O- and -S-; or L” is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-.

[1397] L”' is selected from covalent bonds, -O-, and -S-; or L”' is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-.

[1398] R' is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-NR”'R””, -L”-C6-C 10 Aryl, -L”-3 to 14-membered carbocyclic, -L”-3 to 14-membered heterocyclic and -L”-5 to 14-membered heteroaryl;

[1399] R” is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-NR”'R””, -L”-C6-C 10 Aryl, -L”-3 to 14-membered carbocyclic, -L”-3 to 14-membered heterocyclic and -L”-5 to 14-membered heteroaryl;

[1400] Alternatively, R' and R” together with the N atoms they are attached to form 3 to 14-membered heterocyclic groups;

[1401] R”' and R”” are each independently selected from H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, -L”'-C6-C 10 Aryl, -L”'-3 to 14-membered carbocyclic, -L”'-3 to 14-membered heterocyclic and -L”'-5 to 14-membered heteroaryl; or R”' and R”” together with the N atom to which they are attached to form 3 to 14-membered heterocyclic groups;

[1402] h can be 1, 2, 3, 4, or 5;

[1403] k is 1, 2, 3, 4 or 5;

[1404] r1, r2, r3, r4, r5, and r6 are each independently 0, 1, or 2;

[1405] t can be 0, 1, or 2.

[1406] In one embodiment, the present invention relates to a compound of formula (1) as described above, or a stereoisomer thereof, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug, wherein said compound is represented by one of the following formulas:

[1407]

[1408] in,

[1409] The ring in which it is located can be either aromatic or non-aromatic;

[1410] Each can be a double bond or a single bond independently;

[1411] S is C(R) x1 ) or NR x1 ;

[1412] T is C(R) x2 ) or NR x2 ;

[1413] N is C(R) x4 ) or NR x4 ;

[1414] M is C(R)x5 ) or NR x5 ;

[1415] K is C(R) x6 ) or N;

[1416] The condition is that one or two of S, T, M, and N are absent;

[1417] w1 is selected from (CR) w1 R w1 ') r1 NR w1 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[1418] w2 is selected from (CR) w2 R w2 ') r2 NR w2 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[1419] w3 is selected from (CR) w3 R w3 ') r3 NR w3 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[1420] w4 is selected from (CR) w4 R w4 ') r4 and N;

[1421] w5 is selected from (CR) w5 R w5 ') r5 NR w5 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[1422] w6 is selected from (CR) w6 R w6 ') r6 NR w6 O and S, wherein S is optionally oxidized to form sulfone or sulfoxide;

[1423] and / or

[1424] Among w1, w2, w3, w4, w5, and w6, the two non-adjacent variables can be arbitrarily chosen from -(CH2). t -Bridge, where -(CH2) t One or more methylene groups in - are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; and / or

[1425] In w1, w2, w3, w4, w5, and w6, if a substituent is present on a single atom, it forms a 3-7 membered carbon ring or a 3-7 membered heterocycle together with that atom, thereby forming a spirocyclic group as a whole; and / or

[1426] If substituents on adjacent atoms are present, they may, together with the atoms, optionally form 3-7 membered carbon rings or 3-7 membered heterocycles, thereby forming a fused ring group as a whole.

[1427] R g1 -R g5 Each is independently selected from H, CN, halogen, oxo, C1-C8 alkyl, C1-C8 haloalkyl, -L'-OR', -L'-NR'R", -L'-SR', -L'-3 to 6-membered carbon cycloyl, -L'-4 to 6-membered heterocyclic and -L'-5 to 6-membered heteroaryl;

[1428] R x1 and R x2 Each is independently selected from H, halogen, oxo, -CN, -L'-OR' and -L'-NR'R", or R x1 and R x2 Each is independently selected from C 1-8 Alkyl, C 1-8 Haloalkyl-, L'-phenyl, -L'-3 to 6-membered carbocyclic, -L'-3 to 10-membered heterocyclic and -L'-5 to 6-membered heteroaryl, each optionally dominated by h R gg replace;

[1429] R x4 R x5 and R x6 Each is independently selected from H, halogen, -L'-OR' and -L'-NR'R", or R x4 and R x5 Each is independently selected from C 1-8 Alkyl, C 1-8 Haloalkyl, -L'-phenyl, -L'-3 to 6-membered carbocyclic, -L'-3 to 6-membered heterocyclic and -L'-5 to 6-membered heteroaryl, each optionally dominated by h R gg replace;

[1430] R w1 R w1 '、R w2 R w2 '、R w3 R w3 '、R w4 R w4 '、R w5 R w5 '、R w6 Rw6 Each element is independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C 2- C8 alkenyl, C 2- C8 alkynyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-C(O)OR’, -L”-C(O)NR’R”, -L”-S(O) 0-2 R', -L”-S(O)2NR'R”, -L”-S(O)NR’R”, -L”-OC(O)R’, -L”-OC(O)NR’R”, -L”-NR’R”, -L”-OC(O)NR’R”, -L”-C6-C 10 Aryl, -L”-3 to 14-membered carbocyclic, -L”-3 to 14-membered heterocyclic, and -L”-5 to 14-membered heteroaryl; wherein the aryl, carbocyclic, heterocyclic, and heteroaryl are optionally surrounded by k R ggg replace;

[1431] R gg Independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C 2- C8 alkenyl, C 2- C8 alkynyl, C1-C8 haloalkyl, -L”-OR’, -L”-NR’R”, -L”-C(O)OR’, -L”-C(O)NR’R”, -L”-S(O) 0-2 R', -L”-S(O)2NR'R”, -L”-S(O)NR’R”, -L”-OC(O)R’, -L”-OC(O)NR’R”, -L”-NR’R”, -L”-C(O)NR’R”, -L”-C6-C 10 Aryl, -L”-3 to 14-membered carbocyclic, -L”-3 to 14-membered heterocyclic, and -L”-5 to 14-membered heteroaryl; wherein the aryl, carbocyclic, heterocyclic, and heteroaryl are optionally surrounded by k R ggg replace;

[1432] R ggg Each is independently selected from H, halogen, -CN, -NO2, oxo, C1-C8 alkyl, C 2- C8 alkenyl, C 2- C8 alkynyl, C1-C8 haloalkyl, -L”'-OR', -L”'-NR'R”, -L”'-C(O)OR', -L”'-C(O)NR'R”, -L”'-S(O) 0-2R', -L"'-S(O)2NR'R", -L"'-S(O)NR'R", -L"'-OC(O)R', -L"'-OC(O)NR'R", -L"'-NR'R", -L"'-OC(O)NR'R", -L"'-C6-C 10 Aryl, -L”'-3 to 14-membered carbocyclic, -L”'-3 to 14-membered heterocyclic and -L”'-5 to 14-membered heteroaryl;

[1433] L' is selected from covalent bonds, -O-, -S-, -NR'-, -S(O)2-, -C(O)-, -C(O)O-, -C(O)NR'-, -OC(O)-, -OC(O)NR'-, -N(R')C(O)O-, -N(R')C(O)- and -N(R')S(O)2-; or L' is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -C(R')2-, -N(R')-, -N(R')C(O)-, -C(O)N(R')-, -N(R')S(O)2-, -S(O)2N(R')-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

[1434] L” is selected from covalent bonds, -O- and -S-; or L” is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-.

[1435] L”' is selected from covalent bonds, -O-, and -S-; or L”' is a C1-C8 alkylene group, wherein one or more methylene units are optionally and independently replaced by -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-.

[1436] R' is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-NR”'R””, -L”-C6-C 10 Aryl, -L”-3 to 14-membered carbocyclic, -L”-3 to 14-membered heterocyclic and -L”-5 to 14-membered heteroaryl;

[1437] R” is independently selected from H, C1-C8 alkyl, -L”-OR”', C1-C8 haloalkyl, -L”-NR”'R””, -L”-C6-C 10 Aryl, -L”-3 to 14-membered carbocyclic, -L”-3 to 14-membered heterocyclic and -L”-5 to 14-membered heteroaryl;

[1438] Alternatively, R' and R” together with the N atoms they are attached to form 3 to 14-membered heterocyclic groups;

[1439] R”' and R”” are each independently selected from H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, -L”'-C6-C 10 Aryl, -L”'-3 to 14-membered carbocyclic, -L”'-3 to 14-membered heterocyclic and -L”'-5 to 14-membered heteroaryl; or R”' and R”” together with the N atom to which they are attached to form 3 to 14-membered heterocyclic groups;

[1440] h can be 1, 2, 3, 4, or 5;

[1441] k is 1, 2, 3, 4 or 5;

[1442] r1, r2, r3, r4, r5, and r6 are each independently 0, 1, or 2;

[1443] t can be 0, 1, or 2.

[1444] This invention relates to specific compounds, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs, wherein said compounds are selected from:

[1445]

[1446]

[1447]

[1448]

[1449]

[1450]

[1451]

[1452]

[1453] In one embodiment, the present invention relates to a pharmaceutical composition comprising the compound of the present invention or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs, and pharmaceutically acceptable carriers, adjuvants, or mediators.

[1454] In one embodiment, the present invention relates to the use of the compound of the invention or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs or pharmaceutical compositions comprising the thereof in the preparation of a medicament for the prevention and / or treatment of HPK1-mediated disorders, diseases or conditions.

[1455] Furthermore, the disorder, disease, or symptom mentioned therein is a proliferative disorder.

[1456] Furthermore, the proliferative disorder mentioned above is cancer.

[1457] Furthermore, the proliferative impairment is associated with one or more activating mutations in HPK1.

[1458] In one implementation, the obstacle, disease, or symptom is a chronic viral infection.

[1459] In one embodiment, the present invention relates to the use of the compounds of the present invention or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs, or pharmaceutical compositions comprising the thereof in the preparation of a medicament for increasing the efficacy of a vaccine.

[1460] Pharmaceutical Compositions and Kits

[1461] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention (also referred to as the "active component") and a pharmaceutically acceptable carrier, adjuvant, or mediator. In some embodiments, the pharmaceutical composition comprises an effective amount of the compound of the present invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound of the present invention. In some embodiments, the pharmaceutical composition comprises a preventatively effective amount of the compound of the present invention.

[1462] Pharmaceutically acceptable carriers, adjuvants, or mediators used in this invention refer to non-toxic carriers, adjuvants, or mediators that do not impair the pharmacological activity of the compounds formulated together. Pharmaceutically acceptable carriers, adjuvants, or mediators that can be used in the compositions of this invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[1463] Suitable formulations for administering the compounds of the present invention will be apparent to those skilled in the art, and include, for example, tablets, pills, capsules, suppositories, lozenges, sugar lozenges, solutions (particularly for injection (subcutaneous, intravenous, intramuscular) and infusion), elixirs, syrups, capsules, emulsions, inhalers, or dispersible powders. If necessary, the specified dosage may be administered several times daily.

[1464] The present invention also includes a kit (e.g., a pharmaceutical package). The provided kit may include the compounds of the present invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the compounds of the present invention and other therapeutic agents. In some embodiments, the provided kit may optionally include a third container containing pharmaceutical excipients for diluting or suspending the compounds of the present invention and / or other therapeutic agents. In some embodiments, the compounds of the present invention and other therapeutic agents provided in the first and second containers are combined to form a unit dosage form.

[1465] use

[1466] The compounds and compositions described herein are generally suitable for inhibiting the kinase activity of one or more enzymes. In some embodiments, the kinase inhibited by the compounds and methods of the present invention is HPK1.

[1467] The compounds disclosed in this invention can be used to inhibit the activity of HPK1 enzyme. HPK1 is a member of the germinal center kinase subfamily of Ste20-associated serine / threonine kinases. HPK1 exerts the function of MAP4K by phosphorylating and activating MAP3K proteins (including MEKK1, MLK3, and TAK1), thereby activating MAPK Jnk.

[1468] In one embodiment, the subject matter disclosed herein relates to a method for inhibiting HPK1, the method comprising contacting HPK1 with an effective amount of the compound or pharmaceutical composition of the present invention.

[1469] In some embodiments, the subject matter disclosed in the invention relates to a method for enhancing the immune response of a subject in need, wherein the method comprises administering to the subject an effective amount of the compound of the invention or the pharmaceutical composition of the invention. In some aspects of this embodiment, the subject's T cells, compared to before administration of the compound or pharmaceutical composition, exhibit at least one of the following: enhanced activation, increased activation, enhanced migration, enhanced proliferation, enhanced survival, and enhanced cytolytic activity. In some aspects of this embodiment, T cell activation is characterized by an increased incidence of γ-IFN+CD8 T cells or an increased production of IL-2 or granzyme B by T cells compared to before administration of the compound or pharmaceutical composition. In some aspects of this embodiment, the number of T cells increases compared to before administration of the compound or pharmaceutical composition. In some aspects of this embodiment, the T cells are antigen-specific CD8 T cells. In some aspects of this embodiment, the subject's antigen-presenting cells exhibit enhanced maturation and activation compared to before administration of the compound or pharmaceutical composition. In some aspects of this embodiment, the antigen-presenting cells are dendritic cells. In some aspects of this embodiment, the maturation of antigen-presenting cells is characterized by an increased incidence of CD83+ dendritic cells. In some aspects of this embodiment, the activation of antigen-presenting cells is characterized by an increased expression of CD80 and CD86 on dendritic cells.

[1470] The compounds disclosed in this invention bind directly to HPK1 and inhibit its kinase activity. In some embodiments, the compounds disclosed in this invention reduce, inhibit, or otherwise decrease HPK1-mediated phosphorylation of SLP76 and / or Gads.

[1471] The compounds disclosed in this invention may or may not be specific HPK1 antagonists. Specific HPK1 antagonists reduce the biological activity of HPK1 by a statistically greater amount than the inhibitory effect of the antagonist on any other protein (e.g., other serine / threonine kinases). In some embodiments, the compounds disclosed in this invention specifically inhibit the serine / threonine kinase activity of HPK1. In some of these embodiments, the HPK1 antagonist targets the IC50 of HPK1. 50 HPK1 antagonists target another serine / threonine kinase or another type of kinase (such as tyrosine kinase) with an IC50 value. 50 Approximately 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001%, or less.

[1472] The compounds disclosed in this invention can be used in methods for inhibiting HPK1. Such methods involve contacting HPK1 with an effective amount of the compound of this invention. "Contact" means bringing the compound into sufficient proximity to the isolated HPK1 enzyme or cells expressing HPK1 (e.g., T cells, B cells, dendritic cells) such that the compound can bind to HPK1 and inhibit its activity. Contact with HPK1 can be achieved in vitro or in vivo by administering the compound to a subject.

[1473] Whether HPK1 has been inhibited can be determined using any method known in the art for measuring HPK kinase activity, including in vitro kinase assays, Western blotting with antibodies specific to HPK1 phosphorylation targets (such as SLP76 and Gads), or measurements of downstream biological effects of HPK1 kinase activity, such as recruitment of 14-3-3 protein to phosphorylated SLP7 and Gads, release of the SLP76-Gads-14-3-3 complex from LAT-containing microclusters, or T or B cell activation.

[1474] The compounds disclosed in this invention can be used to treat HPK1-dependent conditions. As used herein, "HPK1-dependent condition" refers to a pathological condition in which HPK1 activity is the cause of or maintenance of the pathological condition. In some embodiments, HPK1-dependent condition is cancer.

[1475] The compounds disclosed in this invention can also be used to enhance the immune response in subjects who require them. Such methods involve administering an effective amount of the compounds of this invention.

[1476] As used herein, “enhanced immune response” refers to any modification of the immunogenic response to an antigen. Non-limiting examples of modifications of the immunogenic response to an antigen include enhanced dendritic cell maturation or migration, enhanced T cell (e.g., CD4 T cells, CD8 T cells) activation, enhanced T cell (e.g., CD4 T cells, CD8 T cells) proliferation, enhanced B cell proliferation, increased T cell and / or B cell survival, modified antigen presentation via antigen-presenting cells (e.g., dendritic cells), modified antigen clearance, increased production of interleukins (e.g., interleukin-2) via T cells, increased resistance to prostaglandin E2-induced immunosuppression, and enhanced activation and / or cytolytic activity of CD8 T cells.

[1477] In some embodiments, the individual's antigen-presenting cells exhibit enhanced maturation and activation prior to administration of the compound of the present invention or its pharmaceutically acceptable salt, prodrug, or metabolite. In some embodiments, the antigen-presenting cells are dendritic cells. In some embodiments, antigen-presenting cell maturation is characterized by an increased incidence of CD83+ dendritic cells. In some embodiments, antigen-presenting cell activation is characterized by increased expression of CD80 and CD86 on the dendritic cells.

[1478] The compounds disclosed in this invention, or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs, and pharmaceutically acceptable substances suitable for treating T-cell dysfunction disorders. "T-cell dysfunction disorder" is a T-cell disorder or impairment characterized by a reduced response to antigenic stimulation. In one specific embodiment, T-cell dysfunction disorder is a disorder specifically associated with an increase in HPK1 kinase activity. In another embodiment, T-cell dysfunction disorder is a disorder in which T cells lack the ability to secrete cytokines, proliferate, or perform cytolytic activity. In one specific aspect, the reduced response can lead to ineffective control of pathogens or tumors that express immunogens. Examples of T-cell dysfunction disorders characterized by T-cell dysfunction include acute infections of unknown origin, chronic infections, and tumor-associated immune disorders.

[1479] Therefore, the compounds disclosed in this invention can be used to treat diseases in which enhanced immunogenicity is required, such as enhancing tumor immunogenicity for the treatment of cancer.

[1480] The term "dysfunction" in the context of immune dysfunction refers to a reduced immune response to antigen stimulation. This term encompasses common components where exhaustion and / or loss of antigen recognition can occur, but the subsequent immune response is ineffective in controlling infection or tumor growth.

[1481] As used herein, the term “functional impairment” also includes resistance to or non-responsiveness to antigen recognition, specifically, a diminished ability to translate antigen recognition into downstream T cell effector functions such as proliferation, intercytokine production (e.g., IL-2, γ-IFN), and / or target cell killing.

[1482] The term "loss of capacity" refers to a state of unresponsiveness to antigenic stimulation caused by incomplete or insufficient signaling delivered via T cell receptors (e.g., intracellular Ca2+ in the absence of ras activation). +2(Elevated). In the absence of co-stimulation, T cell dysfunction can also be induced by antigen stimulation, causing cells to become resistant to subsequent antigen activation even under co-stimulatory conditions. The unresponsive state can usually be resolved by the presence of interleukin-2. Dysfunctional T cells do not undergo homologous expansion and / or acquire effector function.

[1483] The term "exhaustion" refers to T cell depletion, such as the state of T cell dysfunction caused by persistent TCR signaling during various chronic infections and cancers. It differs from impaired capacity in that it is not caused by incomplete or insufficient signaling, but by persistent signaling. It is defined by adverse effector function, persistent expression of inhibitory receptors, and a transcriptional state distinct from functional effector or memory T cells. Exhaustion prevents optimal control of infection and tumors. Exhaustion can be caused by exogenous negative regulatory pathways (e.g., immunomodulatory cytokines) and endogenous negative regulatory (co-stimulatory) pathways (PD-1, B7-H3, B7-H4, etc.).

[1484] "Immunogenicity" refers to the ability of a specific substance to elicit an immune response. In the process of eliminating tumor cells through an immune response, the tumor is immunogenic and enhances the immunogenicity of the tumor.

[1485] In some embodiments, the subject matter disclosed herein relates to a method for treating HPK1 dependence syndrome, the method comprising administering an effective amount of the compound or pharmaceutical composition of the present invention to a subject in need. In some aspects of this embodiment, the HPK1 dependence syndrome is cancer. In some aspects of this embodiment, the cancer includes at least one selected from the following cancers: colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, breast cancer, pancreatic cancer, hematologic malignancies, and renal cell carcinoma. In some aspects of this embodiment, the cancer has elevated T-cell infiltration. In some aspects of this embodiment, the subject's cancer cells selectively exhibit elevated expression of class I MHC antigens compared to before administration of the compound or composition.

[1486] In some embodiments, the subject matter disclosed herein relates to a method for treating chronic viral infections. In some embodiments, the subject matter disclosed herein relates to using HPK1 inhibitors as adjunctive therapy to enhance the efficacy of vaccination.

[1487] In some aspects, the present invention provides a method for treating cell proliferation diseases, including cancer, benign papilloma, gestational trophoblastic disease, and benign neoplastic diseases such as cutaneous papillomas (warts) and genital papillomas.

[1488] Examples of cancers that can be treated with the compounds of this invention include, but are not limited to, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, malignant melanoma of the skin or eye, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, and chronic or acute leukemia (including...). Acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia), childhood solid tumors, lymphocytic lymphoma, bladder cancer, kidney cancer or urethral cancer, renal pelvis cancer, central nervous system (CNS) sarcoma, primary CNS lymphoma, tumor angiogenesis, spinal tumors, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers (including asbestos-induced cancers), and combinations of these cancers.

[1489] In some embodiments, cancers that can be treated with the compounds of the present invention include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), hematologic cancers (e.g., lymphoma, leukemia, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), DLBCL, mantle cell lymphoma, non-Hodgkin lymphoma (including relapsed or refractory NHL and relapsed follicular lymphoma), Hodgkin lymphoma, or multiple myeloma), and combinations of such cancers.

[1490] In some embodiments, the cancer is brain cancer, leukemia, skin cancer, prostate cancer, thyroid cancer, colon cancer, lung cancer, or sarcoma. In another embodiment, the cancer is selected from the following: glioma, glioblastoma multiforme, paraganglioma, supratentorial primitive neuroectodermal tumor, acute myeloid leukemia, myelodysplastic syndrome, chronic myeloid leukemia, melanoma, breast cancer, prostate cancer, thyroid cancer, colon cancer, lung cancer, central chondrosarcoma, central and periosteal chondroma, fibrosarcoma, and cholangiocarcinoma.

[1491] In some embodiments, the cancer is selected from brain and spinal cord cancer, head and neck cancer, leukemia and blood cancer, skin cancer, reproductive system cancer, gastrointestinal system cancer, liver and bile duct cancer, kidney and bladder cancer, bone cancer, lung cancer, degenerative mesothelioma, sarcoma, lymphoma, adenocarcinoma, thyroid cancer, cardiac tumors, germ cell tumors, malignant neuroendocrine (carcinoid) tumors, midline carcinoma, and cancers of unknown primary origin (including cancers where metastatic cancer has been found but the original cancer site is unknown). In certain embodiments, the cancer is present in adult patients; in other embodiments, the cancer is present in pediatric patients. In a specific embodiment, the cancer is AIDS-related.

[1492] In another embodiment, the cancer is selected from brain cancer and spinal cord cancer. In a specific embodiment, the cancer is selected from the following: pleomorphic astrocytoma, glioblastoma, astrocytoma, and sensitive neuroblastoma (olfactory blastoma). In a specific embodiment, the brain cancer is selected from the following: astrocytic tumors (e.g., pilocytic astrocytoma, subependymal giant cell astrocytoma, diffuse astrocytoma, pleomorphic xanthoastrocytoma, degenerative astrocytoma, astrocytoma, giant cell glioblastoma, glioblastoma, secondary glioblastoma, primary adult glioblastoma, and primary pediatric glioblastoma), oligodendroglial tumors (e.g., oligodendroglioma and degenerative oligodendroglioma). Gliomas), oligodendroastrocytic tumors (e.g., oligodendroastrocytomas and degenerative oligodendroastrocytomas), ependymomas (e.g., myxopapillary ependymomas and degenerative ependymomas); neuroduct germ cell tumors, primitive neuroectodermal tumors, schwannomas, meningiomas, atypical meningiomas, anaplastic meningiomas, pituitary adenomas, brainstem gliomas, cerebellar astrocytomas, cerebral astrocytomas / degenerative gliomas, visual pathway and hypothalamic gliomas, and primary central nervous system lymphomas. In specific examples of these implementation schemes, brain cancer is selected from: gliomas, glioblastoma multiforme, paragangliomas, and supratentorial primitive neuroectodermal tumors (sPNETs).

[1493] In a specific embodiment, the cancer is selected from head and neck cancers, including nasopharyngeal carcinoma, nasal cavity and paranasal sinus cancer, hypopharyngeal cancer, oral cancer (e.g., squamous cell carcinoma, lymphoma, and sarcoma), lip cancer, oropharyngeal cancer, salivary gland tumors, laryngeal cancer (e.g., laryngeal squamous cell carcinoma, rhabdomyosarcoma), and eye cancer or ocular cancer. In a specific embodiment, the ocular cancer is selected from intraocular melanoma and retinoblastoma.

[1494] In a specific implementation, the cancer is selected from leukemia and blood cancers. In a specific implementation, the cancer is selected from: myelodysplastic neoplasm, myelodysplastic syndrome, myelodysplastic / myelodysplastic neoplasm, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML), myelodysplastic neoplasm (MPN), post-MPN AML, post-MDS AML, del(5q)-associated high-risk MDS or AML, blastocyst-stage chronic myeloid leukemia, angioimmunoblastic lymphoma, acute lymphoblastic leukemia, Langerhans cell histiocytosis, hairy cell leukemia, and plasmacytoma including plasmacytoma and multiple myeloma. The leukemia mentioned herein may be acute or chronic.

[1495] In a specific embodiment, the cancer is selected from skin cancer. In a specific embodiment, the skin cancer is selected from melanoma, squamous cell carcinoma, and basal cell carcinoma.

[1496] In certain embodiments, the cancer is selected from cancers of the reproductive system. In certain embodiments, the cancer is selected from: breast cancer, cervical cancer, vaginal cancer, ovarian cancer, prostate cancer, penile cancer, and testicular cancer. In specific examples of these embodiments, the cancer is breast cancer selected from the group consisting of ductal carcinoma and phyllodes tumors. In specific examples of these embodiments, the breast cancer can be male breast cancer or female breast cancer. In specific examples of these embodiments, the cancer is cervical cancer selected from squamous cell carcinoma and adenocarcinoma. In specific examples of these embodiments, the cancer is ovarian cancer selected from epithelial carcinoma.

[1497] In specific implementation schemes, the cancer is selected from cancers of the gastrointestinal system. Specifically, the cancer is selected from: esophageal cancer, gastric cancer, gastrointestinal carcinoid tumors, pancreatic cancer, gallbladder cancer, colorectal cancer, and anal cancer. In examples of these implementation schemes, the cancer is selected from: esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gastric lymphoma, gastrointestinal lymphoma, solid pseudopapillary pancreatic tumors, pancreatic germ cell tumors, islet cell tumors, pancreatic cancer (including acinar cell carcinoma and ductal adenocarcinoma), gallbladder adenocarcinoma, colorectal adenocarcinoma, and anal squamous cell carcinoma.

[1498] In specific implementation schemes, the cancer is selected from liver cancer and bile duct cancer. In specific implementation schemes, the cancer is liver cancer (hepatocellular carcinoma). In specific implementation schemes, the cancer is bile duct cancer; in examples of these implementation schemes, the bile duct cancer is selected from intrahepatic bile duct cancer and extrahepatic bile duct cancer.

[1499] In a specific implementation plan, the cancer is selected from kidney cancer and bladder cancer. In a specific implementation plan, the cancer is selected from the following types of kidney cancer: renal cell carcinoma, Wim's tumor, and transitional cell carcinoma. In a specific implementation plan, the cancer is selected from the following types of bladder cancer: urethral epithelial carcinoma (transitional cell carcinoma), squamous cell carcinoma, and adenocarcinoma.

[1500] In the specific implementation plan, the cancer is selected from bone cancer. Specifically, the bone cancer is selected from: osteosarcoma, malignant fibrous histiocytoma of bone, Ewing's sarcoma, and chordoma.

[1501] In the specific implementation plan, the cancer is selected from lung cancer. Specifically, the lung cancer is selected from: non-small cell lung cancer, small cell lung cancer, bronchial tumors, and pleural pulmonary blastoma.

[1502] In a specific implementation, the cancer is selected from malignant mesothelioma. In a particular embodiment, the cancer is selected from the group consisting of epithelial mesothelioma and sarcomatoid carcinoma.

[1503] In the specific implementation plan, the cancer is selected from sarcomas. Specifically, the sarcoma is selected from: central chondrosarcoma, central and periosteal chondroma, fibrosarcoma, clear cell tenosynovitis, and Kaposi's sarcoma.

[1504] In the specific implementation plan, the cancer is selected from lymphomas. Specifically, the cancer is selected from: Hodgkin lymphoma (e.g., Reed-Stemberg cell), non-Hodgkin lymphoma (e.g., diffuse large B-cell lymphoma, follicular lymphoma, mycosis fungoides, Cézare syndrome, primary central nervous system lymphoma), cutaneous T-cell lymphoma, and primary central nervous system lymphoma.

[1505] In the specific implementation plan, the cancer is selected from adenocarcinoma. Specifically, the cancer is selected from: adrenocortical carcinoma, pheochromocytoma, paraganglioma, pituitary tumor, thymoma, and thymic carcinoma.

[1506] In a specific implementation, the cancer is selected from thyroid cancer. In a particular embodiment, the thyroid cancer is selected from: medullary thyroid carcinoma, papillary thyroid carcinoma, and follicular thyroid carcinoma.

[1507] In specific implementation schemes, the cancer is selected from germ cell tumors. In specific implementation schemes, the cancer is selected from: malignant extracranial germ cell tumors and degenerative extragonadal germ cell tumors. In specific examples of these implementation schemes, the degenerative extragonadal germ cell tumor is selected from non-seminomatous tumors and seminomas.

[1508] In a specific implementation scheme, the cancer is selected from cardiac tumors. In a particular embodiment, the cardiac tumor is selected from: malignant teratoma, lymphoma, rhabdomyosarcoma, angiosarcoma, chondrosarcoma, infantile fibrosarcoma, and synovial sarcoma.

[1509] In a specific implementation plan, the trophoblastic disease is selected from benign papillomas, benign neoplastic diseases, and gestational trophoblastic diseases. In a specific implementation plan, the benign neoplastic disease is selected from cutaneous papillomas (warts) and genital papillomas. In a specific implementation plan, the gestational trophoblastic disease is selected from: cystic hydatidiform moles and gestational trophoblastic tumor formation (e.g., invasive hydatidiform mole, choriocarcinoma, placental locus trophoblastic tumor, and epithelial trophoblastic tumor).

[1510] In some embodiments, the subject has melanoma. The melanoma may be in an early or late stage. In some embodiments, the subject has colorectal cancer. The colorectal cancer may be in an early or late stage. In some embodiments, the subject has non-small cell lung cancer. The non-small cell lung cancer may be in an early or late stage. In some embodiments, the subject has pancreatic cancer. The pancreatic cancer may be in an early or late stage. In some embodiments, the subject has a blood disorder. The blood disorder may be in an early or late stage. In some embodiments, the subject has ovarian cancer. The ovarian cancer may be in an early or late stage. In some embodiments, the subject has breast cancer. The breast cancer may be in an early or late stage. In some embodiments, the subject has renal cell carcinoma. The renal cell carcinoma may be in an early or late stage. In some embodiments, the cancer has elevated T-cell infiltration.

[1511] In some embodiments, cancers treatable with the compounds of the present invention include melanoma (e.g., metastatic malignant melanoma), renal cell carcinoma (e.g., clear cell carcinoma), prostate cancer (e.g., hormone-refractory prostate cancer), breast cancer, triple-negative breast cancer, colon cancer, and lung cancer (e.g., non-small cell lung cancer and small cell lung cancer). Additionally, the present invention includes refractory or recurrent malignant diseases whose growth can be inhibited by the compounds of the present invention.

[1512] In some embodiments, diseases and indications for which the compounds of the present invention can be used for treatment include, but are not limited to, hematologic malignancies, sarcomas, lung cancer, gastrointestinal cancer, genitourinary tract cancers, liver cancer, bone cancer, nervous system cancers, gynecological cancers, and skin cancers.

[1513] Exemplary hematologic malignancies include lymphomas and leukemias such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin lymphoma (including relapsed or refractory NHL and relapsed follicular lymphoma), Hodgkin lymphoma, myeloproliferative disorders (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocythemia (ET)), spinal dysplasia syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, Waldenström's macroglobulinemia, pilocellular lymphoma, chronic myeloid lymphoma, and Burkitt's lymphoma.

[1514] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, and teratoma.

[1515] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer, bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, chondroma hamartoma, and mesothelioma.

[1516] Exemplary gastrointestinal cancers include the following cancers: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid, Kaposi's sarcoma, leiomyosarcoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyosarcoma), and colorectal cancer.

[1517] Examples of genitourinary cancers include the following: kidney (adenocarcinoma, Wim's tumor [nephroblastoma]), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), and testis (seminomatous cyst, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoma-like tumor, lipoma).

[1518] Exemplary liver cancers include liver cancer (e.g., hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[1519] Exemplary bone cancers include, for example, osteosarcoma (e.g., osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malformed giant cell tumor chordoma, osteochondroma (osteochondroma), benign chondroma, chondroblastoma, chondromycinous fibroma, osteoid osteoma, and giant cell tumor.

[1520] Typical examples of neurological cancers include cancers of the following: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, neuroblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cord (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitte-Ducios disease.

[1521] Typical gynecological cancers include cancers of the following: uterus (endometrial cancer), cervix (cervical cancer, pretumoral cervical dysplasia), ovaries (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, cancer of unknown type), follicular cell tumor, Settly-Radigau cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma)), and fallopian tubes (cancer).

[1522] Exemplary skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, dysplasia, lipoma, hemangioma, dermatofibroma, and keloid. In some embodiments, diseases and indications for which the compounds of the present invention can be used for treatment include, but are not limited to, sickle cell diseases (e.g., sickle cell anemia), triple-negative breast cancer (TNBC), myelodysplastic syndrome, testicular carcinoma, bile duct cancer, esophageal cancer, and urothelial carcinoma.

[1523] Exemplary head and neck cancers include glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinoma, adenocarcinoma, oral cancer, laryngeal cancer, nasopharyngeal carcinoma, nasal cancer and paranasal sinus cancer, thyroid cancer and parathyroid cancer.

[1524] In some implementations, HPK1 inhibitors can be used to treat PGE2-producing tumors (e.g., tumors overexpressing Cox-2) and / or adenosine-producing tumors (tumors overexpressing CD73 and CD39). Cox-2 overexpression has been detected in a variety of tumors, such as colorectal cancer, breast cancer, pancreatic cancer, and lung cancer, where it is associated with poor prognosis. Cox-2 overexpression has been reported in hematologic malignancies, such as RAJI (Burkitter lymphoma) and U937 (acute promonocyte leukemia), and in the embryonic cells of patients. CD73 is upregulated in various human cancers, including colon cancer, lung cancer, pancreatic cancer, and ovarian cancer. Importantly, higher levels of CD73 expression are associated with tumor angiogenesis, invasiveness, and metastasis, and are also associated with shorter patient survival in breast cancer.

[1525] Dosage

[1526] The pharmaceutical compositions provided by this invention can be administered via a variety of routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration via implantation, or other routes of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intra-synovial administration, intrasternal administration, intramenstrual administration, intralesional administration, and intracranial injection or infusion techniques.

[1527] Typically, an effective amount of the compound described herein is administered. The actual amount of compound administered may be determined by the physician based on relevant circumstances, including the condition being treated, the chosen route of administration, the compound actually administered, the individual patient's age, weight and response, the severity of the patient's symptoms, etc.

[1528] When used to prevent the conditions described in this invention, the compounds provided herein are administered to subjects at risk of developing the conditions, typically based on a physician's advice and under physician supervision, at the dosage levels described above. Subjects at risk of developing a specific condition generally include subjects with a family history of the condition, or those identified through genetic testing or screening as particularly susceptible to developing the condition.

[1529] Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by bolus injection, for instance, to increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active component through the body; for example, an intramuscular or subcutaneous bolus dose results in a slow release of the active component, while a bolus dose delivered directly to a vein (e.g., via IV intravenous infusion) allows for a more rapid delivery, causing the concentration of the active component in the blood to rapidly increase to an effective level. In other embodiments, the pharmaceutical composition can be administered in the form of a continuous infusion, for example, via IV intravenous infusion, thereby providing a steady-state concentration of the active component in the subject's body. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition can be administered first, followed by a continuous infusion.

[1530] Oral compositions may be in the form of bulk liquid solutions, suspensions, or bulk powders. However, more commonly, for the purpose of precise dosing, the compositions are provided in unit dose form. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined quantity of active substance and suitable pharmaceutical excipients suitable for producing the desired therapeutic effect. Typical unit dose forms include pre-filled, pre-measured ampoules or syringes for liquid compositions, or, in the case of solid compositions, pills, tablets, capsules, etc.

[1531] HPK1 antagonists were administered to subjects at doses ranging from approximately 0.001 μg / kg to approximately 1000 mg / kg, including but not limited to approximately 0.001 μg / kg, 0.01 μg / kg, 0.05 μg / kg, 0.1 μg / kg, 0.5 μg / kg, 1 μg / kg, 10 μg / kg, 25 μg / kg, 50 μg / kg, 100 μg / kg, 250 μg / kg, 500 μg / kg, 1 mg / kg, 5 mg / kg, 10 mg / kg, 25 mg / kg, 50 mg / kg, 100 mg / kg, and 200 mg / kg.

[1532] Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers, as well as buffers, suspending and dispersing agents, colorants, flavoring agents, etc. Solid forms may include, for example, any of the following components, or compounds with similar properties: binders, such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginic acid, Primogel, or corn starch; lubricants, such as magnesium stearate; gliding agents, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavorings.

[1533] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline, or other injectable excipients known in the art.

[1534] Transdermal compositions are typically formulated as topical ointments or creams containing an active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffin-based or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with, for example, an oil-in-water emulsion base. Such transdermal formulations are well known in the art and generally include other components to enhance stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope of this invention.

[1535] The compounds of this invention can also be administered via transdermal devices. Therefore, transdermal drug delivery can be achieved using reservoirs or porous membrane types, or patches with various solid matrices.

[1536] The above-described components for oral, injectable, or topical administration are merely representative. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[1537] The compounds of this invention can also be administered in a sustained-release form or from a sustained-release drug delivery system. Descriptions of representative sustained-release materials can be found at Remington's Pharmaceutical Sciences.

[1538] This invention also relates to pharmaceutically acceptable formulations of the compounds of this invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, respectively, composed of 6, 7, and 8 α-1,4-linked glucose units, optionally including one or more substituents on the linked sugar moieties, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfonyl ether-substituted groups. In some embodiments, the cyclodextrin is a sulfonyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. In some embodiments, the formulation comprises hexapropyl-β-cyclodextrin.

[1539] Combination therapy

[1540] Depending on the specific disorder or disease to be treated, other therapeutic agents for treating that disease are often used in combination with the compounds and compositions of the present invention. As used herein, additional therapeutic agents administered to treat a particular disease or disorder are generally referred to as “the disease or disorder appropriate for treatment”.

[1541] Another therapeutic agent that can be administered in combination with the compounds of the present invention includes, but is not limited to: anti-proliferative compounds including, but not limited to, aromatase inhibitors; anti-estrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule-activating compounds; alkylating compounds, etc.; anti-estrogens such as tamoxifen, etc.; anti-androgen drugs such as bicalutamide, etc.; "topoisomerase I inhibitors" such as topotecan, etc.; topoisomerase II inhibitors such as epirubicin, etc.; "microtubule activators" such as docetaxel, etc.; alkylating agents such as cyclophosphamide, etc.; H DAC inhibitors, such as succinyl aniline oxime acid (SAHA); "anti-growth antimetabolites," such as capecitabine; "platinum compounds," such as cisplatinum; "compounds that target / reduce the activity of protein or lipid kinases or protein or lipid phosphatases, or other anti-angiogenic compounds," such as protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors; PI3K inhibitors; BTK inhibitors; SYK inhibitors; Bd-2 inhibitors; JAK inhibitors; anti-angiogenic compounds, such as thalidomide; proteasome inhibitors, such as bortezomib; and so on.

[1542] Chemical synthesis section

[1543] The present invention will be described in detail below with reference to embodiments, but this does not imply any adverse limitation on the invention. This application has been described in detail, and specific embodiments thereof have also been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the invention without departing from the spirit and scope thereof. All solvents used in this application are commercially available and can be used without further purification. The initial compound raw materials used for synthesis in this application are commercially available or can be prepared by methods in the prior art.

[1544] Synthesis of Example 1

[1545]

[1546] Synthesis of intermediates 1-2

[1547] Compound 1-1 (100 g) was dissolved in methanol (3 L), and Raney nickel (150 g) was added under nitrogen protection. The mixture was heated to 40 °C, and hydrazine hydrate (34 g) was added dropwise. The reaction was carried out for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a brown solid compound 1-2 (65 g, yield 66.6%).

[1548] Synthesis of compounds 1-3

[1549] Compounds 1-2 (55 g) and potassium carbonate (224 g) were dissolved in acetonitrile (825 mL). Chloroacetyl chloride (36.7 g) was added dropwise at 15 °C. After reacting for 2 hours, the temperature was increased to 40 °C and reacted for another 14 hours. The reaction solution was completely quenched with methanol (10 mL), filtered, and the filter cake was washed with tetrahydrofuran / methanol = 2 / 1 (100 mL x 5). The mixture was then combined with the organic phase and concentrated to give a brown solid compound 1-3 (78 g). LCMS (ESI) m / z: 243, 245 [M+H] + .

[1550] Synthesis of compounds 1-4

[1551] Compounds 1-3 (68 g) were dissolved in tetrahydrofuran (136 mL), and a borane-tetrahydrofuran complex (1 M, 320 mL) was added dropwise at 20 °C. The reaction mixture was heated to 70 °C and reacted for 12 hours. The reaction solution was then quenched dropwise with methanol (1 L) at 0-10 °C and concentrated to give a brown solid product 1-4 (68 g). LCMS (ESI) m / z: 229, 231 [M+H] + .

[1552] Synthesis of compounds 1-5

[1553] Compound 1-4 (58 g) was dissolved in tetrahydrofuran (580 mL), and di-tert-butyl carbonate (77.7 g) was added. The mixture was cooled to 0 °C, and potassium bis(trimethylsilyl)amino (1 M, 356 mL) was added dropwise. The reaction was carried out at 25 °C for 2 hours. Methanol (100 mL) was added dropwise to quench the reaction mixture. The organic phase was concentrated under reduced pressure and purified by column chromatography (eluent polarity: petroleum ether / ethyl acetate = 100 / 1-5 / 1) to give off-white compound 1-5 (45 g, yield 46%).

[1554] Synthesis of compounds 1-6

[1555] Compounds 1-5 (25 g) were dissolved in dioxane (250 mL), and bis-pinacolborate (16.9 g) and potassium acetate (17.8 g) were added. Under nitrogen protection, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride·dichloromethane (4.96 g) was added, and the reaction was carried out at 90 °C for 20 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to give brown solid 1-6 (24 g, yield 84%).

[1556] Synthesis of intermediates 1-8

[1557] Under nitrogen atmosphere at 0°C, N-bromosuccinimide (21.9 g) was added to compounds 1-7 (15 g) dissolved in N,N-dimethylformamide (105 mL). The reaction mixture was stirred at 40°C for 2 hours. The reaction mixture was cooled to room temperature and then poured into ice water. The solid was collected by filtration to give white solid 1-8 (18.5 g, yield 77.6%). LCMS (ESI) m / z: 213, 215 [M+H] + .

[1558] Synthesis of intermediates 1-9

[1559] Compounds 1-8 (10 g) were dissolved in phosphorus oxychloride (21.6 g) and phosphorus pentachloride (2.93 g) at 25 °C, and then stirred at 100 °C for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with sodium bicarbonate solution, filtered, and the filter cake was dried to give a white solid 1-9 (9 g, yield 82.8%). LCMS (ESI) m / z: 231, 233 [M+H] + .

[1560] Synthesis of intermediates 1-10

[1561] At 25°C, 12.9 g of N,N-dimethylformamide dimethyl acetal was added to compound 1-9 (5 g) dissolved in N,N-dimethylformamide (50 mL), and the mixture was stirred at 120°C for 4 hours. The reaction solution was concentrated to obtain a crude product, and 50 mL of 12N hydrochloric acid was added. The mixture was stirred at 50°C for 1 hour. The reaction solution was adjusted to pH 8-9 with ammonia, filtered, the filter cake was washed with water, and the mixture was stirred with 20 mL of ethyl acetate at 25°C for 1 hour. The mixture was then filtered and dried under vacuum. Column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) yielded a brown solid 1-10 (3.5 g, yield 62.4%).

[1562] Synthesis of intermediates 1-11

[1563] Compound 1-10 (500 mg) and 3-aminopyridine (272 mg) were stirred in a dioxane (10 mL) solution at 100 °C for 2 hours. The mixture was concentrated, and the crude product was purified by reversed-phase high-performance liquid chromatography (using an alkaline system containing 0.1% ammonia) to give a yellow solid 1-11 (100 mg, yield 16.3%). LCMS (ESI) m / z: 317, 319 [M+H] + .

[1564] Synthesis of intermediates 1-12

[1565] Compounds 1-11 (60 mg), 1-6 (71.2 mg), potassium carbonate (52.3 mg), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (13.8 mg) were dissolved in dioxane (5 mL) and water (1 mL) at 25 °C, and the mixture was stirred at 90 °C for 1 hour. The solution was diluted with water (10 mL), extracted with ethyl acetate (8 mL x 3), dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to give a white solid 1-12 (100 mg, crude). LCMS (ESI) m / z: 487 [M+H] + .

[1566] Synthesis of Compound 1

[1567] Compounds 1-12 (100 mg) were dissolved in hydrochloric acid / ethyl acetate (4 M, 62.5 mL) and stirred at 25 °C for 2 hours. The crude product was concentrated and purified by reversed-phase high-performance liquid chromatography (RP-HPLC) (column: Waters Xbridge BEH 250*50 mm*10 μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 30%-55%, 10 min) to obtain a yellow solid 1 (5.5 mg, yield 6.9%). LCMS (ESI) m / z: 387 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δppm: 8.29 (br s, 1H), 8.24 (br s, 1H), 8.15 (s, 1H), 7.82 (br d, J=5.6Hz, 1H), 7.76 (br s,2H),7.28(s,1H),6.60(brs,2H),5.83(br d,J=5.6Hz,1H),5.70-5.76(m,1H),4.31(br s,2H),1.81(s,3H).

[1568] Synthesis of Example 2

[1569]

[1570] Synthesis of intermediate 2-2

[1571] Compound 1-10 (see Example 1, 500 mg) was dissolved in dioxane (5 mL), followed by the addition of compound 2-1 (407 mg) and potassium carbonate (532 mg). The reaction was stirred at 130 °C for 5 hours. The reaction solution was cooled to room temperature and concentrated. Column chromatography yielded a brown solid compound 2-2 (600 mg, crude product). LCMS (ESI) m / z: 415, 417 [M+H] + .

[1572] Synthesis of Compound 2

[1573] Compounds 2-2 (600 mg) and 2-3 (223 mg) were dissolved in dioxane (4 mL) and water (1 mL). Under nitrogen protection, potassium carbonate (399 mg) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (105 mg) were added sequentially to the reaction solution. The reaction was then stirred at 100 °C for 10 hours. After filtration, the filtrate was concentrated under reduced pressure and purified by high performance liquid chromatography (HPLC) (column: Waters Xbridge BEH 250*50mm*10µm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 30%-55%, 10 min) to obtain a grayish-white solid compound 2 (21 mg, yield 5.13%). LCMS (ESI) m / z: 467 [M+H] + ; 1 H NMR (400MHz, CDCl3) δppm: 11.38-11.32 (m, 1H), 11.35 (s, 1H), 10.04 (br s,1H),10.09-9.99(m,1H),8.49(d,J=2.63Hz,1H),8.43(d,J=4.88Hz,1H),8 .34-8.31(m,1H),8.33(s,1H),8.05-8.00(m,1H),7.23-7.18(m,1H),7.13(br d,J=3.00Hz,1H),7.05(d,J=4.88Hz,1H),6.76-6.69(m,1H),6.44(d,J=7.25Hz,1H),6.28 (d,J=3.50Hz,1H),4.02-3.91(m,2H),3.63-3.49(m,4H),2.61-2.51(m,4H),2.36(s,3H).

[1574] Synthesis of Example 3

[1575]

[1576] Synthesis of intermediate 3-2

[1577] Compound 1-10 (200 mg) was dissolved in dioxane (10 mL), and compound 3-1 (137 mg), anhydrous potassium carbonate (266 mg), and... Molecular sieve (200 mg), the mixture was stirred at 130 °C for 48 hours under nitrogen atmosphere. After cooling to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure to give a brown solid compound 3-2 (80 mg). LCMS (ESI) m / z: 385, 387 [M+H] + .

[1578] Synthesis of Compound 3

[1579] Compound 3-2 (40 mg) was dissolved in dioxane (0.8 mL) and water (0.2 mL). Compound 2-3 (53.6 mg) and anhydrous potassium carbonate (28.7 mg) were added, and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (7.6 mg) was added under nitrogen atmosphere. The mixture was stirred at 100 °C for 12 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The solution was purified by high performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 30%-50%, 8 min) to obtain a white solid compound 3 (14.5 mg, yield 32.1%). LCMS (ESI) m / z: 437 [M+H] + ; 1 H NMR(400MHz,MeOD)δppm:11.94(s,1H),8.36-8.33(m,1H),8.25(s,1H),7.62( d,J=1.2Hz,1H),7.53(dd,J=1.6,8.4Hz,1H),7.40(d,J=3.6Hz,1H),7.27(d,J =7.2Hz,1H),7.16-7.11(m,2H),6.36(d,J=7.2Hz,1H),6.29(d,J=3.6Hz,1H), 3.93(s,3H),3.66(s,2H),2.97-2.91(m,2H),2.81-2.75(m,2H),2.48(s,3H).

[1580] Synthesis of Example 4

[1581]

[1582] Synthesis of intermediate 4-1

[1583] Compound 3-2 (see Example 3, 40 mg) was dissolved in dioxane (4 mL) and water (1 mL), and compound 1-6 (see Example 1, 78.1 mg) and anhydrous potassium carbonate (28.7 mg) were added. [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (7.6 mg) was added under nitrogen atmosphere. The mixture was stirred at 100 °C for 12 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a brown solid compound 4-1 (100 mg). LCMS (ESI) m / z: 555 [M+H] + .

[1584] Synthesis of Compound 4

[1585] Compound 4-1 (100 mg) was dissolved in methanol (1 mL), and hydrochloric acid methanol solution (1 mL) was added. The mixture was stirred at 25 °C for 12 hours. The filtrate was concentrated under reduced pressure. The solution was purified by high performance liquid chromatography (HPLC) (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 20%-50%, 8 min) to give a yellow solid compound 4 (8.4 mg, yield 10.3%). LCMS (ESI) m / z: 455 [M+H) + ; 1 H NMR(400MHz,MeOD)δppm:7.81-7.74(m,2H),7.57(s,1H),7.54-7.45(m,3H),6.24(br d,J=6.8Hz,1H),4.72-4.67(m,2H),4.45(brd,J=15.6Hz,1H),3.83(br d,J=8.8Hz,1H),3.68(br d,J=3.6Hz,2H),3.55-3.34(m,2H),3.29-3.21(m,1H),3.10(s,3H),2.66(s,1H),2.14-2.06(m,3H).

[1586] Synthesis of Example 5

[1587]

[1588] Synthesis of intermediate 5-2

[1589] Compound 5-1 (10 g) and trimethyl orthoformate (6.9 g) were dissolved in methanol (50 mL), and p-toluenesulfonic acid (748 mg) was added at room temperature. The mixture was reacted at 65 °C for 2 hours. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (10 mL), extracted with ethyl acetate (10 mL), washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give an off-white solid 5-2 (11.5 g, yield: 95.8%). 1 H NMR (400MHz, CDCl3) δppm: 8.73 (d, J = 2.8 Hz, 1H), 8.48 (d, J = 2.8 Hz, 1H), 8.06 (dd, J = 2.8, 8.8 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 5.58 (s, 1H), 3.41 (s, 6H).

[1590] Synthesis of intermediate 5-4

[1591] Compound 5-2 (11.5 g), compound 5-3 (10.5 g), and potassium phosphate (26.5 g) were dissolved in dioxane (155 mL) and water (45 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride·dichloromethane complex (3.4 g) was added under nitrogen protection at room temperature. The mixture was reacted under reflux for 16 hours. The mixture was poured into water (200 mL), extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give a yellow oily substance 5-4 (11.8 g, crude product). 1 H NMR (400MHz, CDCl3) δppm: 10.2 (s, 1H), 8.76 (d, J = 2.4Hz, 1H), 8.50 (d, J = 2.4Hz, 1H), 8.41 ( dd,J=2.4,8.5Hz,1H),8.17(dd,J=2.4,8.4Hz,1H),7.54(d,J=8.4Hz,1H),7.32(d,J=8.4Hz ,1H),5.86-5.82(m,1H),5.81-5.75(m,1H),5.46(s,1H),4.38(q,J=2.8Hz,1H),4.33(q,J= 2.8Hz,2H),4.01(t,J=5.6Hz,1H),3.95(t,J=5.6Hz,2H),3.50(s,3H),3.35(s,6H),2.52(br dd,J=2.8,4.4Hz,1H),2.40(br dd,J=2.8,4.8Hz,2H).

[1592] Synthesis of intermediate 5-5

[1593] Compound 5-4 (11.8 g) was dissolved in dioxane (237 mL), and dilute hydrochloric acid (3 M, 56.7 mL) was added dropwise at 20 °C. The mixture was stirred at 20 °C for 5 hours. The mixture was poured into ice-cold saturated sodium bicarbonate aqueous solution (250 mL), extracted with ethyl acetate (200 mL), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow oily substance 5-5 (9.6 g, yield: 96.7%). 1 H NMR (400MHz, CDCl3) δppm: 10.2 (s, 1H), 8.75 (d, J = 2.4Hz, 1H), 8.40 (dd, J = 2.4, 8.5Hz, 1H), 7. 55(d,J=8.8Hz,1H),5.88-5.78(m,1H),4.38(d,J=2.8Hz,2H),4.00(t,J=5.6Hz,2H),2.52(br dd,J=2.8,4.4Hz,2H).

[1594] Synthesis of intermediates 5-6

[1595] Compound 5-5 (9.6 g) was dissolved in acetonitrile (96 mL), and dimethylamine tetrahydrofuran solution (2 M, 41.1 mL) was added dropwise at 20 °C. The mixture was reacted at 20 °C for half an hour. Sodium triacetoxyborohydride (17.4 g) was added to the reaction flask, and the mixture was reacted at 20 °C for 16 hours. The mixture was poured into ice-cold saturated sodium bicarbonate aqueous solution (150 mL), extracted with ethyl acetate (100 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give a yellow oily compound 5-6 (8.6 g, yield 76.9%). LCMS (ESI) m / z: 263 [M+H] + ; 1 H NMR (400MHz, CDCl3) δppm: 8.39 (d, J = 2.4Hz, 1H), 8.08 (dd, J = 2.4, 8.4Hz, 1H), 7.29 (d, J = 2.0H z,1H),5.79-5.69(m,1H),4.33(d,J=2.8Hz,2H),3.96(t,J=5.2Hz,2H),3.48(s,2H),2.38(br d,J=2.0Hz,2H),2.26(s,6H).

[1596] Synthesis of intermediates 5-7

[1597] Wet palladium / carbon (10% wt, 50% wet, 800 mg) and wet palladium hydroxide (10% wt, 50% wet, 800 mg) were added to a hydrogenation flask. Compound 5-6 (8.6 g) was dissolved in methanol (100 mL) and poured into the hydrogenation flask. The reaction flask was purged with hydrogen three times and then reacted at 50 °C and 50 psi for 32 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give an off-white solid 5-7 (5.6 g, yield 66.4%). LCMS (ESI) m / z: 235 [M+H] + ; 1 H NMR (400MHz, CDCl3) δppm: 7.07 (d, J = 8.0Hz, 1H), 6.67 (d, J = 2.4Hz, 1H), 6.62 (dd, J = 2.4, 8.0Hz, 1H), 4.07 (dd, J = 4.0, 11.2Hz, 2 H),3.53(dt,J=2.0,11.2Hz,3H),3.35(s,2H),3.06(tt,J=3.6,11.9Hz,1H),2.23(s,6H),1.85-1.71(m,2H),1.69-1.60(m,2H).

[1598] Synthesis of intermediates 5-8

[1599] Compounds 5-7 (216 mg) and potassium carbonate (319 mg) were dissolved in dioxane (10 mL) and stirred at 20 °C for 30 minutes. Compounds 1-10 (see Example 1, 200 mg) were added to the reaction system and reacted at 130 °C for 72 hours. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated, and purified by plate chromatography to give a brown oily substance 5-8 (180 mg, yield 37.9%). LCMS (ESI) m / z: 457, 459 [M+H] + .

[1600] Synthesis of Compound 5

[1601] Compounds 5-8 (90 mg), 5-9 (47.2 mg), and potassium phosphate (125 mg) were dissolved in dioxane (1.6 mL) and water (0.4 mL). Under nitrogen protection, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (16 mg) was added, and the reaction was carried out at 100 °C for 16 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. Purification was performed by high-performance liquid chromatography (HPLC) (column: Waters XbridgePrep OBD C18 150 x 40 mm x 10 μm; mobile phase: [water (ammonia + ammonium bicarbonate) - acetonitrile]; B%: 20%-50%, 8 min) to obtain a white solid 5 (9.4 mg, yield 8.9%). LCMS (ESI) m / z: 495 [M+H) + ; 1HNMR (400MHz, CDCl3) δppm: 11.63 (s, 1H), 9.54-9.43 (m, 1H), 9.21 (br s,1H),8.40(s,2H),7.88(dd,J=2.0,8.4Hz,1H),7.56(d,J=1.6Hz,1H),7.39-7.29(m,2H),7.09(br d,J=4.8Hz,2H),6.43(d,J=7.2Hz,1H),6.36(dd,J=1.6,3.2Hz,1H),4.15-4.03(m,2H),3.56(br t,J=11.2Hz,2H),3.47(s,2H),3.25-3.14(m,1H),2.27(s,6H),1.86(dq,J=4.0,12.4Hz,2H),1.71(brd,J=12.4Hz,3H).

[1602] Synthesis of Example 6

[1603]

[1604] Synthesis of intermediate 6-2

[1605] Compound 1-10 (see Example 1, 0.2 g) was dissolved in dioxane (3 mL), and compound 6-1 (147 mg), potassium carbonate (320 mg), and... Molecular sieve (200 mg). The mixture was stirred at 130 °C for 12 hours. After cooling to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by slurrying with dichloromethane / methanol to give a brown solid compound 6-2 (160 mg, yield 50.1%). LCMS (ESI) m / z: 414, 416 [M+H] + .

[1606] Synthesis of Compound 6

[1607] Compound 6-2 (150 mg) was dissolved in dioxane (4 mL) and water (1 mL), and compound 5-9 (88.4 mg), potassium carbonate (100 mg), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride·dichloromethane complex (29.6 mg) were added under nitrogen atmosphere. The mixture was stirred at 100 °C for 5 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (HPLC) (column: Waters Xbridge Prep OBD C18 150 x 40 mm x 10 μm; mobile phase: [water (ammonia + ammonium bicarbonate) - acetonitrile]; B%: 20%-50%, 10 min) to give a yellow solid compound 6 (74.3 mg, yield 38.3%). LCMS (ESI) m / z: 452 [M+H]+ ; 1 H NMR(400MHz,DMSO-d6)δppm:12.32-12.43(m,2H),12.21(s,1H),11.02(s,1H) ,8.44(d,J=5.2Hz,1H),8.13(s,1H),7.63-7.65(m,3H),7.52-7.54(m,1H),7.2 9(d,J=5.6Hz,1H),7.09(d,J=8.8Hz,2H),6.39(s,1H),6.25(d,J=6.8Hz,1H),3 .80-3.83(m,2H),3.48-3.51(m,2H),3.09-3.21(m,4H),2.81(d,J=3.6Hz,3H).

[1608] Synthesis of Example 7

[1609]

[1610] Synthesis of intermediate 7-1

[1611] Compounds 5-8 (see Example 5, 90 mg), compounds 1-6 (see Example 1, 74 mg), and potassium carbonate (125 mg) were dissolved in dioxane (1.6 mL) and water (0.4 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (16 mg) was added under nitrogen atmosphere, and the reaction was carried out at 100 °C for 16 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a yellow oily crude product 7-1 (123 mg). LCMS (ESI) m / z: 627 [M+H] + .

[1612] Synthesis of Compound 7

[1613] Compound 7-1 (123 mg) was dissolved in methanol (1 mL), and hydrochloric acid / methanol solution (4 M, 9 mL) was added dropwise. The reaction was carried out at 20 °C for 16 hours. The solution was concentrated under reduced pressure and purified by high-performance liquid chromatography (HPLC) (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (hydrochloric acid)-acetonitrile]; B%: 1%-30%, 8 min) to give a yellow solid 7 (9.6 mg, yield 8.7%). LCMS (ESI) m / z: 527 [M+H) + ; 1H NMR (400MHz, MeOD) δppm: 8.01-7.50 (m, 8H), 4.70 (br s, 2H), 4.60 (br s, 2H), 4.06 (br d, J = 8.8Hz, 3H), 3.81-3.62 (m, 5H), 2.98 (br s, 6H), 2.12 (br s,3H),2.01-1.84(m,3H),1.75(br d,J=12.4Hz,2H).

[1614] Synthesis of Example 8

[1615]

[1616] Synthesis of intermediate 8-2

[1617] Compound 8-1 (10 g), N-methylpiperazine (6.5 g), and N,N-diisopropylethylamine (16.8 g) were dissolved in N,N-dimethylformamide (70 mL) and stirred at 20 °C for 2 hours. The reaction solution was poured into water (400 mL), and the aqueous phase was extracted three times with ethyl acetate (300 mL). The organic phases were combined and washed once with saturated brine (300 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow solid compound 8-2 (6 g, yield 40.7%).

[1618] Synthesis of intermediate 8-3

[1619] Compound 8-2 (2 g), dimethylamine (8 mL, 2 M MeOH solution), and sodium triacetoxyborohydride (3.4 g) were dissolved in acetonitrile (20 mL) and stirred at 20 °C for 10 hours. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution (50 mL), and the aqueous phase was extracted three times with ethyl acetate (30 mL). The combined organic phases were washed once with saturated brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow solid compound 8-3 (1.5 g, yield 67.1%).

[1620] Synthesis of intermediate 8-4

[1621] Compound 8-3 (400 mg) and ammonium chloride (384 mg) were dissolved in ethanol (5 mL) and water (5 mL), heated to 50 °C, and iron powder (401 mg) was added. The mixture was then heated to 75 °C and stirred for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give a yellow solid compound 8-4 (100 mg, yield 28%).

[1622] Synthesis of intermediate 8-5

[1623] Compound 8-4 (200 mg) was dissolved in dioxane (3 mL), and compound 1-10 (see Example 1, 230 mg), potassium carbonate (426 mg), and... Molecular sieve (200 mg). The mixture was stirred at 130 °C for 12 hours. After cooling to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by slurrying with dichloromethane / methanol to give a brown solid compound 8-5 (100 mg, yield 27.5%). LCMS (ESI) m / z: 471, 473 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δppm: 12.40 (s, 1H), 8.24 (s, 1H), 7.89 (d, J = 3.2Hz, 1H), 7.78 (t, J = 4.2Hz, 2H), 7.63 (d, J = 6 .8Hz,1H),7.50(d,J=2.8Hz,1H),7.06(d,J=8.8Hz,1H),6.49-6.53(m,1H),2.86(s,4H),2.23(s,3H),2.19(s,6H).

[1624] Synthesis of Compound 8

[1625] Compound 8-5 (75 mg) was dissolved in dioxane (4 mL) and water (1 mL), and compound 5-9 (38.8 mg), potassium carbonate (44 mg), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride·dichloromethane complex (13 mg) were added under nitrogen atmosphere. The mixture was stirred at 100 °C for 5 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (HPLC) (column: Phenomenex C18 75*30mm*3um; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 20%-50%, 10 min) to give a yellow solid compound 8 (7.8 mg, yield 8.9%). LCMS (ESI) m / z: 509 [M+H] + ; 1 H NMR(400MHz,MeOD)δppm:8.58(t,J=4.6Hz,1H),8.14(s,1H),7.98(d,J=2.8Hz,1H),7.79-7.81(m,2H),7.66-7.72(m,3H),6.78(d,J =3.6Hz,2H),6.46(d,J=7.2Hz,1H),4.53(s,2H),3.58-3.63(m,4H),3.32-3.35(m,3H),3.25-3.28(m,3H),3.03(s,3H),2.99(s,6H).

[1626] Synthesis of Example 9

[1627]

[1628] Synthesis of intermediate 9-2

[1629] Compounds 5-2 (10 g), 9-1 (9.7 g), and potassium phosphate (23 g) were dissolved in dioxane (160 mL) and water (40 mL). A [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride·dichloromethane complex (2.96 g) was added under nitrogen protection at room temperature. The mixture was reacted at 80 °C for 16 hours. The mixture was poured into water (200 mL), extracted with ethyl acetate (100 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a brown oily substance 9-2 (11.8 g, crude product).

[1630] Synthesis of intermediate 9-3

[1631] Compound 9-2 (16 g) was dissolved in dioxane (320 mL), and dilute hydrochloric acid (3 M, 72.9 mL) was added dropwise at 20 °C. The mixture was stirred at 20 °C for 5 hours. The mixture was poured into ice-cold saturated sodium bicarbonate aqueous solution (100 mL), extracted with ethyl acetate (50 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a black oily substance 9-3 (12 g, yield 57.9%). LCMS (ESI) m / z: 247 [M+H] + .

[1632] Synthesis of intermediate 9-4

[1633] Compound 9-3 (8 g) was dissolved in acetonitrile (80 mL), and dimethylaminetetrahydrofuran solution (2 M, 32.4 mL) was added dropwise at 20 °C. The mixture was reacted at 20 °C for 0.5 h. Sodium triacetoxyborohydride (13.7 g) was added to the reaction flask, and the mixture was reacted at 20 °C for 16 h. The mixture was poured into ice-cold saturated sodium bicarbonate aqueous solution (100 mL), extracted with ethyl acetate (50 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a brown oily substance 9-4 (8.9 g, crude product).

[1634] Synthesis of intermediate 9-5

[1635] Wet palladium / carbon (10% wt, 50% wet, 15 mg) and wet palladium hydroxide (10% wt, 50% wet, 15 mg) were added to a hydrogenation flask. Compound 9-4 (300 mg) was dissolved in methanol (10 mL) and poured into the hydrogenation flask. The reaction flask was purged with hydrogen three times and reacted at 50 °C and 50 psi for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give an off-white solid 9-5 (200 mg, yield 60.2%). LCMS (ESI) m / z: 248 [M+H] + .

[1636] Synthesis of intermediate 9-6

[1637] Compound 9-5 (200 mg) and potassium carbonate (279 mg) were dissolved in dioxane (10 mL) and stirred at 20 °C for 0.5 h. Compound 1-10 (see Example 1, 175 mg) was added to the reaction system and stirred at 130 °C for 72 h. After cooling to room temperature, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and purified by slurrying with tetrahydrofuran (2 mL) to give a brown solid compound 9-6 (70 mg, yield 17.5%). LCMS (ESI) m / z: 470, 472 [M+H] + ; 1 HNMR (400Hz, DMSO-d6) δppm: 11.89 (s, 1H), 8.36 (s, 1H), 7.79 (dd, J = 2.0, 8.8Hz, 1H), 7.58 (d ,J=7.2Hz,1H),7.38(d,J=2.4Hz,1H),7.24(d,J=8.4Hz,1H),6.59(d,J=7.2Hz,1H),3.60(br t,J=6.4Hz,7H),2.21(s,3H),2.16(s,7H),1.76(td,J=3.2,6.6Hz,7H).

[1638] Synthesis of Compound 9

[1639] Compounds 9-6 (30 mg), 5-9 (18.6 mg), and potassium phosphate (26.4 mg) were dissolved in dioxane (1 mL) and water (0.2 mL). Under nitrogen protection, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (4.7 mg) was added, and the reaction was carried out at 100 °C for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by preparative high-performance liquid chromatography (HPLC) (column: Phenomenex Luna C18 100*30mm*5µm; mobile phase: [water (hydrochloric acid)-acetonitrile]; B%: 1%-20%, 10 min) to give a yellow solid 9 (2.08 mg, yield 6.23%). LCMS (ESI) m / z: 508 [M+H] + ; 1HNMR(400MHz,MeOD)δppm:8.54(d,J=6.0Hz,1H),8.23(s,1H),7.97(d,J=2.0Hz,1H),7.89(dd,J=2.0,8.8Hz,1H ),7.76(d,J=3.6Hz,1H),7.69-7.55(m,3H),6.73(d,J=3.6Hz,1H),6.46(d,J=7.2Hz,1H),4.59(s,2H),3.64(br d,J=12.0Hz,2H),3.47-3.35(m,3H),3.00(s,6H),2.96(s,3H),2.12(br d,J=2.4Hz,4H).

[1640] Synthesis of Example 10

[1641]

[1642] Synthesis of intermediate 10-2

[1643] N-methylpiperazine (10.4 g) and triethylamine (10.5 g) were dissolved in ethyl acetate (90 mL), and compound 10⁻¹ (15 g) was added. The mixture was stirred at 25 °C for 12 hours. The mixture was quenched with water (80 mL), the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give a deep yellow solid compound 10⁻² (12.9 g, yield 57.1%). LCMS (ESI) m / z: 240 [M+H] + .

[1644] Synthesis of intermediate 10-3

[1645] Palladium / carbon (0.4 g, 10.0% purity) was dissolved in ethyl acetate (200 mL) and ethanol (100 mL), and compound 10⁻² (8 g) was added. The mixture was stirred at 25°C for 12 hours under hydrogen atmosphere at 30 psi. The mixture was filtered, and the filtrate was concentrated to give a brown solid compound 10⁻³ (6.8 g, 97.1% yield). LCMS (ESI) m / z: 210 [M+H] + .

[1646] Synthesis of intermediate 10-4

[1647] Compound 10-3 (0.2 g) was dissolved in dioxane (3 mL), and compound 1-10 (see Example 1, 177 mg), potassium carbonate (320 mg), and... Molecular sieve (200 mg). The mixture was stirred at 130 °C for 12 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by slurrying with dichloromethane / methanol to give a brown solid compound 10⁻⁴ (300 mg, yield 90.0%). LCMS (ESI) m / z: 432, 434 [M+H] + .

[1648] Synthesis of Compound 10

[1649] Compound 10-4 (100 mg) was dissolved in dioxane (2 mL) and water (0.5 mL), and compound 27 (56.5 mg) and potassium carbonate (63.9 mg) were added. [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride·dichloromethane complex (18.9 mg) was added under nitrogen atmosphere. The mixture was stirred at 100 °C for 5 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (HPLC) (column: Phenomenex Luna C18 100*30mm*5um; mobile phase: [water (hydrochloric acid)-acetonitrile]; B%: 1%-20%, 10 min) to give a yellow solid compound 10 (24.4 mg, yield 18.9%). LCMS (ESI) m / z: 470 [M+H] + ; 1 H NMR(400MHz,MeOD)δppm:8.55(d,J=6.0Hz,1H),8.07(s,1H),7.77(d,J=3.6Hz,1H),7.68(d,J=7.6Hz,1H),7.62-7.64(m,2H),6 .71(d,J=3.6Hz,1H), 6.44(d,J=7.2Hz,1H), 3.67(t,J=15.0Hz,4H), 3.37(t,J=7.2Hz,2H), 3.25(t,J=11.8Hz,2H), 3.00(s,3H).

[1650] Synthesis of Example 11

[1651]

[1652] Synthesis of intermediate 11-1

[1653] Compound 10-1 (500 mg), triethylamine (477 mg), and 4-hydroxypiperidine (476 mg) were dissolved in methanol (10 mL) and stirred at 60 °C for four hours. The reaction solution was concentrated under reduced pressure, and N,N-dimethylformamide (2 mL) was added to the crude product. Water (10 mL) was slowly added to the system, and a solid precipitated out. The solid was filtered and dried to give a yellow solid compound 11-1 (500 mg, yield 66.2%).

[1654] Synthesis of intermediate 11-2

[1655] Palladium / carbon (1 g, 10% purity) and compound 11-1 (400 mg) were added to methanol (10 mL). The mixture was stirred at 50 °C and 50 psi for 12 hours in a hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated to give compound 11-2 (340 mg, 97.1% yield), an off-white solid.

[1656] Synthesis of intermediate 11-3

[1657] Compound 1-10 (see Example 1, 100 mg) and potassium carbonate (159 mg) were dissolved in dioxane (10 mL) and stirred at 20 °C for half an hour. Compound 11-2 (89.1 mg) was added to the reaction system and stirred at 130 °C for 12 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give a yellow solid compound 11-3 (50 mg, yield 29.9%). LCMS (ESI) m / z: 433, 435 [M+H] + .

[1658] Synthesis of Compound 11

[1659] Compound 11-3 (50 mg), compounds 5-9 (33.8 mg), and potassium phosphate (47.8 mg) were dissolved in dioxane (1.6 mL) and water (0.4 mL). Under nitrogen protection, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (8.4 mg) was added, and the reaction was carried out at 100 °C for 16 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. Purification by high-performance liquid chromatography (HPLC) (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (hydrochloric acid)-acetonitrile]; B%: 1%-30%, 8 min) yielded a yellow solid 11 (32 mg, yield 57%). LCMS (ESI) m / z: 471 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δppm:12.18(s,1H),11.85-12.05(m,1H),11.80(br s,1H),8.24-8.35(m,2H),7.99(dd,J=15.2,2.4Hz,1H),7.45-7.53(m,1H),7.38(d,J=7.2Hz,1H), 7.28(dd,J=8.8,2.0Hz,1H),6.97-7.10(m,2H),6.17-6.26(m,2H),4.70(d,J=4.0Hz,1H),3.60(br d,J=4.0Hz,1H),3.15-3.25(m,2H),2.68-2.80(m,2H),1.75-1.93(m,2H),1.45-1.63(m,2H).

[1660] Synthesis of Example 12

[1661]

[1662] Synthesis of intermediate 12-1

[1663] Compound 5-5 (see Example 5, 4 g) and tetrahydropyrrole (1.7 mL) were added to dichloroethane (40 mL), followed by acetic acid (2.8 mL), and then sodium triacetoxyborohydride (4.4 g). The mixture was stirred at 25 °C for 16 hours. The mixture was quenched with saturated NaHCO3 solution. The mixture was extracted twice with 25 mL of dichloromethane, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography to give a yellow solid compound 12-1 (2.3 g, yield 44.6%). LCMS (ESI) m / z: 289 [M+H] + .

[1664] Synthesis of intermediate 12-2

[1665] Compound 12-1 (1.6 g) was dissolved in methanol (40 mL), and palladium / carbon (1.6 g) was added under nitrogen protection. The mixture was stirred at 25 °C and H₂ (15 psi) for 16 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the crude product. Compound 12-2 (2.3 g, yield 84.8%) was obtained by high performance liquid chromatography (HPLC). LCMS (ESI) m / z: 261 [M+H] + .

[1666] Synthesis of intermediate 12-3

[1667] Compound 12-2 (209 mg) was dissolved in dioxane (3 mL), and compound 1-10 (see Example 1, 210 mg), potassium carbonate (334 mg), and... Molecular sieve (209 mg). The mixture was stirred at 130 °C for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was slurryed and purified to give a brown solid compound 12-3 (120 mg, yield 30.8%). LCMS (ESI) m / z: 483 [M+H] + .

[1668] Synthesis of Compound 12

[1669] Compound 12-3 (120 mg) was dissolved in dioxane (4 mL) and water (1 mL), and compound 5-9 (60.6 mg), potassium carbonate (68.6 mg), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride·dichloromethane complex (20.3 mg) were added under nitrogen atmosphere. The mixture was stirred at 100 °C for 5 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 5%-50%, 8 min) to give a white solid compound 12 (5.3 mg, yield 3.6%). LCMS (ESI) m / z: 521 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δppm: 12.1 (s, 1H), 11.8-11.9 (m, 2H), 8.31 (d, J = 4.8Hz, 1H), 8.25(s,1H),7.91(s,1H),7.48-7.52(m,2H),7.37(d,J=7.2Hz,1H),7.26(d,J=8.4Hz ,1H),7.07(d,J=4.8Hz,1H),6.21(t,J=5.4Hz,2H),3.95(d,J=8.0Hz,2H),3.64(s,2 H), 3.43 (t, J = 10.8Hz, 2H), 3.12-3.15 (m, 1H), 2.50-2.52 (m, 4H), 1.60-1.69 (m, 8H).

[1670] Synthesis of Example 13

[1671]

[1672] Synthesis of intermediate 13-2

[1673] Compound 13-1 (2.3 g) was dissolved in dichloromethane (30 mL), followed by the addition of 4-dimethylaminopyridine (130 mg) and Boc₂O (2.6 g). The mixture was purged three times with nitrogen, and then stirred at 20 °C for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Water (50 mL) was added to the residue, and the mixture was extracted twice with ethyl acetate (60 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give a yellow solid, compound 13-2 (3 g, yield 79.6%). LCMS (ESI) m / z: 255, 257 [M-56+H] + .

[1674] Synthesis of intermediate 13-3

[1675] Compound 13-2 (3 g) was dissolved in dioxane (30 mL), followed by the addition of potassium acetate (1.9 g) and bis-pinacolborate (2.5 g), then [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (350 mg) under nitrogen protection. The reaction was carried out at 90 °C for 16 hours. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 13-3 (3 g, yield 86.9%) as a white solid. LCMS (ESI) m / z: 221 [M-56-82+H] + .

[1676] Synthesis of intermediate 13-4

[1677] Compounds 5-8 (see Example 5, 70 mg), compound 13-3 (65.7 mg), and potassium carbonate (63.4 mg) were dissolved in dioxane (2 mL) and water (0.2 mL). Under nitrogen protection, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (11.2 mg) was added, and the reaction was carried out at 100 °C for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a yellow oily substance 13-4 (90 mg), which was used directly in the next step. LCMS (ESI) m / z: 609 [M+H] + .

[1678] Synthesis of Compound 13

[1679] Intermediate 13-4 (90 mg) was dissolved in methanol (3 mL), and hydrochloric acid / methanol solution (4 M, 3 mL) was added dropwise. The mixture was stirred at 20 °C for 6 hours. The solution was concentrated under reduced pressure and purified by high-performance liquid chromatography (HPLC) (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (hydrochloric acid)-acetonitrile]; B%: 5%-35%, 8 min) to give compound 13 (11.9 mg, yield 15.4%). LCMS (ESI) m / z: 509 [M+H) + ; 1 HNMR(400MHz,MeOD)δppm:8.54-8.42(m,1H),8.17-8.03(m,1H),7.90(br t,J=2.8Hz,2H),7.71-7.40(m,4H),6.25-6.11(m,1H),4.53(s,2H),4.07(dd,J=3.2,11.3Hz,2H) ,3.76-3.62(m,2H),3.26-3.09(m,1H),2.97(s,6H),2.02-1.84(m,5H),1.73(brd,J=12.4Hz,2H).

[1680] Synthesis of Example 14

[1681]

[1682] Synthesis of intermediate 14-1

[1683] 4-Hydroxypiperidine (1.2 g), N,N-dimethylformamide (20 mL), and potassium carbonate (2.4 g) were added to a 100 mL single-necked flask. Then, 8-1 (2 g) was added and stirred until homogeneous. The mixture was reacted at 50 °C for 12 hours. Water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain a yellow solid 14-1 (2.4 g, 81%). LCMS (ESI) m / z: 251 [M+H] + .

[1684] Synthesis of intermediate 14-2

[1685] 14-1 (1.2 g) and dimethylamine (0.6 g) were dissolved in anhydrous methanol (20 mL), and two drops of acetic acid were added. The reaction mixture was stirred at 50 °C for 0.5 h, and then sodium cyanoborohydride (0.6 g, 9.6 mmol) was added. The reaction mixture was stirred at 50 °C for 12 h. Water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain a yellow solid 14-2 (0.6 g, 48%). LCMS (ESI) m / z: 280 [M+H] + .

[1686] Synthesis of intermediate 14-3

[1687] In a 100 mL single-necked flask, 14-2 (640 mg) was dissolved in ethanol (10 mL), and palladium / carbon (240 mg) was added. The mixture was reacted at room temperature under hydrogen atmosphere for 2 hours. After filtration and concentration under reduced pressure, a black solid 14-3 (640 mg, crude product) was obtained. LCMS (ESI) m / z: 250 [M+H] + .

[1688] Synthesis of intermediate 14-4

[1689] Compound 14-3 (200 mg, crude) was dissolved in dioxane (3 mL), and compound 1-10 (192 mg), potassium carbonate (320 mg), and... Molecular sieve (200 mg). The mixture was stirred at 130 °C for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried with dichloromethane / methanol to give a brown solid compound 14-4 (300 mg, yield 82.4%). LCMS (ESI) m / z: 472 [M+H] + .

[1690] Synthesis of Compound 14

[1691] Compound 14-4 (250 mg) was dissolved in dioxane (4 mL) and water (1 mL), and compounds 5-9 (129 mg) and potassium carbonate (146 mg) were added. Under nitrogen atmosphere, a [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride·dichloromethane complex (43.2 mg) was added. The mixture was stirred at 100 °C for 5 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (column chromatography: Phenomenex luna C18 80*40mm*3um; mobile phase: [water (hydrochloric acid)-acetonitrile]; B%: 15%-45%, 7 min) to give a brown solid compound 14 (91.8 mg, yield 32.7%). LCMS (ESI) m / z: 510 [M+H] + ; 1H NMR (400MHz, MeOD) δppm: 8.57 (d, J = 6.0Hz, 1H), 8.12 (s, 1H), 7.90 (s, 1H), 7.7 8(d,J=3.6Hz,1H),7.71-7.75(m,1H),7.66(d,J=6.0Hz,1H),7.61(s,1H),6.77 (d,J=3.6Hz,1H),6.46(d,J=7.2Hz,1H),4.52(s,2H),3.85(s,1H),3.16-3.18 (m,2H),2.97(s,6H),2.91-2.93(s,2H),2.06-2.09(m,2H),1.77-1.84(m,2H).

[1692] Synthesis of Example 15

[1693]

[1694] Synthesis of intermediate 15-2

[1695] Compound 15-1 (5 g) was dissolved in glacial acetic acid (10 mL) and water (30 mL), and hexamethylenetetramine (5.3 g) was added to the mixture. The mixture was reacted at 120 °C for 12 hours. The solution was filtered to give a yellow solid compound 15-2 (5 g, yield 87.5%).

[1696] Synthesis of intermediate 15-3

[1697] Compound 15-2 (3 g) was dissolved in dioxane (25 mL) and water (25 mL), and aminosulfonic acid (7.7 g), sodium chlorite (1.5 g), and potassium dihydrogen phosphate (21.7 g) were added. The reaction was carried out at 25 °C for 2 hours. The reaction solution was extracted with ethyl acetate (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to give a yellow oily compound 15-3 (5 g, yield 62.2%).

[1698] Synthesis of intermediate 15-4

[1699] 2.9 g of 1-chloromethyl-4-fluoro-1,4-diazotized bicyclo[2.2.2]octane di(tetrafluoroborate) salt (Select-F) was dissolved in ethyl acetate (20 mL) and water (10 mL). Lithium carbonate (1.2 g) and compound 15-3 (1 g) were added to the mixture. The reaction was carried out at 25 °C for 4 hours. The reaction solution was extracted with ethyl acetate (10 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give a yellow oily compound 15-4 (300 mg, yield 33.6%).

[1700] Synthesis of intermediate 15-5

[1701] Compound 15-4 (100 mg) was dissolved in dioxane (2 mL), and bis(pinacolborate) (177.1 mg) and potassium acetate (136.9 mg) were added. Then, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride·dichloromethane complex (37.9 mg) was added under nitrogen. The mixture was stirred at 90 °C for 4 hours under nitrogen. After filtration, the filtrate was used directly for the next reaction. LCMS (ESI) m / z: 181 [M+H] + .

[1702] Synthesis of Compound 15

[1703] Compound 5-8 (see Example 5, 60 mg) and potassium carbonate (54.4 mg) were added to a dioxane solution of 15-5 mL. Then, under nitrogen atmosphere, a [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride-dichloromethane complex (10.7 mg) was added. The mixture was stirred at 100 °C for 10 hours under nitrogen atmosphere. The mixture was filtered, and the filtrate was purified by high-performance liquid chromatography (HPLC) (column: Phenomenexluna C18 80 x 40 mm x 3 μm; mobile phase: [water (hydrochloric acid)-acetonitrile]; B%: 18%-48%, 7 min) to give a yellow solid, compound 15 (21.2 mg, yield 30.3%). LCMS (ESI) m / z: 513 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δppm: 12.0 (s, 1H), 11.9 (br s, 1H), 11.6 (br s, 1H), 8.35 (br d, J = 4.4Hz, 1H), 8.23 ​​(s, 1H), 7.92 (br d, J = 8.8Hz, 1H), 7.47 (br d,J=7.6Hz,2H),7.37(br d,J=7.6Hz,1H),7.28(brd,J=8.0Hz,1H),7.09(br d,J=4.4Hz,1H),6.20(br d,J=7.2Hz,1H),3.95(br d,J=10.0Hz,2H),3.43(br s,4H),3.13(br s,1H),2.19(br s,6H),1.54-1.79(m,4H).

[1704] Synthesis of Example 16

[1705]

[1706] Synthesis of intermediate 16-2

[1707] Compound 16-1 (20 g) was dissolved in N,N-dimethylformamide (200 mL), followed by the addition of potassium carbonate (20.4 g) and morpholine (17.1 g). The reaction mixture was stirred at 80 °C for 8 hours. After cooling to room temperature, crushed ice was added, and the mixture was filtered. The filter cake was washed with water and collected. The mixture was purified by column chromatography to give a yellow solid, compound 16-2 (8 g, yield 28.5%). LCMS (ESI) m / z: 270 [M+H] + .

[1708] Synthesis of intermediate 16-3

[1709] Compound 16-2 (4 g) was dissolved in 1,2-dichloroethane (40 mL), followed by the addition of dimethylaminetetrahydrofuran solution (2 M, 22.2 mL) and sodium triacetoxyborohydride (3.7 g). The mixture was stirred at 20 °C for 16 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to give a yellow solid compound 16-3 (2 g, yield 40.6%). LCMS (ESI) m / z: 299 [M + H] + ; 1 H NMR (400MHz, CDCl3) δppm: 7.59 (d, J = 2.45Hz, 1H), 7.35 (dd, J = 8.50, 2.51Hz, 1H), 6.9 5(d,J=8.56Hz,1H),3.75-3.96(m,4H),3.45(s,2H),2.85-2.99(m,4H),2.25(s,6H).

[1710] Synthesis of intermediate 16-4

[1711] Compound 16-3 (280 mg) and benzophenone imine (180 mg) were added to toluene (8.5 mL), followed by sodium tert-butoxide (130 mg), tris(dibenzylacetone)dipalladium (85.6 mg), and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (110 mg). The reaction was carried out at 90 °C for 12 hours under nitrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give a yellow solid compound 16-4 (400 mg, crude product). LCMS (ESI) m / z: 400 [M+H] + .

[1712] Synthesis of intermediate 16-5

[1713] Compound 16-4 (300 mg, crude) was added to methanol (5.00 mL), followed by hydroxylamine hydrochloride (100 mg) and sodium acetate (120 mg). The reaction mixture was reacted at 20 °C for 2 hours. The reaction solution was concentrated under reduced pressure to give a yellow oily compound 16-5 (250 mg, crude). LCMS (ESI) m / z: 236 [M+H] + .

[1714] Synthesis of intermediate 16-6

[1715] Compound 16-5 (200 mg, crude product) and compound 1-10 (see Example 1, 180 mg) were added to dioxane (3 mL), followed by potassium carbonate (320 mg). Molecular sieve (200 mg) was used in the reaction solution, which was reacted at 130 °C for 16 hours. The mixture was filtered and purified by high-performance liquid chromatography (HPLC) to give a brown solid compound 16-6 (40 mg, yield 10.4%). LCMS (ESI) m / z: 458 [M+H] + .

[1716] Synthesis of Compound 16

[1717] Compounds 16-6 (35 mg) and 5-9 (34.8 mg) were added to dioxane (2 mL) and water (0.5 mL), followed by potassium carbonate (19.5 mg). Then, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride·dichloromethane complex (5 mg) was added under nitrogen atmosphere. The reaction mixture was reacted at 100 °C for 5 hours. The reaction mixture was filtered and purified by high-performance liquid chromatography (HPLC) (column: Phenomenex luna C18 80 x 40 mm x 3 μm; mobile phase: [water (hydrochloric acid)-acetonitrile]; B%: 20%-50%, 7 min) to obtain a yellow solid compound 16 (11.7 mg, yield 30.2%). LCMS (ESI) m / z: 496 [M+H] + ; 1 H NMR (400MHz, MeOD) δppm: 8.56 (d, J = 6.0Hz, 1H), 8.13 (s, 1H), 7.90 (d, J = 2.4Hz, 1H), 7.77-7.82 (m, 2H), 7.70 (d, J = 7.2Hz, 1H), 7.66 (d, J = 6.0 Hz,1H),7.61(d,J=8.4Hz,1H),6.76(d,J=3.6Hz,1H),6.46(d,J=7.2Hz,1H),4.52(s,2H),3.86-3.95(m,4H),2.99-3.04(m,4H),2.97(s,6H).

[1718] Synthesis of Example 17

[1719]

[1720] Synthesis of intermediate 17-2

[1721] Compound 17-1 (2.4 g) was dissolved in DCM (20 mL). N-bromosuccinimide (NBS) (3.45 g) was added to the reaction solution, and the mixture was stirred at 25 °C for 2 hours. The solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to give compound 17-2 (3 g, yield 79.1%) as a white solid. LCMS (ESI) m / z: 215, 217 [M+H] + .

[1722] Synthesis of intermediate 17-3

[1723] Compound 17-2 (1 g) was dissolved in THF (10 mL), and iPrMgCl (2 M, 4.65 mL) was added dropwise to the solution at -10 °C. The reaction mixture was stirred at -10 °C for 30 minutes. Bu3SnCl (1.5 g) was added dropwise to the reaction mixture at -10 °C, and then the temperature was gradually increased to 25 °C, and stirring was continued for 2 hours. The reaction was quenched with water (20 mL), and the aqueous phase was extracted with ethyl acetate (60 mL). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a brownish-yellow oily compound 17-3 (1.5 g), which was used directly in the next step. LCMS (ESI) m / z: 427 [M+H] + .

[1724] Synthesis of Compound 17

[1725] In a 10 mL microwave-safe tube, 17-3 (43 mg) was dissolved in 5 mL of dry N,N-dimethylformamide, and 14-4 (see Example 14, 50 mg), tetrakis(triphenylphosphine)palladium (23 mg), and cuprous iodide (4 mg) were added. The mixture was microwaved at 80 °C for 0.5 h under nitrogen protection, concentrated under reduced pressure, extracted with water and ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and prepared by high-performance liquid chromatography (HPLC) (column: Gemini-C18 150 x 21.2 mm, 5 μm; mobile phase: ACN-H2O (0.1% FA); gradient: 10-25%) to obtain an orange-yellow solid 17 (1 mg, yield 1%). LCMS (ESI) m / z: 528 [M+H] + ; 1H NMR (400MHz, MeOD) δppm: 8.52 (br s, 1H), 8.26 (d, J = 1.8Hz, 1H), 7.99-7.97 (m, 2H), 7.90-7.86 (m 1H),7.74-7.68(m,2H),7.42-7.33(m,3H),5.94(d,J=7.2Hz,1H),4.33(s,2H),3.80(d,J= 11.6Hz,1H),3.12-3.09(m,2H),2.86-2.83(m,8H),2.05-2.03(m,2H),1.76-1.71(m,2H).

[1726] Synthesis of Example 18

[1727]

[1728] Synthesis of intermediate 18-2

[1729] Compound 1-10 (70 mg) was dissolved in dioxane (700 μL), and compound 18-1 (52.5 mg), anhydrous potassium carbonate (111 mg), and... Molecular sieve (70 mg), the mixture was stirred at 130 °C for 48 hours under nitrogen atmosphere. Filtered, the filtrate was concentrated under reduced pressure to give a brown solid compound 18-2 (120 mg). LCMS (ESI) m / z: 400, 402 [M+H] + .

[1730] Synthesis of Compound 18

[1731] Compound 18-2 (120 mg) was dissolved in dioxane (0.6 mL) and water (0.1 mL), and compound 5-9 (33.6 mg) and anhydrous potassium carbonate (38.1 mg) were added. [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (10 mg) was added under nitrogen atmosphere. The mixture was stirred at 100 °C for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The solution was purified by high performance liquid chromatography (HPLC) (column: Phenomenex luna C18 80 x 40 mm x 3 μm; mobile phase: [water (hydrochloric acid)-acetonitrile]; B%: 18%-48%, 7 min) to give a yellow solid compound 18 (21.5 mg, yield 35.6%). LCMS (ESI) m / z: 438 [M+H] + ; 1H NMR(400MHz,MeOD)δppm:1.75-1.89(m,4H),2.91-3.01(m,1H),3.55-3.63(m,2H),4.02-4.11(m,2H),6.43(d,J=7.2Hz,1H ),6.72(d,J=3.6Hz,1H),7.33-7.58(m,4H),7.63(d,J=6.0Hz,1H),7.73-7.82(m,2H),7.90(s,1H),8.57(d,J=6.0Hz,1H).

[1732] Synthesis of Example 19

[1733]

[1734] Synthesis of intermediate 19-2

[1735] Compound 19-1 (900 mg) was dissolved in dioxane (3.6 mL) and water (0.9 mL), and compound 5-3 (977 mg) and anhydrous potassium phosphate (2.47 g) were added. Under nitrogen atmosphere, a [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride·dichloromethane complex (316 mg) was added. The mixture was stirred at 100 °C for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give a yellow solid 19-2 (600 mg, yield 65.7%). LCMS (ESI) m / z: 236 [M+H] + .

[1736] Synthesis of intermediate 19-3

[1737] Compound 19-2 (600 mg) was dissolved in anhydrous methanol (4.2 mL), and wet palladium / carbon (60 mg) was added. The mixture was stirred at 50 °C and 50 psi for 12 hours. The solution was filtered, and the filtrate was concentrated under reduced pressure to give an off-white solid 19-3 (450 mg, yield 85.1%). LCMS (ESI) m / z: 208 [M+H] + .

[1738] Synthesis of intermediate 19-4

[1739] Compound 1-10 (see Example 1, 70 mg) was dissolved in dioxane (700 mL), and compound 19-3 (67.1 mg), anhydrous potassium carbonate (111 mg), and... Molecular sieve (70 mg), the mixture was stirred at 130 °C for 48 hours under nitrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a brown solid 19-4 (120 mg). LCMS (ESI) m / z: 430, 432 [M+H] + .

[1740] Synthesis of Compound 19

[1741] Compound 19-4 (120 mg) was dissolved in dioxane (0.6 mL) and water (0.1 mL), and compound 5-9 (14.9 mg) and anhydrous potassium carbonate (16.9 mg) were added. [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (4.49 mg) was added under nitrogen atmosphere. The mixture was stirred at 100 °C for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Purification by high performance liquid chromatography (HPLC) (column: Phenomenex luna C18 80 x 40 mm x 3 μm; mobile phase: [water (hydrochloric acid)-acetonitrile]; B%: 20%-50%, 7 min) yielded a yellow solid 19 (7.25 mg, yield 25.2%). LCMS (ESI) m / z: 468 [M+H] + ; 1 H NMR (400MHz, MeOD) δppm: 1.78-1.93 (m, 4H), 2.88-3.01 (m, 1H), 3.60 (td, J=11.2, 2.8Hz, 2H), 3.95 (s, 3H), 4.08 (br dd, J=10.8, 2.8Hz, 2H), 6.43 (br d,J=6.4Hz,1H),6.68(br d,J=2.8Hz,1H),7.08(br d,J=7.2Hz,1H),7.18(s,1H),7.49-7.65(m,2H),7.70-7.79(m,2H),7.94(s,1H),8.55(br d,J=4.4Hz,1H).

[1742] Synthesis of Example 20

[1743]

[1744] Synthesis of intermediate 20-2

[1745] In a 100 mL single-necked flask, 1.4 g of 20-1, 30 mL of N,N-dimethylformamide, and 3.26 g of potassium carbonate were added, followed by 2 g of 8-1. The mixture was stirred thoroughly and reacted at 90 °C for 16 hours. Water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2.5 g of a yellow solid, 67.8% yield. LCMS (ESI) m / z: 251 [M+H] + .

[1746] Synthesis of intermediate 20-3

[1747] In a 100 mL single-necked flask, 20-2 (2.5 g) was dissolved in methanol (50 mL), and a tetrahydrofuran solution of dimethylamine (20 mL, 2 M) was added. The mixture was heated to 50 °C and stirred for 2 hours. After cooling to room temperature, sodium cyanoborohydride (1.26 g) was added, and the mixture was then heated to 50 °C and reacted for 12 hours. The solution was concentrated under reduced pressure and purified by column chromatography to give a yellow solid 20-3 (2 g, yield 64%), LCMS (ESI) m / z: 280 [M+H]. + .

[1748] Synthesis of intermediate 20-4

[1749] In a 100 mL single-necked flask, 1 g of 20-3 was dissolved in 20 mL of methanol, and 380 mg of palladium / carbon was added. The gas was purged three times with a hydrogen balloon, and the reaction was carried out at room temperature under hydrogen atmosphere for 12 hours. The mixture was filtered, concentrated under reduced pressure, and a brown oily substance, 800 mg of 20-4 (72% yield), was obtained. LCMS (ESI) m / z: 250 [M+H] + .

[1750] Synthesis of intermediate 20-5

[1751] In a 50 mL single-necked flask, 100 mg of 20-4 was dissolved in 3 mL of dioxane, and 144 mg of 1-10 (see Example 1) was added. The reaction was carried out at 100 °C for 2 hours, and the solution was concentrated under reduced pressure to obtain 300 mg of crude product, which was used directly in the next step. LCMS (ESI) m / z: 472, 474 [M+H] + .

[1752] Synthesis of Compound 20

[1753] In a 50 mL single-necked flask, 20-5 (300 mg, crude product) was dissolved in dioxane and water (10 mL, 4:1), followed by the addition of 5-9 (140 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (28 mg), and potassium carbonate (105 mg). The reaction was carried out at 100 °C for 12 hours under nitrogen atmosphere. The solution was concentrated under reduced pressure, extracted with water and ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and prepared by high-performance liquid chromatography (HPLC) (column: Gemini-C18 150 x 21.2 mm, 5 μm mobile phase: ACN-H2O (0.1% FA), gradient: 10-40%) to obtain a yellow product 20 (5.1 mg, yield 2.5%). LCMS (ESI) m / z: 510 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δppm:12.09(s,1H),11.95(br s,1H),11.82(s,1H),8.34-8.22(m,3H),7.90(d,J=2.5Hz,1H),7.58(d,J=2.4H z,1H),7.55-7.43(m,1H),7.38(d,J=7.2Hz,1H),7.12-7.06(m,2H),6.25-6.17( m,2H),3.74-3.64(m,1H),3.55(d,J=8.2Hz,2H),3.05(d,J=7.6Hz,1H),2.93(d, J=10.9Hz,1H),2.57(s,1H),2.48-2.42(m,1H),2.27(s,6H),2.05-1.53(m,4H).

[1754] Synthesis of Example 21

[1755]

[1756] Synthesis of intermediate 21-2

[1757] 5 g of 21-1 was dissolved in 50 mL of anhydrous methanol in a 100 mL three-necked flask. A methanol solution of sodium methoxide (13 mL, 5.4 mol / L) was added under nitrogen atmosphere at 0 °C, and the mixture was stirred at room temperature for 12 hours. The solution was concentrated under reduced pressure, the crude product was dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 6.2 g of yellow solid 21-2 (91% yield). LCMS (ESI) m / z: 246 [M+H] + .

[1758] Synthesis of intermediate 21-3

[1759] In a 100 mL single-necked flask, 1.2 g of 21-2 was dissolved in a dioxane solution (4 mol / L, 20 mL) of hydrochloric acid. The reaction was carried out at room temperature for 12 hours, followed by concentration under reduced pressure to give 0.67 g (87% yield) of a yellow solid, 21-3. LCMS (ESI) m / z: 146 [M+H] + .

[1760] Synthesis of intermediate 21-4

[1761] In a 100 mL single-necked flask, 21-3 (630 mg), N,N-dimethylformamide (20 mL), and potassium carbonate (1.5 g) were added, followed by 8-1 (670 mg). The mixture was stirred until homogeneous and reacted at 50 °C for 12 hours. Water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to column chromatography to obtain a yellow solid, 21-4 (500 mg, 45% yield). LCMS (ESI) m / z: 295 [M+H] + .

[1762] Synthesis of intermediate 21-5

[1763] 21-4 (2.5 g) and a tetrahydrofuran solution of dimethylamine (12.7 mL, 2 M) were dissolved in anhydrous methanol (25 mL). Two drops of acetic acid were added, and the reaction mixture was stirred at 50 °C for 0.5 hours. After cooling to room temperature, sodium cyanoborohydride (1 g) was added, and the reaction mixture was stirred at 50 °C for 12 hours. Water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain a yellow solid 21-5 (2.8 g). LCMS (ESI) m / z: 324 [M+...

Claims

1. A compound, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, said compound being selected from: and .

2. A compound or its stereoisomer or pharmaceutically acceptable salt, wherein the compound is selected from: and .

3. A pharmaceutical composition comprising a compound of any one of claims 1-2 or a stereoisomer thereof or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, adjuvant or mediator.

4. Use of the compound of any one of claims 1-2 or its stereoisomer or pharmaceutically acceptable salt or the pharmaceutical composition of claim 3 in the preparation of a medicament for the prevention and / or treatment of HPK1-mediated disorders, diseases or conditions.

5. The use of claim 4, wherein the disorder, disease, or symptom is a proliferative disorder.

6. The use of claim 5, wherein the proliferative disorder is cancer.

7. The use of claim 5, wherein the proliferative disorder is associated with one or more activating mutations in HPK1.

8. The use of claim 4, wherein the obstacle, disease, or symptom is a chronic viral infection.

9. Use of the compound of any one of claims 1-2 or its stereoisomer or pharmaceutically acceptable salt or the pharmaceutical composition of claim 3 in the preparation of a medicament for increasing the efficacy of a vaccine.

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