Proteolysis-inducing chimeric molecules

Abstract

The present invention provides targeted degradation chimeric compounds that target protein tyrosine phosphatases, particularly compounds represented by formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates thereof. The present invention also provides methods for preparing the compounds, pharmaceutical compositions containing the compounds, and the effects of the compounds in the prevention and treatment of related diseases, such as hematological or solid tumor diseases. [C1] TIFF2026504953000252.tif27156

Description

[Technical Field]

[0001] This disclosure claims priority to Chinese Application No. 202310095725.2, filed January 20, 2023, and Chinese Application No. 202410052474.4, filed January 12, 2024, the entire contents of which are incorporated herein by reference.

[0002] (Technical field) The present disclosure relates to chimeric compounds for targeted protein degradation, in particular compounds represented by formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof: [Background technology]

[0003] The protein tyrosine phosphatase (PTP) superfamily contains approximately 112 proteins, whose active site sequences are highly conserved and are (H / V)C(X)5R(S / T). Based on structural and functional differences, the PTP superfamily can be divided into four subfamilies: classical tyrosine-specific phosphatases (classical pTyr-specific PTPs), dual-specificity phosphatases (DSPs), Cdc25 phosphatases, and low-molecular-weight PTPs (LMW-PTPs). Based on their intracellular location, tyrosine-specific PTPs can be further divided into two classes: receptor-like PTPs, such as CD45 and PTP-α, which contain a transmembrane region, several domains on one side of the cytoplasm, and a domain capable of binding to ligands on the outside of the cell; and intracellular PTPs, such as PTP1B, SHP1, and SHP2, which contain a single catalytic domain. The N- or C-termini of this type of PTP have various structures; for example, SH-PTP is a PTP with several tandem SH domains, and these SH structures play important roles in localization and regulation.

[0004] Src homology domain-containing protein tyrosine phosphatases (also known as Src homology domain PTPs, SH-PTPs) are non-receptor tyrosine phosphatases encoded by a series of PTPN genes, including PTP1B, SHP1, SHP2, TCPTP, and MEG-PTP. SH-PTPs are commonly expressed in various tissues and cell types, among which PTP1B contains only one tyrosine phosphatase active domain and is one of the smallest protein tyrosine phosphatases. Both SHP1 and SHP2 contain a conserved tyrosine phosphatase domain, two tandem SH2 domains linked in different ways, and a C-terminal tail structure. The structure and arrangement of the two tandem SH2 domains determine the distinct subcellular localization and regulatory functions of SHP1 and SHP2. In their inactive states, the two SH2 domains bind to the PTP domain, masking the active region and inactivating it. When an SH2 domain binds to a specific tyrosine residue on a receptor or adaptor protein, the PTP domain is exposed. For example, exposure of the catalytic site, triggered by cytokine and growth factor stimulation, leads to activation of such enzymes. They play an important role in various signaling pathways that regulate cellular biological processes and are involved in various growth factor and cytokine signaling pathways. Within a single signaling pathway, PTP family members can simultaneously play both positive (signal enhancement) and negative (signal attenuation) roles during intracellular signaling, acting by attenuating local signaling flow through dephosphorylation of their associated signaling molecules. For example, SHP2 is a positive regulator of the Ras-Raf and ERK / MAPK signaling pathways and plays a key role in controlling cell proliferation and survival. (For an overview of SHP2 phosphatases, see (e.g.) K.S. Grossman et al., Adv. Cancer Res. 2010, 106, 53-89 and references cited therein.)

[0005] In its basal state, SHP2 is typically inhibited automatically by an intramolecular interaction between its N-terminal SH2 (N-SH2) domain and its catalytic (PTP) domain, blocking access to the catalytic site. Activation of proteins that interact with the SH2 domain reverses this inhibition and induces a conformational change that allows substrate access to the catalytic site. Mutations in the PTPN11 gene affect N-SH2 or PTP domain residues involved in the basal inhibition of SHP2, resulting in a more readily activated form of the SHP2 protein, which can lead to uncontrolled or increased SHP2 activity. SHP2 is widely expressed and is involved in multiple cell signaling processes, including the Ras-Erk, PI3K-Akt, Jak-Stat, Met, FGFR, and EGFR pathways, as well as the insulin receptor and NF-kB pathways, and plays a crucial role in cell proliferation, differentiation, cell cycle, and migration. Overactivation of SHP2, caused by germline or somatic mutations, has been found in Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, myelodysplastic syndrome, B-cell acute lymphoblastic leukemia, and acute myeloid leukemia. Furthermore, activating mutations in PTPN11 have also been found in solid tumors, such as lung cancer, colon cancer, ovarian cancer, cervical cancer, prostate cancer, melanoma, neuroblastoma, and liver cancer. Furthermore, phosphatases such as TCPTP and PTP-MEG2 have also been reported to be highly correlated with the development and progression of hematologic and solid tumors. Therefore, activated or upregulated phosphatases in human tumors and other diseases represent novel therapeutic targets, and there is an urgent need to develop therapeutics against intracellular protein phosphatases, including SHP2. Summary of the Invention

[0006] In one aspect, the present disclosure provides compounds represented by Formula (I), or pharmaceutically acceptable salts, stereoisomers, tautomers, cis-trans isomers, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof: [ka]

[0007] During the ceremony,

[0008] The POI is: [ka] and;

[0009] [ka] represents a single or double bond, alternatively a double bond;

[0010] Each R P are independently H, D, halogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl and C 2~6 alkynyl;

[0011] s is selected from 1, 2 and 3;

[0012] X P are N and CR P Selected from;

[0013] W is H, D, halogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 selected from aryl and 5-10 membered heteroaryl;

[0014] The W may be one, two or three R W optionally replaced by;

[0015] R W H, D, -C(O)R a , -C(O)NR b R c , -C(O)ORa or -OC(O)R a , -NR b C(O)R a , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl and C 2~6 alkynyl;

[0016] The a-terminus of the POI is C 0~3 is connected to Q via alkylene, and the b end is connected to L;

[0017] L is [ka] and;

[0018] [ka] represents a single bond, a cis or trans double bond, alternatively a cis double bond;

[0019] each X L are independently chemical bonds, -O-, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 3~10 Cycloalkylene, 5-10 membered heterocyclylene, C 6~10 arylene and 5- to 10-membered heteroarylene; L is optionally deuterated, up to fully deuterated;

[0020] each m is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0021] each n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0022] each p is independently selected from 0, 1, 2, 3, 4, and 5;

[0023] each q is independently selected from 1, 2, 3, 4, and 5;

[0024] the b-terminus of L is connected to the POI and the c-terminus is connected to the E3, or the c-terminus of L is connected to the POI and the b-terminus is connected to the E3;

[0025] E3 is [ka] and;

[0026] R E1 , R E2 , R E3 or R E4 is independently selected from H and D; R E1 and R E2 , R E3 and R E4 at least one pair represents =O, =S or =N-OH;

[0027] The c-terminus of E3 is connected to L, and the d-terminus is C 0~3 connected to Q via an alkylene;

[0028] Q is [ka] and;

[0029] L1 and L2 are independently selected from NH and O;

[0030] X Q is -P(O)(Y Q -R Q )-, -S(O)- and -C(O)-X Q1 -C(O)-;

[0031] Y Q is selected from NH and O;

[0032] X Q1is a chemical bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, -C 1~6 Alkylene-OC 1~6 Alkylene, -C 1~6 Alkylene-NR b -C 1~6 Alkylene, C 3~10 Cycloalkylene, 5-10 membered heterocyclylene, C 6~10 arylene and 5- to 10-membered heteroarylene, Q1 is optionally replaced by 1, 2, 3, 4, or 5 independently selected R#;

[0033] R Q is H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, 5-10 membered heterocyclyl, C 6~10 selected from aryl and 5-10 membered heteroaryl;

[0034] R a , R b and R c are independently H, C 1~6 Alkyl and C 1~6 haloalkyl;

[0035] R# is H, halogen, OH, NH2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl and C 2~6 alkynyl.

[0036] In another aspect, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure and optionally a pharmaceutically acceptable excipient, such as a carrier, adjuvant, or vehicle.

[0037] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient, further comprising an additional therapeutic agent.

[0038] In another aspect, the present disclosure provides the use of a compound of the present disclosure in the manufacture of a medicament for the treatment and / or prevention of a tumor disease.

[0039] In another aspect, the disclosure provides the use of a compound of the disclosure in the manufacture of a medicament for the treatment and / or prevention of a hematological or solid tumor disease.

[0040] In another aspect, the present disclosure provides a method for treating and / or preventing a tumor disease in a subject, the method comprising administering to the subject a compound of the present disclosure or a pharmaceutical composition of the present disclosure.

[0041] In another aspect, the present disclosure provides a method for treating and / or preventing a hematological or solid tumor disease in a subject, the method comprising administering to the subject a compound or pharmaceutical composition of the present disclosure.

[0042] In another aspect, the present disclosure provides a compound of the present disclosure or a pharmaceutical composition of the present disclosure for use in the treatment and / or prevention of a tumor disease.

[0043] In another aspect, the present disclosure provides a compound of the present disclosure or a pharmaceutical composition of the present disclosure for use in the treatment and / or prevention of a hematological or solid tumor disease.

[0044] In certain embodiments, the present disclosure is used in the treatment and / or prevention of solid tumors such as breast cancer, lung cancer, neuroblastoma, oral squamous cell carcinoma, colorectal tumors, ovarian cancer, cervical cancer, prostate cancer, and pancreatic cancer, hematological oncological diseases such as myeloid and lymphoid leukemia, and other relapsed and refractory advanced solid and hematological tumors.

[0045] definition

[0046] chemical definition

[0047] Definitions of certain functional groups and chemical terms are described in more detail below.

[0048] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1~6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 and C 5~6 It is intended to include alkyl.

[0049] "C 1~6 "Alkyl" refers to the radical of a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1~4 Alkyl and C 1~2 Alkyl is an alternative. 1~6 Examples of alkyl 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). 1~6The term "alkyl" also includes heteroalkyl, in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced with a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkyl groups can be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional abbreviations for alkyl include Me(-CH), Et(-CHCH), iPr(-CH(CH)), nPr(-CHCHCH), n-Bu(-CHCHCHCHCH), or i-Bu(-CHCH(CH)).

[0050] "C 1~6 "Alkylene" is C 1~6 refers to a divalent group formed by removing another hydrogen from an alkyl, and can be substituted or unsubstituted. In some embodiments, C 1~4 Alkylene, C 2~4 Alkylene and C 1~3 Alkylene is an alternative. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), butylene (-CHCHCHCHCH-), pentylene (-CHCHCHCHCHCH-), hexylene (-CHCHCHCHCHCHCH-), and the like. Examples of substituted alkylene groups, such as 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 propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0051] "C 2~6"Alkenyl" refers to the radical of a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2~4 Alkenyl is an alternative. 2~6 Examples of alkenyl include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. 2~6 The term "alkenyl" also includes heteroalkenyl, in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkenyl groups can be optionally substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0052] "C 2~6 "Alkenylene" refers to a C alkyl group, which may be substituted or unsubstituted, in which another hydrogen is removed to provide a divalent radical of alkenylene. 2~6 In some embodiments, C refers to an alkenyl group. 2~4 Alkenylene is an alternative.

[0053] "C 2~6 "Alkynyl" refers to the radical of a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2~4 Alkynyl is an alternative. 2~6 Examples of alkynyl include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), hexynyl (C6), and the like. 2~6The term "alkynyl" also includes heteroalkynyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkynyl groups can be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0054] "C 2~6 "Alkynylene" refers to a C alkyl group, which may be substituted or unsubstituted, in which another hydrogen is removed to provide a divalent radical of alkynylene. 2~6 In some embodiments, C refers to an alkynyl group. 2~4 Alkynylene is an alternative.

[0055] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0056] Therefore, "C 1~6 "Haloalkyl" refers to any of the above "C" groups substituted with one or more halogens. 1~6 In some embodiments, C 1~4 Haloalkyl is a further alternative, and still alternatively, C 1~2 haloalkyl. Exemplary haloalkyl groups include, but are not limited to, -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. Haloalkyl can be substituted at any available attachment point with, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0057] "C 3~10 "Cycloalkyl" refers to the radical of a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and 0 heteroatoms. In some embodiments, C 3~8 Cycloalkyl, C 3~7 Cycloalkyl, and C 3~5Cycloalkyl is a further alternative, and still alternatively, C 5~6 Cycloalkyl. Cycloalkyl also includes ring systems in which the cycloalkyl described herein is fused to one or more aryl or heteroaryl groups, and the point of attachment is on the cycloalkyl ring; in such cases, the number of carbon atoms still refers to the number of carbon atoms in the cycloalkyl system. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), cycloheptyl (C), cycloheptenyl (C), cycloheptadienyl (C), cycloheptatrienyl (C), and the like. The cycloalkyl group can be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0058] "C 3~10 "Cycloalkylene" is C 3~10 refers to a divalent group formed by removing another hydrogen from cycloalkyl, which may be substituted or unsubstituted. In some embodiments, C 3~7 Cycloalkylene, C 3~5 Cycloalkylene and C 5~6 Cycloalkylene is an alternative.

[0059] "5- to 10-membered heterocyclyl" refers to a saturated or unsaturated radical of a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each of which is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyls containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, valence permitting. In some embodiments, a 4- to 7-membered heterocyclyl is an alternative, which is a radical of a 4- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms, and a 5- to 6-membered heterocyclyl is a further alternative, which is a radical of a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes ring systems in which the above heterocyclyl is fused to one or more cycloalkyl groups, with the point of attachment being on the cycloalkyl ring, or the above heterocyclyl is fused to one or more aryl or heteroaryl groups, with the point of attachment being on the heterocyclyl ring, in which case the number of ring members still refers to the number of ring members in the heterocyclyl ring system. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidyl, tetrahydropyranyl, dihydropyridyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl.Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 5-membered heterocyclyl groups fused with a C6 aryl (also referred to herein as 5,6-bicyclic heterocyclyl) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused with a C6 aryl (also referred to herein as 6,6-bicyclic heterocyclyl) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Heterocyclyl also includes bridged or spiro rings formed by the above heterocyclyl and a cycloalkyl, heterocyclyl, aryl, or heteroaryl group sharing one or two atoms, and the shared atom may be a carbon atom or a nitrogen atom, as far as valence permits. Heterocyclyl also includes heterocyclyl groups as defined above as well as heterocyclyl groups which can be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0060] "5- to 10-membered heterocyclylene" refers to a divalent group formed by removing another hydrogen from a 5- to 10-membered heterocyclyl, and can be substituted or unsubstituted. In some embodiments, a 5- to 6-membered heterocyclylene is an alternative.

[0061] "C 6~10 "Aryl" refers to the radical of a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system having 6 to 10 ring carbon atoms and 0 heteroatoms (e.g., having 6 or 10 shared π electrons in the ring arrangement). In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10Aryl" (e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). Aryl groups also include ring systems in which the aryl ring as described above is fused to one or more cycloalkyl or heterocyclyl groups, the point of attachment of which is on the aryl ring; in such cases, the number of carbon atoms still refers to the number of carbon atoms in the aryl ring system. Aryl can be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0062] "C 6~10 "Arylene" is C 6~10 It refers to a divalent group formed by removing another hydrogen from aryl, and can be substituted or unsubstituted. In some embodiments, phenylene is an alternative.

[0063] "5-10-membered heteroaryl" refers to the radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms (e.g., 6 or 10 shared π electrons in the ring arrangement), each heteroatom independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, valence permitting. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl groups, the point of attachment being on the heteroaryl ring. In such cases, the number of carbon atoms still refers to the number of carbon atoms in the heteroaryl ring system. In some embodiments, a 5- to 6-membered heteroaryl group is an alternative, which is a radical of a 5- to 6-membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl. 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 (such as 1,2,4-oxadiazolyl), and thiadiazolyl. 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, pyridyl. 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 tetrazinyl, respectively.Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Heteroaryl can be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0064] "5- to 10-membered heteroarylene" refers to a divalent group formed by removing another hydrogen from a 5- to 10-membered heteroaryl, and can be substituted or unsubstituted. In some embodiments, 5- to 6-membered heteroarylene is an alternative.

[0065] The ring-forming groups defined above, such as cycloalkyl, cycloalkylene, heterocyclyl, heterocyclylene, aryl, arylene, heteroaryl and heteroarylene, are collectively referred to as "cyclyl groups."

[0066] Alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclylene, aryl, arylene, heteroaryl and heteroarylene, as defined herein, are optionally substituted groups.

[0067] Exemplary substituents on carbon atoms include, but are not limited to, halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —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)SRaa , -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)(NR bb )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, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with a group,

[0068] Or two geminal hydrogens on a carbon atom are =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 is replaced by a group,

[0069] R aa are each independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or R aa two of the groups are joined to form a heterocyclyl or heteroaryl ring, where each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with a group,

[0070] R bb each independently represents 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(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, heterocyclyl, aryl and heteroaryl, or two R bb groups joined to form a heterocyclyl or heteroaryl ring, where each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R ddis substituted with a group,

[0071] R cc are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R cc groups joined to form a heterocyclyl or heteroaryl ring, where each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with a group,

[0072] R dd each independently represents a 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 , -NR ff 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, -NRff 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, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group or two geminal R dd the substituents may combine to form =O or =S;

[0073] R ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg is substituted with a group,

[0074] R ff are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R ffgroups joined to form a heterocyclyl or heteroaryl ring, where each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg is substituted with a group,

[0075] Each R gg each independently represents a 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), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -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), -NHC(=O)NH2, -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C 1~6 alkyl), -OC(=NH)OC1~6 Alkyl, -C(=NH)N(C 1~6 alkyl)2, -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 alkyl)2, -OC(NH)NH(C 1~6 alkyl), -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), -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, -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 alkynyl, C3-C7 cycloalkyl, C6-C 10 Aryl, C3-C7 heterocyclyl or C5-C 10 Heteroaryl or two geminal R gg The substituents may combine to form =O or =S, where X - is the counterion.

[0076] Exemplary substituents on a nitrogen atom include 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, including but not limited to alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R bonded to a nitrogen atom cc groups joined to form a heterocyclyl or heteroaryl ring, where each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with an R aa , R bb , R cc and R dd is as described herein.

[0077] As used herein, unless otherwise specified, a bivalent structure can be attached to the remainder of the compound in any direction, from left to right or right to left (or from top to bottom or bottom to top). In one embodiment, alternatively, the bivalent structure is attached to the remainder of the compound in a left to right direction. For example, in general formula (I): [ka]

[0078] Q is [ka] When defined as , it represents the following two connection modes: [ka]

[0079] Other divalent structures should be understood similarly.

[0080] Other definitions

[0081] The term "cancer" includes, but is not limited to, pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, ovarian cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal carcinoma, and sarcoma.

[0082] As used herein, the term "treating" refers to reversing, alleviating, or inhibiting the progression of, or preventing, the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition. As used herein, the noun "treatment" refers to the act of treating, which is a verb, as just defined.

[0083] As used herein, the term "pharmaceutically acceptable salts" refers to carboxylate and amino acid addition salts of compounds of the present disclosure that are, within the scope of sound medical judgment, suitable for contact with patient tissues and do not cause undue toxicity, irritation, allergy, or the like, that are commensurate with a reasonable benefit / risk ratio and are effective for their intended use. The term includes, whenever possible, zwitterionic forms of compounds of the present disclosure.

[0084] Pharmaceutically acceptable base addition salts are 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, calcium, etc. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.

[0085] Base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the necessary base to form the salt in a conventional manner. The free acid can be regenerated by contacting the salt form with an acid in a conventional manner and then isolating the free acid. The free acid forms differ somewhat from their respective salt forms in physical properties, such as solubility in polar solvents. However, for purposes of this disclosure, the salts are still equivalent to their respective free acids.

[0086] Salts can be prepared from inorganic acids, including sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, and iodide. Examples of acids include 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, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthalate, methanesulfonate, glucoheptanoate, lactobionate, laurylsulfonate, and isethionate. Salts can also be prepared from organic acids, including aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, naphthoate, besylate, tosylate, phenylacetate, citrate, lactate, tartrate, methanesulfonate, and the like. Pharmaceutically acceptable salts can include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. Also included are salts of amino acids such as arginine salts, gluconate salts, galacturonate salts, and the like (see, e.g., Berge, S. M. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19, for review).

[0087] "Subjects" to which administration is contemplated include, but are not limited to, humans (e.g., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or the elderly)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, 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" may be used interchangeably herein.

[0088] "Disease," "disorder," and "condition" may be used interchangeably herein.

[0089] Unless otherwise specified, as used herein, the term "treatment" includes an effect on a subject suffering from a particular disease, disorder, or condition, thereby reducing the severity of the disease, disorder, or condition, or slowing or retarding the progression of the disease, disorder, or condition ("therapeutic treatment"). The term also includes an effect that occurs before the subject begins to suffer from a particular disease, disorder, or condition ("prophylactic treatment").

[0090] Generally, the "effective amount" of a compound refers to an amount sufficient to induce a desired biological response. As will be understood by those skilled in the art, the effective amount of the compound of the present disclosure may vary depending on the following factors: the desired biological endpoint, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age, health condition and symptoms of the subject. The effective amount includes a therapeutically effective amount and a prophylactically effective amount.

[0091] Unless otherwise specified, a "therapeutically effective amount" of a compound as used herein is an amount sufficient to provide a therapeutic benefit in the course of treating a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent that, when used alone or in combination with other therapies, provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effect of another therapeutic agent.

[0092] Unless otherwise specified, a "prophylactically effective amount" of a compound used herein is an amount sufficient to prevent a disease, disorder, or condition, or to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent the recurrence of a disease, disorder, or condition. A prophylactically effective amount of a compound refers to the amount of a therapeutic agent that, when used alone or in combination with other agents, provides a prophylactic benefit in the prevention of a disease, disorder, or condition. The term "prophylactically effective amount" can include an amount that improves overall prevention or an amount that enhances the prophylactic effect of other prophylactic agents.

[0093] "Combination" and related terms refer to simultaneous or sequential administration of a compound of the present disclosure and another therapeutic agent. For example, a compound of the present disclosure can be administered simultaneously or sequentially with the other therapeutic agent in separate unit dosages, or simultaneously with the other therapeutic agent in a single unit dosage. DETAILED DESCRIPTION OF THE INVENTION

[0094] As used herein, "compounds of the disclosure" refers to compounds of formula (I) below, or pharmaceutically acceptable salts, stereoisomers, tautomers, cis-trans isomers, solvates, hydrates, polymorphs, prodrugs or isotopic variants thereof, and mixtures thereof.

[0095] In one embodiment, the present disclosure relates to compounds represented by formula (I), or pharmaceutically acceptable salts, stereoisomers, tautomers, cis-trans isomers, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof: [ka]

[0096] During the ceremony,

[0097] The POI is: [ka] and;

[0098] [ka] represents a single or double bond, alternatively a double bond;

[0099] Each R P are independently H, D, halogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl and C 2~6 alkynyl;

[0100] s is selected from 1, 2 and 3;

[0101] X P are N and CR P Selected from;

[0102] W is H, D, halogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 selected from aryl and 5-10 membered heteroaryl;

[0103] The W may be one, two or three R Woptionally replaced by;

[0104] R W H, D, -C(O)R a , -C(O)NR b R c , -C(O)OR a or -OC(O)R a , -NR b C(O)R a , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl and C 2~6 alkynyl;

[0105] The a-terminus of the POI is C 0~3 is connected to Q via alkylene, and the b end is connected to L;

[0106] L is [ka] and;

[0107] [ka] represents a single bond, a cis or trans double bond, alternatively a cis double bond;

[0108] each X L are independently chemical bonds, -O-, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 3~10 Cycloalkylene, 5-10 membered heterocyclylene, C 6~10 arylene and 5- to 10-membered heteroarylene; L is optionally deuterated, up to fully deuterated;

[0109] each m is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0110] each n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0111] each p is independently selected from 0, 1, 2, 3, 4, and 5;

[0112] each q is independently selected from 1, 2, 3, 4, and 5;

[0113] the b-terminus of L is connected to the POI and the c-terminus is connected to the E3, or the c-terminus of L is connected to the POI and the b-terminus is connected to the E3;

[0114] E3 is [ka] and;

[0115] R E1 , R E2 , R E3 or R E4 is independently selected from H and D; R E1 and R E2 , R E3 and R E4 at least one pair represents =O, =S or =N-OH;

[0116] The c-terminus of E3 is connected to L, and the d-terminus is C 0~3 connected to Q via an alkylene;

[0117] Q is [ka] and;

[0118] L1 and L2 are independently selected from NH and O;

[0119] X Q is -P(O)(Y Q -R Q )-, -S(O)- and -C(O)-X Q1-C(O)-;

[0120] Y Q is selected from NH and O;

[0121] X Q1 is a chemical bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, -C 1~6 Alkylene-OC 1~6 Alkylene, -C 1~6 Alkylene-NR b -C 1~6 Alkylene, C 3~10 Cycloalkylene, 5-10 membered heterocyclylene, C 6~10 arylene and 5- to 10-membered heteroarylene, Q1 is optionally replaced by 1, 2, 3, 4, or 5 independently selected R#;

[0122] R Q is H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, 5-10 membered heterocyclyl, C 6~10 selected from aryl and 5-10 membered heteroaryl;

[0123] R a , R b and R c are independently H, C 1~6 Alkyl and C 1~6 haloalkyl;

[0124] R# is H, halogen, OH, NH2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl and C 2~6 alkynyl.

[0125] POI

[0126] In certain embodiments, the POI is [ka] and in another particular embodiment, the POI is [ka] is.

[0127] In certain embodiments, the POI is [ka] and in another particular embodiment, the POI is [ka] and in another particular embodiment, the POI is [ka] and in another particular embodiment, the POI is [ka] is.

[0128] The a-terminus of POI is C 0~3 It is connected to Q via alkylene, and the b end is connected to L.

[0129] [ka]

[0130] [ka] represents a single or double bond, alternatively a double bond;

[0131] W

[0132] In certain embodiments, W is H; in another particular embodiment, W is D; in another particular embodiment, W is halogen; in another particular embodiment, W is C 1~6 In another particular embodiment, W is C 1~4 In another particular embodiment, W is C 1~6 haloalkyl; in another particular embodiment, W is C 1~4 haloalkyl; in another particular embodiment, W is C 2~6 alkenyl; in another particular embodiment, W is C 2~6 In another particular embodiment, W is C 6~10 aryl; in another particular embodiment, W is a 5-10 membered heteroaryl.

[0133] In certain embodiments, W is [ka] is.

[0134] In certain embodiments, W is H; in other particular embodiments, W is a halogen, such as I; in other particular embodiments, W is [ka] and in another particular embodiment, W is [ka] and in another particular embodiment, W is [ka] is.

[0135] In certain embodiments, W is unsubstituted; in other certain embodiments, W is one R W In another particular embodiment, W is substituted with two independently selected R WIn another particular embodiment, W is substituted with three independently selected R W is replaced by .

[0136] R W

[0137] In certain embodiments, R W is H; in another particular embodiment, R W is D; in another particular embodiment, R W is -C(O)R a and in another particular embodiment, R W is -C(O)NR b R c and in another particular embodiment, R W is -C(O)OR a and in another particular embodiment, R W is -OC(O)R a and in another particular embodiment, R W is -NR b C(O)R a and in another particular embodiment, R W is C 1~6 alkyl; in another particular embodiment, R W is C 1~6 haloalkyl; in another particular embodiment, R W is C 2~6 alkenyl; in another particular embodiment, R W is C 2~6 It is alkynyl.

[0138] R a , R b and R c are independently H, C 1~6 Alkyl and C 1~6 haloalkyl.

[0139] X P

[0140] In certain embodiments, X P is N; in another particular embodiment, X PCR such as CH P is.

[0141] X W1 and X W2

[0142] In certain embodiments, X W1 is N; in another particular embodiment, X W1 is CR W is.

[0143] In certain embodiments, X W2 is N; in another particular embodiment, X W2 is CR W is.

[0144] R P

[0145] In certain embodiments, R P is H; in another particular embodiment, R P is D; in another particular embodiment, R P is halogen; in another particular embodiment, R P is C 1~6 alkyl; in another particular embodiment, R P is C 1~4 alkyl; in another particular embodiment, R P is C 1~6 haloalkyl; in another particular embodiment, R P is C 1~4 haloalkyl; in another particular embodiment, R P is C 2~6 alkenyl; in another particular embodiment, R P is C 2~6 It is alkynyl.

[0146] s

[0147] In certain embodiments, s is 1; in other particular embodiments, s is 2; and in other particular embodiments, s is 3.

[0148] L

[0149] In certain embodiments, L is [ka] and in another more particular embodiment, L is [ka] is selected from.

[0150] The b-terminus of L is connected to the POI and the c-terminus is connected to the E3, or the c-terminus of L is connected to the POI and the b-terminus is connected to the E3.

[0151] [ka]

[0152] [ka] represents a single bond, a cis or trans double bond, alternatively a cis double bond.

[0153] X L

[0154] In certain embodiments, X L is a chemical bond; in another particular embodiment, X L is —O—; in another particular embodiment, X L is C 1~4 C such as alkylene 1~6 alkylene; in another particular embodiment, X L is C 2~6 alkenylene; in another particular embodiment, X L is C 2~6 alkynylene; in another particular embodiment, X L is C 3~10 cycloalkylene; in another particular embodiment, X L is a 5- to 10-membered heterocyclylene; in another particular embodiment, XL is C 6~10 arylene; in another particular embodiment, X L is a 5- to 10-membered heteroarylene.

[0155] In more particular embodiments, X L is independently selected from a chemical bond; in another more particular embodiment, X L is —O—; in another more particular embodiment, X L is -CH2-; in another more particular embodiment, X L teeth, [ka] and in another more particular embodiment, X L teeth, [ka] is.

[0156] X L is optionally deuterated, up to fully deuterated.

[0157] m

[0158] In certain embodiments, m is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0159] n

[0160] In certain embodiments, n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0161] p

[0162] In certain embodiments, p is independently selected from 0, 1, 2, 3, 4, and 5.

[0163] q

[0164] In certain embodiments, q is independently selected from 1, 2, 3, 4, and 5.

[0165] E3

[0166] In certain embodiments, E3 is [ka] is.

[0167] In a more particular embodiment, E3 is [ka] In another more particular embodiment, E3 is [ka] In another more particular embodiment, E3 is [ka] is.

[0168] The c-terminus of E3 is connected to L, and the d-terminus is C 0~3 It is connected to Q via an alkylene.

[0169] R E1 , R E2 , R E3 or R E4

[0170] In certain embodiments, R E1 is H; in another particular embodiment, R E1 is D.

[0171] In certain embodiments, R E2 is H; in another particular embodiment, R E2 is D.

[0172] In certain embodiments, R E3 is H; in another particular embodiment, RE3 is D.

[0173] In certain embodiments, R E4 is H; in another particular embodiment, R E4 is D.

[0174] In certain embodiments, R E1 and R E2 represents ═O, ═S, or ═N—OH; in another particular embodiment, R E3 and R E4 represents ═O, ═S, or ═N—OH; in another particular embodiment, R E1 and R E2 , R E3 and R E4 At least one pair of represents =O, =S or =N-OH.

[0175] Q

[0176] In certain embodiments, Q is [ka] is.

[0177] In more particular embodiments, Q is [ka] and in another more particular embodiment, Q is [ka] and in another more particular embodiment, Q is [ka] and in another more particular embodiment, Q is [ka] and in another more particular embodiment, Q is [ka] and in another more particular embodiment, Q is [ka] and in another more particular embodiment, Q is [ka] and in another more particular embodiment, Q is [ka] and in another more particular embodiment, Q is [ka] and in another more particular embodiment, Q is [ka] and in another more particular embodiment, Q is [ka] and in another more particular embodiment, Q is [ka] and in another more particular embodiment, Q is [ka] and in another more particular embodiment, Q is [ka] and in another more particular embodiment, Q is [ka] and in another more particular embodiment, Q is [ka] and in another more particular embodiment, Q is [ka] and in another more particular embodiment, Q is [ka] and in another more particular embodiment, Q is [ka] and in another more particular embodiment, Q is [ka] and in another more particular embodiment, Q is [ka] is.

[0178] L1 and L2

[0179] In certain embodiments, L1 is NH; in other certain embodiments, L1 is O.

[0180] In certain embodiments, L2 is NH; in other certain embodiments, L2 is O.

[0181] X Q

[0182] In certain embodiments, X Q is -P(O)(Y Q -R Q )-; in another particular embodiment, X Q is —S(O)—; in another particular embodiment, X Q is -C(O)-X Q1 -C(O)-.

[0183] Y Q

[0184] In certain embodiments, Y Q is NH; in another particular embodiment, Y Q is O.

[0185] X Q1

[0186] In certain embodiments, X Q1 is a chemical bond; in another particular embodiment, X Q1 is C 1~6 alkylene; in another particular embodiment, X Q1 is C 1~4 alkylene; in another particular embodiment, X Q1 is C 2~6 alkenylene; in another particular embodiment, X Q1 is C 2~6 alkynylene; in another particular embodiment, X Q1 -C 1~4 Alkylene-OC 1~4 -C such as alkylene 1~6 Alkylene-OC 1~6 alkylene; in another particular embodiment, X Q1 -C 1~4 Alkylene-NR b -C 1~4 -C such as alkylene 1~6 Alkylene-NR b -C 1~6 alkylene; in another particular embodiment, X Q1 is C 3~10 cycloalkylene; in another particular embodiment, X Q1 is a 5- to 10-membered heterocyclylene; in another particular embodiment, X Q1 is 5-10 membered heteroarylene; in another particular embodiment, X Q1 teeth, [ka] In another particular embodiment, X Q1 is C 6~10arylene; in another particular embodiment, X Q1 is phenylene.

[0187] In certain embodiments, X Q1 is unsubstituted; in another particular embodiment, X Q1 is substituted with one R#; in another particular embodiment, X Q1 is substituted with two independently selected R#; in another particular embodiment, X Q1 is substituted with three independently selected R#; in another particular embodiment, X Q1 is substituted with four independently selected R#; in another particular embodiment, X Q1 is replaced with five independently selected R#s.

[0188] R Q

[0189] In certain embodiments, R Q is H; in another particular embodiment, R Q is C 1~6 alkyl; in another particular embodiment, R Q is C 1~4 alkyl; in another particular embodiment, R Q is C 2~6 alkenyl; in another particular embodiment, R Q is C 2~6 alkynyl; in another particular embodiment, R Q C such as phenyl 6~10 It is aryl.

[0190] R#

[0191] In certain embodiments, R# is H; in another particular embodiment, R# is halogen; in another particular embodiment, R# is OH; in another particular embodiment, R# is NH2; in another particular embodiment, R# is C 1~4 C such as alkyl 1~6 alkyl; in another particular embodiment, R# is C 1~4C such as haloalkyl 1~6 haloalkyl; in another particular embodiment, R# is C 2~6 alkenyl; in another particular embodiment, R# is C 2~6 It is alkynyl.

[0192] Any technical solution or any combination thereof in any one of the above specific embodiments may be combined with any technical solution or any combination thereof in other specific embodiments. For example, any technical solution or any combination thereof of POI may be combined with any technical solution or any combination thereof of L, E3, and Q, etc. The present disclosure is intended to include all combinations of such technical solutions, which are not exhaustively listed here to save space.

[0193] In more particular embodiments, the present disclosure provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0194] The POI is: [ka] and;

[0195] [ka] represents a single or double bond, alternatively a double bond;

[0196] Each R P are independently H, D, halogen, C 1~4 Alkyl and C 1~4 haloalkyl;

[0197] s is selected from 1, 2 and 3;

[0198] X P are N and CR PSelected from;

[0199] W is H, D, halogen, C 1~4 Alkyl, C 1~4 haloalkyl and [ka] Selected from;

[0200] X W1 and X W2 are, independently, N and CR W Selected from;

[0201] R W H, D, -C(O)R a , -C(O)NR b R c , -C(O)OR a , -OC(O)R a and -NR b C(O)R a Selected from;

[0202] R a , R b and R c are independently H, C 1~4 Alkyl and C 1~4 haloalkyl;

[0203] The a-terminus of the POI is C 0~3 is connected to Q via alkylene, and the b end is connected to L;

[0204] Alternatively,

[0205] The POI is: [ka] and;

[0206] [ka] represents a single or double bond, alternatively a double bond;

[0207] R P is a halogen;

[0208] X P is selected from N and CH;

[0209] W is H, halogen and [ka] Selected from;

[0210] X W1 and X W2 are, independently, N and CR W Selected from;

[0211] R W is H, -C(O)R a and -C(O)NR b R c Selected from;

[0212] R a , R b and R c are independently H, C 1~4 Alkyl and C 1~4 haloalkyl;

[0213] The a-terminus of the POI is C 0~3 is connected to Q via alkylene, and the b end is connected to L;

[0214] Further alternatively,

[0215] The POI is: [ka] Selected from;

[0216] W is H, halogen, [ka] Alternatively, W is selected from H, I and [ka] Selected from;

[0217] The a-terminus of POI is C 0~3 It is connected to Q via alkylene, and the b end is connected to L.

[0218] In more particular embodiments, the present disclosure provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0219] L is [ka] and;

[0220] [ka] represents a single bond, a cis or trans double bond, alternatively a cis double bond;

[0221] each X L are independently chemical bonds, -O-, C 1~4 selected from alkylene, phenylene, and 5- to 6-membered heteroarylene; L is optionally deuterated, up to fully deuterated;

[0222] each m is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0223] each n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0224] each p is independently selected from 0, 1, 2, 3, 4, and 5;

[0225] each q is independently selected from 1, 2, 3, 4, and 5;

[0226] the b-terminus of L is connected to the POI and the c-terminus is connected to the E3, or the c-terminus of L is connected to the POI and the b-terminus is connected to the E3;

[0227] Alternatively,

[0228] L is [ka] and;

[0229] [ka] represents a single bond, a cis or trans double bond, alternatively a cis double bond;

[0230] each X L are independently a chemical bond, -O-, -CH2-, [ka] Alternatively, each X L is independently selected from —O— and —CH—;

[0231] each m is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8, alternatively, each m is independently selected from 0, 1, 2, 3, and 4, and further alternatively, each m is 1;

[0232] each n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8, alternatively, each n is independently selected from 0, 1, 2, 3, 4, and further alternatively, each n is independently selected from 1 and 2;

[0233] each p is independently selected from 0, 1, 2, and 3, alternatively, each p is independently selected from 0 and 1;

[0234] each q is independently selected from 1, 2, 3, 4, and 5, alternatively, each q is 3;

[0235] the b-terminus of L is connected to the POI and the c-terminus is connected to the E3, or the c-terminus of L is connected to the POI and the b-terminus is connected to the E3;

[0236] Further alternatively,

[0237] L is [ka] Selected from;

[0238] Alternatively, L can be [ka] and;

[0239] [ka] represents a single bond, a cis or trans double bond, alternatively a cis double bond;

[0240] The b-terminus of L is connected to the POI and the c-terminus is connected to the E3, or the c-terminus of L is connected to the POI and the b-terminus is connected to the E3.

[0241] In more particular embodiments, the present disclosure provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0242] E3 is [ka] and;

[0243] R E1 , R E2, R E3 or R E4 is independently selected from H and D; R E1 and R E2 , R E3 and R E4 At least one pair of represents =O;

[0244] The c-terminus of E3 is connected to L, and the d-terminus is C 0~3 connected to Q via an alkylene;

[0245] Alternatively,

[0246] E3 is [ka] Selected from;

[0247] The c-terminus of E3 is connected to L, and the d-terminus is C 0~3 It is connected to Q via an alkylene.

[0248] In more particular embodiments, the present disclosure provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0249] Q is [ka] and;

[0250] L1 and L2 are independently selected from NH and O;

[0251] X Q is -P(O)(Y Q -R Q )-, -S(O)- and -C(O)-X Q1 -C(O)-;

[0252] Y Q is selected from NH and O;

[0253] X Q1 is a chemical bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, -C 1~6 Alkylene-NR b -C 1~6 Alkylene, 5- to 10-membered heterocyclylene and C 6~10 arylene, wherein X Q1 is optionally replaced by 1, 2, 3, 4, or 5 independently selected R#;

[0254] R b is H, C 1~4 Alkyl and C 1~4 haloalkyl;

[0255] R Q is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl and C 6~10 aryl;

[0256] R# is H, halogen, OH, NH2, C 1~4 Alkyl, C 2~4 Alkenyl and C 2~4 alkynyl;

[0257] Alternatively,

[0258] Q is [ka] and;

[0259] L1 and L2 are independently selected from NH and O;

[0260] X Q is -P(O)(Y Q -R Q )-, -S(O)- and -C(O)-X Q1-C(O)-;

[0261] Y Q is selected from NH and O;

[0262] X Q1 is a chemical bond, C 1~4 Alkylene, -C 1~4 Alkylene-NR b -C 1~4 Alkylene, 5- to 6-membered heterocyclylene (e.g., [ka] phenylene; 1~4 The alkylene is optionally substituted with one, two, or three independently selected R#;

[0263] R b is H, C 1~4 Alkyl and C 1~4 haloalkyl;

[0264] R Q is H, C 1~4 selected from alkyl and phenyl;

[0265] R# is selected from H and NH2;

[0266] Further alternatively,

[0267] Q is [ka] Alternatively, Q is selected from [ka] and Q is selected from: [ka] is selected from.

[0268] In more particular embodiments, the present disclosure provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0269] The POI is: [ka] and;

[0270] [ka] represents a single or double bond, alternatively a double bond;

[0271] Each R P are independently H, D, halogen, C 1~4 Alkyl and C 1~4 haloalkyl;

[0272] s is selected from 1, 2 and 3;

[0273] X P are N and CR P Selected from;

[0274] W is H, D, halogen, C 1~4 Alkyl, C 1~4 haloalkyl and [ka] Selected from;

[0275] X W1 and X W2 are, independently, N and CR W Selected from;

[0276] R W H, D, -C(O)R a , -C(O)NR b R c , -C(O)OR a, -OC(O)R a and -NR b C(O)R a Selected from;

[0277] The a-terminus of the POI is C 0~3 is connected to Q via alkylene, and the b end is connected to L;

[0278] L is [ka] and;

[0279] [ka] represents a single bond, a cis or trans double bond, alternatively a cis double bond;

[0280] each X L are independently chemical bonds, -O-, C 1~4 selected from alkylene, phenylene, and 5- to 6-membered heteroarylene; L is optionally deuterated, up to fully deuterated;

[0281] each m is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0282] each n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0283] each p is independently selected from 0, 1, 2, 3, 4, and 5;

[0284] each q is independently selected from 1, 2, 3, 4, and 5;

[0285] the b-terminus of L is connected to the POI and the c-terminus is connected to the E3, or the c-terminus of L is connected to the POI and the b-terminus is connected to the E3;

[0286] E3 is [ka] and;

[0287] R E1 , R E2 , R E3 or R E4 is independently selected from H and D; R E1 and R E2 , R E3 and R E4 At least one pair of represents =O;

[0288] The c-terminus of E3 is connected to L, and the d-terminus is C 0~3 connected to Q via an alkylene;

[0289] Q is [ka] and;

[0290] L1 and L2 are independently selected from NH and O;

[0291] X Q is -P(O)(Y Q -R Q )-, -S(O)- and -C(O)-X Q1 -C(O)-;

[0292] Y Q is selected from NH and O;

[0293] X Q1 is a chemical bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, -C 1~6 Alkylene-NR b -C 1~6 Alkylene, 5- to 10-membered heterocyclylene and C 6~10 arylene, wherein X Q1is optionally replaced by 1, 2, 3, 4, or 5 independently selected R#;

[0294] R Q is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl and C 6~10 aryl;

[0295] R a , R b and R c are independently H, C 1~4 Alkyl and C 1~4 haloalkyl;

[0296] R# is H, halogen, OH, NH2, C 1~4 Alkyl, C 2~4 Alkenyl and C 2~4 alkynyl.

[0297] In more particular embodiments, the present disclosure provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0298] The POI is: [ka] and;

[0299] [ka] represents a single or double bond, alternatively a double bond;

[0300] R P is a halogen;

[0301] X P is selected from N and CH;

[0302] W is H, halogen and [ka] Selected from;

[0303] X W1 and X W2 are, independently, N and CR W Selected from;

[0304] R W is H, -C(O)R a and -C(O)NR b R c Selected from;

[0305] The a-terminus of the POI is C 0~3 is connected to Q via alkylene, and the b end is connected to L;

[0306] L is [ka] and;

[0307] [ka] represents a single bond, a cis or trans double bond, alternatively a cis double bond;

[0308] each X L are independently a chemical bond, -O-, -CH2-, [ka] Alternatively, each X L is independently selected from —O— and —CH—;

[0309] each m is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8, alternatively independently selected from 0, 1, 2, 3, 4, and further alternatively independently 1;

[0310] each n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8, alternatively independently selected from 0, 1, 2, 3, 4, and further alternatively independently selected from 1 and 2;

[0311] each p is independently selected from 0, 1, 2, and 3, alternatively, independently selected from 0 and 1;

[0312] each q is independently selected from 1, 2, 3, 4, and 5, alternatively, independently 3;

[0313] the b-terminus of L is connected to the POI and the c-terminus is connected to the E3, or the c-terminus of L is connected to the POI and the b-terminus is connected to the E3;

[0314] E3 is [ka] and;

[0315] R E1 , R E2 , R E3 or R E4 is independently selected from H and D; R E1 and R E2 , R E3 and R E4 At least one pair of represents =O;

[0316] The c-terminus of E3 is connected to L, and the d-terminus is C 0~3 connected to Q via an alkylene;

[0317] Q is [ka] and;

[0318] L1 and L2 are independently selected from NH and O;

[0319] XQ is -P(O)(Y Q -R Q )-, -S(O)- and -C(O)-X Q1 -C(O)-;

[0320] Y Q is selected from NH and O;

[0321] X Q1 is a chemical bond, C 1~4 Alkylene, -C 1~4 Alkylene-NR b -C 1~4 Alkylene, 5- to 6-membered heterocyclylene (e.g., [ka] phenylene; 1~4 The alkylene is optionally substituted with one, two, or three independently selected R#;

[0322] R Q is H, C 1~4 selected from alkyl and phenyl;

[0323] R a , R b and R c are independently H, C 1~4 Alkyl and C 1~4 haloalkyl;

[0324] R# is selected from H and NH2.

[0325] In more particular embodiments, the present disclosure provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0326] The POI is: [ka] Alternatively, the POI is selected from: [ka] Selected from;

[0327] W is H, halogen, [ka] Alternatively, W is selected from H, I and [ka] Selected from;

[0328] The a-terminus of the POI is C 0~3 is connected to Q via alkylene, and the b end is connected to L;

[0329] L is [ka] Selected from;

[0330] Alternatively, L can be [ka] and;

[0331] the b-terminus of L is connected to the POI and the c-terminus is connected to the E3, or the c-terminus of L is connected to the POI and the b-terminus is connected to the E3;

[0332] [ka] represents a single bond, a cis or trans double bond, alternatively a cis double bond;

[0333] E3 is [ka] Selected from;

[0334] The c-terminus of E3 is connected to L, and the d-terminus is C 0~3 connected to Q via an alkylene;

[0335] Q is [ka] Alternatively, Q is selected from [ka] and Q is selected from: [ka] is.

[0336] In more particular embodiments, the present disclosure provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein said compound is [ka] [ka] is selected from

[0337] During the ceremony,

[0338] [ka] represents a single or double bond;

[0339] [ka] represents a single bond, a cis or trans double bond, alternatively a cis double bond;

[0340] [ka] is non-existent or [ka] represents;

[0341] W is H, I, [ka] Alternatively, W is selected from H, I and [ka] Selected from;

[0342] Alternatively, the compound is [ka] is selected from.

[0343] The compounds of the present disclosure may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of the present disclosure may be in the form of individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, such as racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be separated from mixtures by methods known to those skilled in the art, such as chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or alternative isomers can be prepared by asymmetric synthesis.

[0344] The compounds of the present disclosure can also exist as tautomers.When compounds exist in different tautomeric forms, the compounds are not limited to any particular tautomer, and all tautomeric forms are intended to be covered.Tautomers are functional group isomers that are generated by the rapid movement of atoms between two positions in a molecule.Tautomers are special functional group isomers.A pair of tautomers can be converted into each other, but the relatively stable isomer is usually the predominant form.The most important examples are enol and keto tautomers.

[0345] Those skilled in the art will understand that organic compounds can form complexes with solvents in which they react or from which they are precipitated or crystallized. These complexes are known as "solvates." When the solvent is water, the complex is known as a "hydrate." The present disclosure encompasses all solvates of the compounds of the present disclosure.

[0346] The term "solvate" refers to a compound or its salt form that is associated with a solvent, typically through solvolysis. This physical association may involve hydrogen bonding. Typical solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein may be prepared, for example, in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include both stoichiometric and non-stoichiometric solvates. In some cases, solvates may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" includes both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0347] The term "hydrate" refers to a compound associated with water. Generally, the number of water molecules contained in a hydrate of a compound is a fixed ratio to the number of compound molecules in the hydrate. Thus, 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 multiple types of hydrates, such as monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, e.g., hemihydrate (R·0.5H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrate (R·2H2O) and hexahydrate (R·6H2O)).

[0348] The compounds of the present disclosure may be amorphous or crystalline (polymorphic). Furthermore, the compounds of the present disclosure may exist in one or more crystalline forms. Thus, the present disclosure includes within its scope all amorphous or crystalline forms of the compounds of the present disclosure. The term "polymorph" refers to a crystalline form of a compound (or its salt, hydrate, or solvate) in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms generally have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Depending on the recrystallization solvent, crystallization rate, storage temperature, and other factors, one crystalline form may predominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0349] The present disclosure also includes isotopically labeled compounds (isotopic variants) equivalent to those described in formula (I), but in which one or more atoms are replaced by atoms having atomic masses or mass numbers different from those common in nature. Examples of isotopes that can be introduced into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as: 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 CI. Compounds of the present disclosure, prodrugs thereof, and pharmaceutically acceptable salts of the compounds or prodrugs that contain the above isotopes and / or other isotopes of other atoms are all within the scope of the present disclosure. Certain isotopically labeled compounds of the present disclosure, for example, those containing radioactive isotopes (e.g., 3 H and 14 C) can be used to measure drug and / or substrate distribution within tissues. 3 H, tritium, and 14 The C isotope, carbon-14, is a further alternative because it is easy to prepare and detect. 2 Substitution of heavier isotopes, such as deuterium, H, may provide therapeutic benefits due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be an alternative in some cases. Isotopically labeled compounds of formula (A) of the present disclosure and prodrugs thereof may generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents in the procedures disclosed in the following schemes and / or examples and preparations.

[0350] Furthermore, prodrugs are also included within the context of the present disclosure. As used herein, the term "prodrug" refers to a compound that is converted in vivo into an active form that has medical effects, for example, by hydrolysis in blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, "Prodrugs as Novel Delivery Systems," ACS Symposium 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.

[0351] Pharmaceutical Compositions and Kits

[0352] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises an effective amount of a compound of the present disclosure. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the present disclosure.

[0353] Pharmaceutically acceptable excipients for use in the present disclosure refer to non-toxic carriers, auxiliary agents or vehicles that do not destroy the pharmacological activity of the compound that is formulated together.The pharmaceutically acceptable carriers, auxiliary agents or vehicles that can be used in the compositions of the present disclosure include but are not limited to ion exchangers, alumina, aluminum stearate, lecithin, serum protein (for example, human serum albumin), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, 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 materials, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene block polymer, polyethylene glycol and lanolin.

[0354] The present disclosure also includes kits (e.g., pharmaceutical packs). The provided kits may include a compound disclosed herein, another therapeutic agent, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packages or other suitable containers) containing the compound disclosed herein or another therapeutic agent. In some embodiments, the provided kits may also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending the compound disclosed herein and / or another therapeutic agent. In some embodiments, the compound disclosed herein provided in the first container and the other therapeutic agent provided in the second container are combined to form a unit dosage form.

[0355] Administration

[0356] The pharmaceutical compositions provided by the present disclosure can be administered by a variety of routes, including, but not limited to, oral, parenteral, inhalation, topical, rectal, nasal, oral, vaginal, implant, or other administration means. For example, parenteral administration as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intraventricular, intralesional, and intracranial injection or infusion techniques.

[0357] Generally, the compounds provided herein are administered in an effective amount. The amount of compound actually administered is typically determined by a physician in light of the relevant circumstances, including the condition to be treated, the selected route of administration, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0358] When used to prevent the disorders disclosed herein, provided herein is compound typically administered to the subject at risk of developing the condition at the dosage level described above, under the advice and supervision of a physician.The subject at risk of developing a particular condition generally includes the subject with a family history of the condition, or the subject identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0359] The pharmaceutical compositions provided herein can also be administered chronically ("chronic administration"). Chronic administration refers to administration of a compound or pharmaceutical composition thereof for an extended period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or can be continued indefinitely, such as for the remaining lifespan of the subject. In certain embodiments, chronic administration is intended to provide a constant level of the compound in the blood, for example, within a therapeutic window, for an extended period of time.

[0360] The pharmaceutical compositions of the present disclosure can also be delivered using various dosing methods. For example, in certain embodiments, the pharmaceutical composition can be given as a bolus, for example, to raise the concentration of the compound in the blood to an effective level. The placement of the bolus dose depends on the desired systemic level of the active ingredient throughout the body; for example, an intramuscular or subcutaneous bolus dose allows for a sustained release of the active ingredient, while a bolus dose delivered directly into a vein (e.g., via intravenous infusion) allows for a much faster delivery, which quickly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition can be administered as a continuous infusion, for example, by intravenous infusion, to provide for the maintenance of a steady-state concentration of the active ingredient in the subject's body. Furthermore, in still other embodiments, the pharmaceutical composition can be administered initially as a bolus dose, followed by continuous infusion.

[0361] Compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. However, more commonly, compositions are provided in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined amount of active ingredient calculated to produce a desired therapeutic effect, together with appropriate pharmaceutical excipients. Typical unit dosage forms include prefilled, premeasured ampoules or syringes of liquid compositions, or pills, tablets, capsules, and the like for solid compositions. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight, or alternatively about 1 to about 40% by weight), with the remainder being various vehicles or excipients and processing aids useful for forming the desired dosage form.

[0362] For oral dosing, 1 to 5, particularly 2 to 4, and typically 3 oral doses per day is a typical regimen. Using these dosing patterns, each dose provides from about 0.01 to about 20 mg / kg of a compound provided herein, with alternative doses each providing from about 0.1 to about 10 mg / kg, particularly from about 1 to about 5 mg / kg.

[0363] Transdermal doses are generally selected to provide blood levels similar to or lower than those achieved using injection doses, generally in amounts ranging from about 0.01 to about 20% by weight, alternatively from about 0.1 to about 20% by weight, alternatively from about 0.1 to about 10% by weight, and further alternatively from about 0.5 to about 15% by weight.

[0364] Injection dose levels range from about 0.1 mg / kg / hour to at least 10 mg / kg / hour, all for about 1 to about 120 hours, particularly 24 to 96 hours. Pretreatment boluses of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady-state levels. The maximum total dose is not expected to exceed about 2 g / day for a 40 kg to 80 kg human patient.

[0365] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors, etc. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; or a flavoring such as peppermint, methyl salicylate, or orange flavoring.

[0366] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline or other injectable excipients known in the art. As noted above, the active compound in such compositions is typically a minor component, often about 0.05-10% by weight, with the remainder being the injectable excipient, etc.

[0367] Transdermal compositions are typically formulated as topical ointments or creams containing active ingredient(s).When formulated as ointments, active ingredients are typically combined with either a paraffinic ointment base or a water-miscible ointment base.Alternatively, active ingredients can be formulated into creams, including, for example, oil-in-water cream bases.Such transdermal formulations are well known in the art, and generally contain additional ingredients to enhance the transdermal penetration of active ingredients or the stability of formulations.All such known transdermal formulations and ingredients are included within the scope provided herein.

[0368] The compounds provided herein can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type or of a solid matrix variety.

[0369] The above ingredients for orally administrable, injectable, or topically administrable compositions are merely representative. Other materials, processing techniques, and the like are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0370] The compounds of the present disclosure can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0371] The present disclosure also relates to pharmaceutically acceptable formulations of the disclosed compounds. 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, which consist of six, seven, and eight α-1,4-linked glucose units, respectively, optionally containing one or more substituents on the linked sugar moiety, including, but not limited to, methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, also known as Captisol. See, e.g., U.S. Patent No. 5,376,645. In certain embodiments, the formulation comprises hexapropyl-β-cyclodextrin (e.g., 10-50% in water).

[0372] [Example]

[0373] The following examples are intended to illustrate, but not limit, the scope of the disclosure.

[0374] [Table 1]

[0375] Example 1 [ka]

[0376] Synthetic Route [ka]

[0377] 1-1 synthesis [ka]

[0378] 1-a (10 g, 1.2 equiv.) was added to 100 mL of DMF, followed by the addition of 1-b (6.87 g, 1 equiv.), KI (7.5 g, 1.2 equiv.), and NaHCO3 (6.5 g, 2 equiv.) under nitrogen protection. The mixture was stirred at room temperature for 30 minutes, heated to 70 °C, and stirred overnight. LCMS monitoring showed that no starting material remained. The reaction was quenched with saturated aqueous sodium chloride solution. The mixture was washed with saturated brine, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reverse-phase column (0.1% FA / ACN in water = 50%) to give 3.2 g of product 1-1. MS: = 344.4.

[0379] Synthesis of 1 and 2 [ka]

[0380] 1-1 (3.0 g, 1.0 equiv.) was added to 30 mL of DCM. SEMCl (2.1 g, 1.1 equiv.) was added, followed by DBU (2.2 g, 1.2 equiv.) at 0° C. The mixture was stirred at room temperature for 16 hours. LCMS monitoring showed that no starting material remained. The reaction was quenched with saturated aqueous sodium chloride solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reverse phase column (0.1% FA / ACN in water=50%) to give 3.4 g of product 1-2, MS:=474.63

[0381] Synthesis of 1-3 [ka]

[0382] 1-2 (3.0 g, 1.0 equiv.) was added to 30 mL of DCM, followed by the addition of TFA (6 mL). The mixture was stirred at room temperature for 3 hours. LCMS monitoring showed that no starting material remained. The reaction was directly concentrated. The residue was purified by reverse phase column (0.1% FA / ACN in water = 50%) to give 2 g of product 1-3, MS: = 374.4.

[0383] Synthesis of 1-4 [ka]

[0384] 1-c (20 g, 1.0 equiv.) was added to 30 mL of ACN, followed by the addition of 1-d (27 g, 1.2 equiv.) and K2CO3 (21.2 g, 1.2 equiv.). The mixture was stirred at 70 °C for 6 h. LCMS monitoring showed that no starting material remained. The reaction was quenched with saturated aqueous sodium chloride solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by normal phase column chromatography to give 20 g of product 1-4, MS: = 240.7.

[0385] Synthesis of 1-5 [ka]

[0386] 1-4 (3 g, 2.0 equiv.) and 1-e (1.1 g, 1 equiv.) were added to 30 mL of THF, and potassium tert-butoxide (1.35 g, 2 equiv.) was added. The mixture was stirred at 0 °C for 6 h. LCMS monitoring showed that no starting material remained. The reaction was quenched with saturated aqueous sodium chloride solution and adjusted to pH ~5 with hydrochloric acid. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by normal phase column chromatography to give 1.4 g of product 1-5, MS: 532.8.

[0387] Synthesis of 1-6 [ka]

[0388] 1-5 (1.5 g, 1.0 equiv.) was added to 15 mL of DMSO, and a catalytic amount of iodine was added. The mixture was stirred at 110° C. for 6 hours. LCMS monitoring showed that no starting material remained. The reaction was quenched with saturated aqueous sodium chloride solution, and then sodium thiosulfate was added. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by normal phase column to give 900 mg of product 1-6, MS: 532.7.

[0389] Synthesis of 1-7 [ka]

[0390] Starting compounds 1-3 (400 mg, 1.0 eq) and 1-6 (548 mg, 1.0 eq) were added to 20 mL of DCM. Then, triethylamine (324 mg, 3 eq) was added under ice bath conditions. The reaction was stirred for 5 minutes, and then malonyl chloride (226 mg, 1.5 eq) was slowly added to the above system. The reaction was stirred under ice bath conditions for another 0.5 hours. LC-MS monitoring showed that no raw material remained. The residue was directly purified by preparative TLC (DCM:EA=25:75) to give 200 mg of product 1-7 (yield: 20%), MS: 955.

[0391] Synthesis of Example 1 [ka]

[0392] Compound 1-1 (400 mg, 1.0 equivalent) was added to 50 mL of DCE, followed by the addition of Grubbs (II) (107 mg, 0.3 equivalent) at room temperature. The mixture was heated to 80 °C, and the reaction was stirred for 1 hour. LC-MS monitoring showed that no starting material remained. The residue was directly purified by preparative TLC (HO:CHCN = 20:80) to give 114 mg of Example 1 (yield: 29%).

[0393] 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 3H), 7.77 (s, 2H), 7.74 (s, 1H), 7.26 (s, 1H), 6.71-6.60 (m, 4H), 5.82 (m, 1H), 5.32 (s, 2H), 5.21 (d, 1H), 4.35 (s, 1H), 4.02 (s, 1H), 3.78 (d, 5H), 2.06-1.95 (m, 13H).

[0394] MS: 927.1.

[0395] Example 2 [ka]

[0396] Synthetic Route [ka]

[0397] Synthesis of 2-1 [ka]

[0398] 2-a (10 g, 1.2 equiv.) was added to 100 mL of DMF. 2-b (15 g, 1 equiv.), KI (14 g, 1.2 equiv.), and NaHCO3 (9.4 g, 2 equiv.) were added sequentially under nitrogen protection. The reaction was stirred at room temperature for 30 minutes, heated to 90 °C, and stirred overnight. LCMS monitoring showed that no starting material remained. The reaction was quenched with saturated aqueous sodium chloride solution. The mixture was washed with saturated brine, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reverse-phase column (0.1% FA / ACN in water = 50%) to give 10 g of product 2-1 (yield: 51.2%).

[0399] MS:359.

[0400] Synthesis of 2-2 [ka]

[0401] 2-1 (9.0 g, 1.0 equiv.) was added to 100 mL of DMF, followed by the addition of 2-c (7.78 g, 1.1 equiv.). DBU (4.59 g, 1.2 equiv.) was added at 0° C. The reaction was stirred at room temperature for 16 hours. LCMS monitoring showed that no starting material remained. The reaction was quenched with saturated aqueous sodium chloride solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reverse-phase column (0.1% FA / ACN in water=50%) to give 4 g of product 2-2 (yield: 23.7%), MS: 469.

[0402] Synthesis of 2-3 [ka]

[0403] 1-6 (2 g, 1.1 equiv.) was added to 250 ml of THF. Under nitrogen protection, TEA (0.592 g, 1.5 equiv.) was added at 0 °C, followed by dropwise addition of MsCl (816 mg, 1.2 equiv.) at 0 °C. The mixture was allowed to warm to room temperature, and then the reaction was stirred overnight. LCMS monitoring showed that no starting material remained. For quenching, the reaction solution was slowly added dropwise to saturated aqueous NaHCO3. After quenching, the pH of the system was 6-7. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to dryness by rotary evaporation. The obtained product was used directly in the next step without further treatment. MS: 590.8.

[0404] Synthesis of 2-4 [ka]

[0405] 2-3 (2 g, 1.0 equiv.) was added to 200 mL of THF, and LiBr (10 g, 0.0 equiv.) was added under nitrogen protection at 110 °C. The reaction was stirred at room temperature overnight. LCMS monitoring showed that no starting material remained. The reaction was quenched with saturated aqueous sodium chloride solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by normal phase column (DCM:EA=4:1) to give 1.7 g of product 2-4 (yield: 87.6%), MS: 575.6.

[0406] Synthesis of 2-5 [ka]

[0407] 2-2 (0.4 g, 1.0 equiv.) was added to 20 mL of DMF. NaHCO3 (150 mg, 2.2 equiv.) was added under nitrogen protection. The mixture was stirred at 30 °C for 20 minutes, and then 2-4 (587 mg, 1.2 equiv.) was added. The reaction was stirred at 80 °C overnight. LCMS monitoring showed that no starting material remained. The reaction was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reverse-phase column (0.1% FA / ACN in water = 40%) to give 200 mg of product 2-5 (yield: 24.3%), MS: 963.1.

[0408] Synthesis of Example 2 [ka]

[0409] 2-5 (1.15 g, 1.0 equiv.) was added to 140 mL of DCE, followed by the addition of Grubbs (II) (304 mg, 0.3 equiv.) at room temperature. TLC (DCM:MeOH = 3:1, R f The reaction was monitored by HPLC (pH 7.0) and stopped at the point where it showed the most significant product formation. The mixture was directly purified by normal phase column (DCM:MeOH=4:1) to give 300 mg of crude product, which was further purified by high pressure liquid chromatography to give 60 mg of Example 2 (yield: 5.4%).

[0410] 1H NMR (400 MHz, DMSO‐d6) δ 8.37 (s, 1H), 7.65 (s, 2H), 7.57 (s, 1H), 7.22 (s, 2H), 7.14 (s, 1H), 7.04 (s, 1H), 6.82 (s, 1H), 6.57 (s, 1H), 5.80 (s, 2H), 5.32 (s, 2H), 4.98 (s, 1H), 4.66 (s, 2H), 4.24 (s, 4H), 4.03 (s, 4H), 3.75 (s, 4H), 2.88 (s, 1H), 2.59 (s, 3H), 1.99 (s, 2H), 1.46 (s, 1H), 1.24 (s, 8H), 0.85 (s, 2H).

[0411] MS: 935.

[0412] Example 3 [ka]

[0413] Synthetic Route [ka]

[0414] Synthesis of 3-1 [ka]

[0415] 1-3 (314 mg, 1.0 equiv.) and 1-6 (430 mg, 1.0 equiv.) were added to 17 mL of DCM, followed by the addition of triethylamine (254 mg, 3 equiv.) under ice bath conditions. The reaction was stirred for 5 minutes, and then oxalyl chloride (128 mg, 1.2 equiv.) was slowly added to the above system. The reaction was stirred under ice bath conditions for another 0.5 hours. LC-MS monitoring showed that no starting material remained. The mixture was directly purified by preparative TLC (DCM:EA=95:5) to give 210 mg of product 3-1 (yield: 27%). MS: 940.1.

[0416] Synthesis of Example 3 [ka]

[0417] 3-1 (150 mg, 1.0 equiv.) was added to 15 mL of DCE. Then, Grubbs (II) (40.5 mg, 0.3 equiv.) was added at room temperature. The mixture was heated to 80 °C, and the reaction was stirred for 1 hour. LC-MS monitoring showed that no starting material remained. The mixture was directly purified by preparative TLC (HO:CHCN=97:3) to give 30 mg of product Example 3 (yield: 21%).

[0418] 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.79-7.66 (m, 1H), 7.65-7.54 (m, 2H), 6.67 (d, 2H), 5.85 (s, 1H), 5.36 (s, 3H), 4.35 (s, 1H), 3.83-3.64 (m, 1H), 3.49-3.34 (m, 3H), 2.16-1.95 (m, 2H), 1.35 (s, 1H), 1.23 (s, 15H).

[0419] MS: 913.1.

[0420] Example 4 [ka]

[0421] Synthetic Route [ka]

[0422] Synthesis of 4-1 [ka]

[0423] 4-a (10 g, 1.2 equiv.) was added to 100 mL of DMF. Then, 4-b (6.84 g, 1 equiv.), KI (7.5 g, 1.2 equiv.), and NaHCO3 (6.5 g, 2 equiv.) were added sequentially under nitrogen protection. The reaction was stirred at room temperature for 30 minutes, then heated to 70 °C and stirred overnight. LCMS monitoring showed that no starting material remained. The reaction was quenched with saturated aqueous sodium chloride solution. The mixture was washed with saturated brine, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reverse-phase column (0.1% FA / ACN in water = 50%) to give 3.2 g of product 4-1, MS: 342.4.

[0424] Synthesis of 4-2 [ka]

[0425] 4-1 (3.0 g, 1.0 equiv.) was added to 30 mL of DCM, followed by the addition of SEMCl (2.1 g, 1.1 equiv.). DBU (2.2 g, 1.2 equiv.) was then added at 0 °C. The reaction was stirred at room temperature for 16 h. LCMS monitoring showed that no starting material remained. The reaction was quenched with saturated aqueous sodium chloride solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reverse-phase column (0.1% FA / ACN in water = 50%) to give 3.4 g of product 4-2, MS: 472.7.

[0426] Synthesis of 4-3 [ka]

[0427] 4-2 (3.0 g, 1.0 equiv.) was added to 30 mL of DCM, followed by TFA (6 mL). The reaction was stirred at room temperature for 3 hours. LCMS monitoring showed that no starting material remained. The reaction was directly concentrated. The residue was purified by reverse phase column (0.1% FA / ACN in water = 50%) to give 2 g of product 4-3, MS: 372.4.

[0428] Synthesis of 4-4 [ka]

[0429] 4-c (20 g, 1.0 equiv.) was added to 30 mL of CAN. Then, 4-d (27 g, 1.2 equiv.) and K2CO3 (21.2 g, 1.2 equiv.) were added, and the reaction was stirred at 70 °C for 6 h. LCMS monitoring showed that no starting material remained. The reaction was quenched with saturated aqueous sodium chloride solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by normal phase column to give 20 g of product 4-4, MS: 238.7.

[0430] Synthesis of 4-5 [ka]

[0431] 4-4 (3 g, 2.0 equiv.) and 4-e (1 g, 1 equiv.) were added to 30 mL of THF. Potassium tert-butoxide (1.35 g, 2 equiv.) was then added, and the reaction was stirred at 0 °C for 6 h. LCMS monitoring showed no remaining starting material. The reaction was quenched with saturated aqueous sodium chloride solution and adjusted to pH ~5 with hydrochloric acid. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by normal phase column chromatography to give 1.4 g of product 4-5, MS: 404.9.

[0432] Synthesis of 4-6 [ka]

[0433] 4-5 (1.5 g, 1.0 equiv.) was added to 15 mL of DMSO. A catalytic amount of iodine was then added, and the reaction was stirred at 110° C. for 6 hours. LCMS monitoring showed that no starting material remained. The reaction was quenched with saturated aqueous sodium chloride, and then sodium thiosulfate was added. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by normal phase column to give 900 mg of product 4-6, MS: 384.9.

[0434] Synthesis of 4-7 [ka]

[0435] 4-6 (300 mg, 1.0 equiv.) and 4-3 (290 mg, 1.0 equiv.) were added to 15 mL of DCM. Malonyl chloride (100 mg, 1 equiv.) was then added, and the reaction was stirred at 0 °C for 2 h. LCMS monitoring showed that no starting material remained. The reaction was directly concentrated. The residue was purified by normal phase column chromatography to give 150 mg of product 4-7, MS: 825.3.

[0436] Synthesis of Example 4 [ka]

[0437] 4-7 (166 mg, 1.0 equiv.) was added to 17 mL of DCE. Grubbs (II) (51.3 mg, 0.3 equiv.) was then added at room temperature. The mixture was heated to 70° C., and the reaction was stirred for 30 minutes. TLC (DCM:MeOH=30:1, R f The reaction was monitored by HPLC (pH 7.0). The residue was purified by preparative TLC to give 37 mg of Example 4 (yield: 23.1%).

[0438] 1H NMR (400 MHz, DMSO‐d6) δ 8.03 (d, J = 8.1 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.66 (s, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.21 (d, J = 2.5 Hz, 1H), 7.09 (s, 1H), 7.05 (s, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.60 (s, 1H), 5.80 (d, J = 9.7 Hz, 1H), 5.60 (d, J = 9.6 Hz, 1H), 5.42 (s, 2H), 5.33 (d, J = 6.9 Hz, 2H), 5.23 (d, J = 5.2 Hz, 1H), 4.29 (d, J = 17.0 Hz, 1H), 4.17-4.06 (m, 3H), 3.98 (d, J = 6.2 Hz, 2H), 3.70 (d, J = 11.5 Hz, 2H), 3.05 (s, 1H), 2.81 (s, 1H), 2.07-1.97 (m, 5H), 1.70 (s, 4H), 1.47 (s, 5H), 1.23 (s, 7H), 0.85 (d, J = 6.9 Hz, 1H).

[0439] MS:797.2.

[0440] (Example 5)

change

[0441] synthetic road

change

[0442] 5-1 synthesis

change

[0443] 1-3 (374 mg, 1.0 equiv.) and 1-6 (512 mg, 1.0 equiv.) were added to 20 mL of DCM. Then, triethylamine (303 mg, 3 equiv.) was added under ice bath conditions. The reaction was stirred for 5 minutes, and then isophthaloyl chloride (244 mg, 1.2 equiv.) was slowly added to the above system. The reaction was stirred under ice bath conditions for another 0.5 hours. LC-MS monitoring showed that no starting material remained. The mixture was directly purified by preparative TLC (DCM:EA=95:5) to give 217 mg of product 5-1 (yield: 21%). MS: 1017.1.

[0444] Synthesis of Example 5 [ka]

[0445] 5-1 (217 mg, 1.0 equiv.) was added to 23 mL of DCE. Then, Grubbs (II) (54.3 mg, 0.3 equiv.) was added at room temperature. The mixture was heated to 80° C., and the reaction was stirred for 1 hour. LC-MS monitoring showed that no starting material remained. The mixture was directly purified by preparative TLC to give 42 mg of product Example 5 (yield: 20%).

[0446] 1H NMR (400 MHz, DMSO-d6) δ 8.24 (m, 1H), 8.12 (m, 1H), 7.82-7.66 (m, 2H), 7.69-7.52 (m, 1H), 7.21 (d, J = 2.5 Hz, 1H), 7.11-6.95 (m, 2H), 6.62 (d, 1H), 6.03-5.84 (m, 1H), 5.59 (d, 1H), 5.43 (s, 1H), 5.38-5.21 (m, 1H), 4.35-4.12 (m, 1H), 4.09 (m, 2H), 4.06-3.88 (m, 1H), 2.08-1.97 (m, 6H), 1.71 (d, 1H), 1.47 (d, 1H), 1.34 (d, 2H), 1.28 (s, 3H), 1.25 (s, 10H), 1.01-0.77 (m, 3H).

[0447] MS: 989.3.

[0448] Example 6 [ka]

[0449] Synthetic Route [ka]

[0450] Synthesis of 6-1 [ka]

[0451] 4-6 (300 mg, 1.0 equiv.) and 4-3 (290 mg, 1.0 equiv.) were added to 15 mL of DCM. 6-a (157.8 mg, 1 equiv.) was then added, and the reaction was stirred at 0 °C for 2 h. LCMS monitoring showed no starting material remained. The reaction was directly concentrated to give 70 mg of product 6-1, MS: 887.4.

[0452] Synthesis of Example 6 [ka]

[0453] 6-1 (70 mg, 1.0 equiv.) was added to 17 mL of DCE. Then, Grubbs (II) (30 mg, 0.3 equiv.) was added at room temperature. The mixture was heated to 70° C., and the reaction was stirred for 30 minutes. The reaction was monitored by TLC. The mixture was directly purified by preparative TLC to give 11 mg of product Example 6 (yield: 23.1%).

[0454] 1 H NMR (400 MHz, DMSO‐d6) δ 8.51 (s, 1H), 8.35 (d, J = 7.8 Hz, 1H), 8.24 (d, J = 7.8 Hz, 1H), 8.12 (dd, J = 8.2, 4.8 Hz, 1H), 7.81-7.74 (m, 2H), 7.73 (s, 1H), 7.65 (d, J = 8.2 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.21 (d, J = 2.5 Hz, 1H), 7.06 (dd, J = 8.8, 2.5 Hz, 2H), 7.00 (d, J = 8.5 Hz, 1H), 6.62 (d, J = 5.0 Hz, 1H), 5.98 (d, J = 9.6 Hz, 1H), 5.92-5.86 (m, 1H).5.42 (s, 2H), 5.33 (d, J = 6.9 Hz, 2H), 5.23 (d, J = 5.2 Hz, 1H), 4.29 (d, J = 17.0 Hz, 1H), 4.17-4.06 (m, 3H), 3.98 (d, J = 6.2 Hz, 2H), 3.70 (d, J = 11.5 Hz, 2H), 3.05 (s, 1H), 2.81 (s, 1H), 2.07-1.97 (m, 5H), 1.70 (s, 4H), 1.47 (s, 5H), 1.23 (s, 7H), 0.85 (d, J = 6.9 Hz, 1H)

[0455] MS: 859.3.

[0456] Example 7 [ka]

[0457] Synthetic Route [ka]

[0458] Synthesis of 7-1 [ka]

[0459] 1-3 (1.0 g, 1.0 eq) and 7-a (1.03 g, 1.0 eq) were added to 50 mL of DCM. Then, triethylamine (810.1 mg, 3 eq) was added under ice bath conditions. The reaction was stirred for 5 minutes, and then malonyl chloride (561.3 mg, 1.5 eq) was slowly added dropwise to the above system. The reaction was stirred under ice bath conditions for another 0.5 hours. LC-MS monitoring showed that no starting material remained. The mixture was directly purified by preparative TLC to give 300 mg of product; MS: 829.

[0460] Synthesis of Example 7 [ka]

[0461] 7-1 (300 mg, 1.0 equiv.) was added to 50 mL of DCE. Then, Grubbs (II) (92.8 mg, 0.3 equiv.) was added at room temperature. The mixture was heated to 80° C., and the reaction was stirred for 60 minutes. The reaction was monitored by TLC. The mixture was purified by preparative TLC to give 85 mg of product Example 7 (yield: 26.1%).

[0462] 1H NMR (400 MHz, DMSO‐d6) δ 8.06‐8.02 (m, 1H), 7.75 (d, J = 13.0 Hz, 4H), 7.3‐6.95 (m, 4H), 6.70‐6.61 (m, 1H), 5.82 (d, J = 8.3 Hz, 2H), 5.37-5.10 (m, 5H), 4.52-3.89 (m, 8H), 3.78 (d, J = 26.3 Hz, 6H), 3.43 (d, J = 27.5 Hz, 2H), 3.08 (s, 1H), 2.67 (s, 2H), 2.33 (s, 1H)

[0463] MS: 801.2.

[0464] Example 8 [ka]

[0465] Synthesis of 8-1 [ka]

[0466] 5 g of 7-a was added to 100 ml of THF. 23.9 g of N-Fmoc-glutamic acid, 5 g of PPh3, and 4.11 g of DEAD were added under stirring. The reaction was stirred at room temperature under N2 protection until 8-1 was completely consumed. The reaction solution was then directly evaporated to dryness by rotary evaporation, and the residue was purified by column chromatography to give 6 g of product 8-2. MS: [M+H] 738.2.

[0467] Synthesis of 8-2 [ka]

[0468] 6 g of 8-1 was added to 100 ml of THF. Under N2 protection at 0 °C with stirring, 3.65 g of 1-3, 3.2 g of PPh3, and 2.5 g of DEAD were added. The reaction was stirred at room temperature until 8-1 was completely consumed. The reaction solution was directly evaporated to dryness by rotary evaporation, and the residue was purified by column chromatography to give 4.5 g of product, which was used directly in the next step reaction. MS: [M+H] 1094.3

[0469] Synthesis of 8-3 [ka]

[0470] 600 mg of 8-2 was added to 100 ml of DCE. Grubbs' catalyst was then added under stirring, and the mixture was stirred until 8-2 was completely consumed. The reaction solution was evaporated to dryness, and the residue was purified by column chromatography to give 300 mg of 8-3. MS: [M+H] 1066.3.

[0471] Synthesis of Example 8 [ka]

[0472] 282 mg of 8-3 was added to 90 ml of THF. Then, 11 ml of TEA was added under stirring. After the addition, the mixture was stirred at room temperature until 8-3 was completely consumed. The mixture was separated by column chromatography to obtain 50 mg of product. MS: [M+H] 844.

[0473] 1H NMR (400 MHz, DMSO‐d6) δ 8.54 (s, 2H), 8.05 (d, J = 8.0 Hz, 1H), 7.78-7.70 (m, 2H), 7.56 (dt, J = 18.6, 9.7 Hz, 3H), 7.27 (s, 1H), 7.11 (d, J = 6.6 Hz, 2H), 7.03 (s, 1H), 6.61 (s, 1H), 5.78 (s, 2H), 5.66 (d, J = 5.7 Hz, 1H), 5.45-5.30 (m, 2H), 5.22 (s, 2H), 4.32 (s, 1H), 4.19 (dd, J = 32.2, 14.7 Hz, 8H), 4.02 (s, 4H), 3.72 (s, 4H), 2.57 (s, 2H), 2.08 (s, 4H).

[0474] (Example 9)

change

[0475] synthetic road

change

[0476] 9-1 synthesis

change

[0477] 200 mg of 7-a was added to 10 ml of DMF and then cooled to 0 °C in an ice-water bath. 31 mg of NaH was then added at 0 °C. After the addition was completed, the mixture was stirred, and then the mixture was stirred for 0.5 hours under N2 protection at a controlled temperature. 4-Methylmorpholine-2,6-dione dissolved in DMF was added dropwise to the reaction solution. The mixture was stirred overnight until the raw material disappeared and the product was produced. The mixture was quenched with saturated NH4Cl, and the reaction solution was concentrated by evaporation. The residue was separated by column chromatography to obtain 210 mg of the target product 9-1: [M+H] 516.

[0478] Synthesis of 9-2 [ka]

[0479] 100 mg of 9-1, 80 mg of 1-3, and 76.2 mg of triphenylphosphine were dissolved in 10 ml of THF, and then 64.3 mg of DIAD was added in an ice-water bath. After the addition was completed, the mixture was stirred and then stirred at room temperature under N2 protection for 16 hours. The system was cooled to 0 °C and quenched with pure water. The reaction solution was concentrated by evaporation, and the residue was separated by column chromatography to obtain 110 mg of the target product 9-2: [M+H] 872.

[0480] Synthesis of Example 9 [ka]

[0481] 100 mg of 9-2 was dissolved in 100 ml of DCE, and then Grubbs (II) was added at room temperature. The mixture was heated to 90 ° C and stirred under N2 protection for 0.5 hours. The reaction solution was concentrated by evaporation. The residue was dissolved and then purified by column chromatography to obtain 6.4 mg of the target product Example 9: [M + H] 844.

[0482] 1H NMR (400 MHz, DMSO-) d6 ) δ 8.03 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 8.7 Hz, 1H), 7.65-7.56 (m, 2H), 7.48 (d, J = 7.8 Hz, 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.15‐7.08 (m, 2H), 7.03 (dd, J = 8.4, 2.2 Hz, 1H), 6.61 (s, 1H), 5.77 (s, 2H), 5.69 (d, J = 9.6 Hz, 1H), 5.60 (d, J = 9.6 Hz, 1H), 5.28 (s, 2H), 5.23 (dd, J = 13.6, 5.1 Hz, 1H), 4.34 (d, J = 17.2 Hz, 1H), 4.26‐4.10 (m, 5H), 4.01 (d, J = 3.0 Hz, 3H), 3.72 (d, J = 4.1 Hz, 4H), 3.58 (s, 2H), 3.47 (s, 2H), 3.29 (s, 1H), 3.05 (d, J = 13.6 Hz, 1H), 2.81 (d, J = 17.1 Hz, 1H), 2.40 (s, 3H), 2.35‐2.28 (m, 1H), 2.15‐1.95 (m, 1H).

[0483] (Example 10)

change

[0484] synthetic road

change

[0485] Synthesis of Example 10

[0486] 350 mg of Example 9 was added to 30 ml of THF. Then, Lindlar's reagent (10 mg) and quinoline (10 mg, 0.2 equivalents) were added, and the reaction was stirred at room temperature for 0.5 hours. Then, the reaction was stirred at room temperature under an H atmosphere for 6 hours. The reaction solution was concentrated by evaporation, and the residue was separated by column chromatography to give 85 mg of the target product Example 10: [M+H] 846.

[0487] 1 H NMR (400 MHz, DMSO‐d6) δ 8.03 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.63 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.48 (dd, J = 8.2, 1.6 Hz, 1H), 7.27 (d, J = 2.5 Hz, 1H), 7.11 (dt, J = 5.8, 2.8 Hz, 2H), 7.02 (dd, J = 8.5, 2.2 Hz, 1H), 6.61 (s, 1H), 5.69 (d, J = 9.6 Hz, 1H), 5.60 (d, J = 9.6 Hz, 1H), 5.28 (s, 2H), 5.22 (dd, J = 13.4, 5.1 Hz, 1H), 4.34 (d, J = 17.0 Hz, 1H), 4.26‐4.11 (m, 5H), 3.73‐3.64 (m, 4H), 3.57 (s, 2H), 3.46 (d, J = 4.2 Hz, 6H), 3.29 (s, 1H), 3.13‐2.99 (m, 1H), 2.81 (d, J = 17.8 Hz, 1H), 2.40 (s, 3H), 2.05‐1.97 (m, 1H), 1.55 (d, J = 6.1 Hz, 4H).

[0488] Activity experiment

[0489] 1. The biological activity of the compounds was determined by Western blotting using the following method:

[0490] Reagents: Complete 1640 medium was purchased from Gibco. Fetal bovine serum was purchased from ThermoFisher. Trypsin was produced by ThermoFisher. SHP-2 antibody was produced by CST.

[0491] Cell lines: The SUM159 triple-negative breast cancer cell line was established by Rovera.

[0492] Assay procedure: Cells growing in logarithmic phase were harvested and suspended in 1640 medium containing 10% fetal bovine serum, then gently pipetted to form a single-cell suspension. Viable cells were counted under a microscope. 9 mL of the cell suspension was seeded and 2 × 10 cells were cultured in a 10 cm culture dish. 5 The cells were cultured at a final concentration of 1000 cells / mL. After pre-incubation at 37°C and 5% CO2 for 24 hours, DMSO solutions of the disclosed compounds at different concentrations were added (the final DMSO concentration was 0.5% or less), and the same volume of DMSO alone was added to the negative control group. After further incubation for 24 hours, all cells were harvested and washed with PBS. The cells were lysed with RIPA lysis buffer, and the lysate was collected in a 1.7 mL centrifuge tube. After heating in a metal bath at 95°C for 10 minutes, the proteins were completely denatured. After loading the samples onto a gel for Western blotting, electrophoresis was performed at a constant voltage of 100 V until the bromophenol blue band reached the endpoint. Proteins were transferred onto a cellulose acetate membrane using the wet transfer method at a constant current of 300-500 mA for 45 minutes, and then blocked with 5% BSA for 1-2 hours at room temperature. The proteins were then incubated with primary antibodies diluted 1:500-1:8000 for 2 hours at room temperature, followed by three washes. The proteins were then incubated with secondary antibodies at room temperature for 1 hour. Protein detection was performed using an ultra-sensitive ECL luminescence solution such as Enlight, and the signal was captured using an automatic X-ray film developer. For test results, see Example 1 for in vitro Western blot experiments and Example 3 for in vitro Western blot experiments.

[0493] The above results indicate that the DCs of Examples 1 and 3 for SHP2 degradation in vitro 50 are 210 nM and 37 nM, respectively. The compounds of the present disclosure have good in vitro anti-solid tumor activity and anti-hematologic tumor activity, and have low toxicity to normal cells.

[0494] 2. The biological activity of the compounds was determined by the CCK8 method using the following method:

[0495] Reagents: Complete RPMI 1640 medium was purchased from Gibco. Fetal bovine serum was purchased from ThermoFisher. Trypsin was produced by ThermoFisher. SHP-2 antibody was produced by CST. CCK8 was produced by Abcam.

[0496] Cell lines: The SUM159 triple-negative breast cancer cell line was established by Rovera.

[0497] Assay procedure: Cells growing in logarithmic phase were harvested and suspended in RPMI 1640 medium containing 10% fetal bovine serum, then gently pipetted to form a single-cell suspension. Viable cells were counted under a microscope. 3-6 x 10 cells were placed in a 96-well plate. 3 Cells were seeded at a density of 1000 cells / well and cultured for 24 hours in an incubator. Test compounds were diluted 1:1 and then cell culture supernatant was added. The cells were cultured for an additional 72 hours, after which 10 μL of CCK8 detection solution was added to each well. After 1 to 4 hours of incubation, absorbance was measured using a microplate reader.

[0498] 3.PAMPA Experiment

[0499] Reagents: lecithin, n-dodecane, HEPES, dimethyl sulfoxide (DMSO), acetonitrile

[0500] Equipment and devices: Multiscreen 96-well plate (top: Merck Millipore), Multiscreen 96-well plate (bottom: Merck Millipore), electronic analytical balance, constant temperature incubator, high-performance liquid chromatography-mass spectrometry (LC-MS)

[0501] Method for working: Preparation of PAMPA artificial membrane: Approximately 18 mg of lecithin was accurately weighed and placed in a 1.5 mL EP tube. 1 mL of n-dodecane was added. The mixture was dissolved by ultrasound and then thoroughly mixed to obtain a 1.8% lecithin membrane.

[0502] The top layer of the PAMPA model was the plate lid, the middle layer was a 96-well filter plate (donor plate), and the bottom layer was the acceptor plate. 5 μL of the above 1.8% lecithin membrane was added to the filter membrane of the donor plate, and then 150 μL of the drug test solution (10 μM) was added. 300 μL of HEPES solution was added to each well of the acceptor plate (completed within 10 minutes). The donor plate was slowly placed on the acceptor plate and incubated at 37 °C for 16 hours.

[0503] LC-MS detection: 100 μL of the positive control and test compound were weighed out, and 100 μL of acetonitrile-DMSO solution [acetonitrile-DMSO (4:1)] was added to each. The mixture was mixed well and detected by LC-MS at 0 and 16 hours. The corresponding molecular ion peaks were extracted and the peak areas were obtained. After incubating the PAMPA model at 37°C for 16 hours, 100 μL of the test solution in the donor plate and acceptor plate were weighed out, and 100 μL of acetonitrile-DMSO solution [acetonitrile-DMSO (4:1)] was added to each. The mixture was mixed well and detected by LC-MS. The corresponding molecular ion peaks were extracted, the peak areas were obtained, and the concentrations were calculated.

[0504] Calculation formula:

[0505]

number

[0506] The activities of representative compounds of the present disclosure are shown in Table 1.

[0507] [Table 2]

Claims

1. Compounds represented by formula (I) or pharmaceutically acceptable salts, stereoisomers, tautomers, cis-trans isomers, solvates, hydrates, polymorphs, prodrugs or isotopic variants thereof, and mixtures thereof: 【Chemistry 1】 (In the formula, The POI is 【Chemistry 2】 and 【Transformation 3】 represents a single or double bond, alternatively a double bond; Each R Ｐ are independently H, D, halogen, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl and C ２～６ alkynyl; s is selected from 1, 2 and 3; X Ｐ is N and CR Ｐ Selected from: W is H, D, halogen, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ６～１０ selected from aryl and 5-10 membered heteroaryl; The W may be one, two or three R Ｗ optionally substituted with; R Ｗ is H, D, -C(O)R ａ , —C(O)NR ｂ R ｃ , -C(O)OR ａ , -OC(O)R ａ , -NR ｂ C(O)R ａ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl and C ２～６ alkynyl; The a-terminus of the POI is C ０～３ is connected to Q via alkylene, and the b end is connected to L; L is, 【Chemistry 4】 and 【Transformation 5】 represents a single bond, a cis or trans double bond, alternatively a cis double bond; Each X Ｌ are independently a chemical bond, —O—, C １～６ Alkylene, C ２～６ Alkenylene, C ２～６ Alkynylene, C ３～１０ Cycloalkylene, 5- to 10-membered heterocyclylene, C ６～１０ arylene and 5- to 10-membered heteroarylene; Ｌ is optionally deuterated, up to fully deuterated; each m is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each p is independently selected from 0, 1, 2, 3, 4, and 5; each q is independently selected from 1, 2, 3, 4, and 5; the b-terminus of L is connected to a POI and the c-terminus is connected to an E3, or the c-terminus of L is connected to a POI and the b-terminus is connected to an E3; E3 is, 【Transformation 6】 and R Ｅ１ , R Ｅ２ , R Ｅ３ or R Ｅ４ is independently selected from H and D; R Ｅ１ and R Ｅ２ , R Ｅ３ and R Ｅ４ at least one pair of represents =O, =S or =N-OH; The c-terminus of E3 is connected to L, and the d-terminus is C ０～３ connected to Q via an alkylene; Q is, 【Transformation 7】 and L １ and L ２ is independently selected from NH and O; X Ｑ is -P(O)(Y Ｑ -R Ｑ )-, -S(O)- and -C(O)-X Ｑ１ -C(O)-; Y Ｑ is selected from NH and O; X Ｑ１ is a chemical bond, C １～６ Alkylene, C ２～６ Alkenylene, C ２～６ Alkynylene, —C １～６ Alkylene -O-C １～６ Alkylene, -C １～６ Alkylene -NR ｂ -C １～６ Alkylene, C ３～１０ Cycloalkylene, 5- to 10-membered heterocyclylene, C ６～１０ arylene and 5- to 10-membered heteroarylene, Ｑ１ is optionally substituted with 1, 2, 3, 4, or 5 independently selected R#; R Ｑ is H, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～１０ Cycloalkyl, 5- to 10-membered heterocyclyl, C ６～１０ selected from aryl and 5-10 membered heteroaryl; R ａ , R ｂ and R ｃ are independently H, C １～６ Alkyl and C １～６ haloalkyl; R# is H, halogen, OH, NH ２ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl and C ２～６ alkynyl).

2. The POI is 【Transformation 8】 and 【Chemistry 9】 represents a single bond or a double bond, alternatively a double bond; Each R Ｐ are independently H, D, halogen, C １～４ Alkyl and C １～４ haloalkyl; s is selected from 1, 2 and 3; X Ｐ However, N and CR Ｐ Selected from: W is H, D, halogen, C １～４ Alkyl, C １～４ haloalkyl and 【Chemistry 10】 Selected from: X Ｗ１ and X Ｗ２ independently, N and CR Ｗ Selected from: R Ｗ But H, D, -C(O)R ａ , —C(O)NR ｂ R ｃ , -C(O)OR ａ , -OC(O)R ａ and -NR ｂ C(O)R ａ Selected from: R ａ , R ｂ and R ｃ However, independently, H, C １～４ Alkyl and C １～４ haloalkyl; The a-terminus of the POI is C ０～３ connected to Q via alkylene, and the b end is connected to L; Alternatively, The POI is 【Chemistry 11】 and 【Chemistry 12】 represents a single bond or a double bond, alternatively a double bond; R Ｐ is a halogen; X Ｐ is selected from N and CH; W is H, halogen and 【Chemistry 13】 Selected from: X Ｗ１ and X Ｗ２ independently, N and CR Ｗ Selected from: R Ｗ H, -C(O)R ａ and —C(O)NR ｂ R ｃ Selected from: R ａ , R ｂ and R ｃ However, independently, H, C １～４ Alkyl and C １～４ haloalkyl; The a-terminus of the POI is C ０～３ connected to Q via alkylene, and the b end is connected to L; Further alternatively, The POI is 【Chemistry 14】 Selected from: W is H, halogen, 【Chemistry 15】 and alternatively W is selected from H, I and 【Chemistry 16】 Selected from: The a-terminus of the POI is C ０～３ is connected to Q via alkylene, and the b-terminus is connected to L; 10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, cis-trans isomer, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof.

3. L, 【Chemistry 17】 and [Chemistry 18] represents a single bond, a cis or trans double bond, alternatively a cis double bond; Each X Ｌ are independently a chemical bond, —O—, C １～４ alkylene, phenylene, and 5- to 6-membered heteroarylene; Ｌ is optionally deuterated, up to fully deuterated; each m is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each p is independently selected from 0, 1, 2, 3, 4, and 5; each q is independently selected from 1, 2, 3, 4, and 5; the b-terminus of L is connected to POI and the c-terminus is connected to E3, or the c-terminus of L is connected to POI and the b-terminus is connected to E3; Alternatively, L, 【Chemistry 19】 and 【Chemistry 20】 represents a single bond, a cis or trans double bond, alternatively a cis double bond; Each X Ｌ are independently a chemical bond, —O—, —CH ２ -, 【Chemistry 21】 Alternatively, each X Ｌ are independently —O— and —CH ２ - selected from; each m is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8, alternatively independently selected from 0, 1, 2, 3, and 4, and further alternatively, each m is 1; each n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8, alternatively independently selected from 0, 1, 2, 3, and 4, and further alternatively, 1 or 2; each p is independently selected from 0, 1, 2, and 3, alternatively independently or 1; each q is independently selected from 1, 2, 3, 4, and 5, alternatively 3; the b-terminus of L is connected to POI and the c-terminus is connected to E3, or the c-terminus of L is connected to POI and the b-terminus is connected to E3; Further alternatively, L, 【Chemistry 22】 Selected from: Alternatively, L is 【Chemistry 23】 and 【Chemistry 24】 represents a single bond, a cis or trans double bond, alternatively a cis double bond; the b-terminus of the L is connected to the POI and the c-terminus is connected to E3, or the c-terminus of the L is connected to the POI and the b-terminus is connected to E3; 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, cis-trans isomer, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof.

4. E3 is, 【Chemistry 25】 and R Ｅ１ , R Ｅ２ , R Ｅ３ or R Ｅ４ is independently selected from H and D; R Ｅ１ and R Ｅ２ , R Ｅ３ and R Ｅ４ at least one pair of represents =0; The c-terminus of E3 is connected to L, and the d-terminus is C ０～３ connected to Q via an alkylene; Alternatively, E3 is, 【Chemistry 26】 Selected from: The c-terminus of E3 is connected to L, and the d-terminus is C ０～３ connected to Q via alkylene; A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, tautomer, cis-trans isomer, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof.

5. Q is, 【Chemistry 27】 and L １ and L ２ is independently selected from NH and O; X Ｑ But -P(O)(Y Ｑ -R Ｑ )-, -S(O)- and -C(O)-X Ｑ１ -C(O)-; Y Ｑ is selected from NH and O; X Ｑ１ is a chemical bond, C １～６ Alkylene, C ２～６ Alkenylene, C ２～６ Alkynylene, —C １～６ Alkylene -NR ｂ -C １～６ Alkylene, 5- to 10-membered heterocyclylene and C ６～１０ arylene, wherein X Ｑ１ is optionally replaced with 1, 2, 3, 4, or 5 independently selected R#; R ｂ But H, C １～４ Alkyl and C １～４ haloalkyl; R Ｑ But H, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl and C ６～１０ aryl; R# is H, halogen, OH, NH ２ , C １～４ Alkyl, C ２～４ Alkenyl and C ２～４ alkynyl; Alternatively, Q is, 【Chemistry 28】 and L １ and L ２ is independently selected from NH and O; X Ｑ But -P(O)(Y Ｑ -R Ｑ )-, -S(O)- and -C(O)-X Ｑ１ -C(O)-; Y Ｑ is selected from NH and O; X Ｑ１ is a chemical bond, C １～４ Alkylene, -C １～４ Alkylene -NR ｂ -C １～４ alkylene, 5- to 6-membered heterocyclylene (e.g., 【Chemistry 29】 phenylene; １～４ alkylene is optionally substituted with one, two, or three independently selected R#; R ｂ But H, C １～４ Alkyl and C １～４ haloalkyl; R Ｑ But H, C １～４ selected from alkyl and phenyl; R# is H and NH ２ Selected from: Further alternatively, Q is, 【Transformation 30】 Alternatively, Q is selected from 【Chemistry 31】 and Q is selected from: 【Chemistry 32】 or a pharmaceutically acceptable salt, stereoisomer, tautomer, cis-trans isomer, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof.

6. The POI is 【Transformation 33】 and 【Transformation 34】 represents a single bond or a double bond, alternatively a double bond; Each R Ｐ are independently H, D, halogen, C １～４ Alkyl and C １～４ haloalkyl; s is selected from 1, 2 and 3; X Ｐ However, N and CR Ｐ Selected from: W is H, D, halogen, C １～４ Alkyl, C １～４ haloalkyl and 【Chemistry 35】 Selected from: X Ｗ１ and X Ｗ２ independently, N and CR Ｗ Selected from: R Ｗ But H, D, -C(O)R ａ , —C(O)NR ｂ R ｃ , -C(O)OR ａ , -OC(O)R ａ and -NR ｂ C(O)R ａ Selected from: The a-terminus of the POI is C ０～３ connected to Q via alkylene, and the b end is connected to L; L, 【Transformation 36】 and 【Chemistry 37】 represents a single bond, a cis or trans double bond, alternatively a cis double bond; Each X Ｌ are independently a chemical bond, —O—, C １～４ alkylene, phenylene, and 5- to 6-membered heteroarylene; Ｌ is optionally deuterated, up to fully deuterated; each m is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each p is independently selected from 0, 1, 2, 3, 4, and 5; each q is independently selected from 1, 2, 3, 4, and 5; the b-terminus of L is connected to POI and the c-terminus is connected to E3, or the c-terminus of L is connected to POI and the b-terminus is connected to E3; E3 is, 【Transformation 38】 and R Ｅ１ , R Ｅ２ , R Ｅ３ or R Ｅ４ is independently selected from H and D; R Ｅ１ and R Ｅ２ , R Ｅ３ and R Ｅ４ at least one pair of represents =0; The c-terminus of E3 is connected to L, and the d-terminus is C ０～３ connected to Q via an alkylene; Q is, 【Chemistry 39】 and L １ and L ２ is independently selected from NH and O; X Ｑ But -P(O)(Y Ｑ -R Ｑ )-, -S(O)- and -C(O)-X Ｑ１ -C(O)-; Y Ｑ is selected from NH and O; X Ｑ１ is a chemical bond, C １～６ Alkylene, C ２～６ Alkenylene, C ２～６ Alkynylene, —C １～６ Alkylene -NR ｂ -C １～６ Alkylene, 5- to 10-membered heterocyclylene and C ６～１０ arylene, wherein X Ｑ１ is optionally replaced with 1, 2, 3, 4, or 5 independently selected R#; R Ｑ But H, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl and C ６～１０ aryl; R ａ , R ｂ and R ｃ However, independently, H, C １～４ Alkyl and C １～４ haloalkyl; R# is H, halogen, OH, NH ２ , C １～４ Alkyl, C ２～４ Alkenyl and C ２～４ alkynyl, 6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, tautomer, cis-trans isomer, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof.

7. The POI is 【Chemistry 40】 and 【Chemistry 41】 represents a single bond or a double bond, alternatively a double bond; R Ｐ is a halogen; X Ｐ is selected from N and CH; W is H, halogen and 【Chemistry 42】 Selected from: X Ｗ１ and X Ｗ２ independently, N and CR Ｗ Selected from: R Ｗ H, -C(O)R ａ and —C(O)NR ｂ R ｃ Selected from: The a-terminus of the POI is C ０～３ connected to Q via alkylene, and the b end is connected to L; L, 【Chemistry 43】 and 【Chemistry 44】 represents a single bond, a cis or trans double bond, alternatively a cis double bond; Each X Ｌ are independently a chemical bond, —O—, —CH ２ -, 【Chemistry 45】 Alternatively, each X Ｌ are independently —O— and —CH ２ - selected from; each m is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8, alternatively independently selected from 0, 1, 2, 3, and 4, and further alternatively, m=1; each n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8, alternatively independently selected from 0, 1, 2, 3, and 4, and further alternatively, n=1 or 2; each p is independently selected from 0, 1, 2, and 3, alternatively, independently selected from 0 and 1; each q is independently selected from 1, 2, 3, 4, and 5, alternatively, independently 3; the b-terminus of L is connected to POI and the c-terminus is connected to E3, or the c-terminus of L is connected to POI and the b-terminus is connected to E3; E3 is, 【Chemistry 46】 and R Ｅ１ , R Ｅ２ , R Ｅ３ or R Ｅ４ is independently selected from H and D; R Ｅ１ and R Ｅ２ , R Ｅ３ and R Ｅ４ at least one pair of represents =0; The c-terminus of E3 is connected to L, and the d-terminus is C ０～３ connected to Q via an alkylene; Q is, 【Chemistry 47】 and L １ and L ２ is independently selected from NH and O; X Ｑ But -P(O)(Y Ｑ -R Ｑ )-, -S(O)- and -C(O)-X Ｑ１ -C(O)-; Y Ｑ is selected from NH and O; X Ｑ１ is a chemical bond, C １～４ Alkylene, -C １～４ Alkylene -NR ｂ -C １～４ alkylene, 5- to 6-membered heterocyclylene (e.g., 【Chemistry 48】 phenylene; １～４ alkylene is optionally substituted with one, two, or three independently selected R#; R Ｑ But H, C １～４ selected from alkyl and phenyl; R ａ , R ｂ and R ｃ However, independently, H, C １～４ Alkyl and C １～４ haloalkyl; R# is H and NH ２ Selected from:

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer, tautomer, cis-trans isomer, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof.

8. The POI is 【Chemistry 49】 Alternatively, the POI is selected from: [Transformation 50] Selected from: W is H, halogen, 【Chemistry 51】 and alternatively W is selected from H, I and 【Chemistry 52】 Selected from: The a-terminus of the POI is C ０～３ connected to Q via alkylene, and the b end is connected to L; L, 【Chemistry 53】 Selected from: Alternatively, L is 【Chemistry 54】 and the b-terminus of L is connected to POI and the c-terminus is connected to E3, or the c-terminus of L is connected to POI and the b-terminus is connected to E3; 【Transformation 55】 represents a single bond, a cis or trans double bond, alternatively a cis double bond; E3 is, 【Transformation 56】 Selected from: The c-terminus of E3 is connected to L, and the d-terminus is C ０～３ connected to Q via an alkylene; Q is, 【Chemistry 57】 Alternatively, Q is selected from 【Transformation 58】 and Q is selected from: 【Chemistry 59】 or a pharmaceutically acceptable salt, stereoisomer, tautomer, cis-trans isomer, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof.

9. The compound is 【Chemistry 60-1】 【Chemistry 60-2】 is selected from During the ceremony, 【Chemistry 61】 represents a single or double bond; 【Transformation 62】 represents a single bond, a cis or trans double bond, alternatively a cis double bond; 【Transformation 63】 but non-existence or 【Chemistry 64】 represents; W is H, I, 【Transformation 65】 and alternatively, W is selected from H, I and 【Chemical Formula 66】 Selected from: Alternatively, the compound is 【Transformation 67】 or a pharmaceutically acceptable salt, stereoisomer, tautomer, cis-trans isomer, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, selected from the group consisting of

10. 10. A pharmaceutical composition comprising a compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt, stereoisomer, tautomer, cis-trans isomer, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, and a pharmaceutically acceptable excipient, optionally wherein the pharmaceutical composition further comprises an additional therapeutic agent.

11. 10. Use of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, stereoisomer, tautomer, cis-trans isomer, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, in the manufacture of a medicament for inhibiting a protein tyrosine phosphatase.

12. 10. Use of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, stereoisomer, tautomer, cis-trans isomer, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, in the manufacture of a medicament for inhibiting SHP2.

13. 10. Use of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, stereoisomer, tautomer, cis-trans isomer, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, in the manufacture of a medicament for treating a tumor disease.

14. 11. A method for treating a tumor disease in a subject, comprising administering to the subject a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, stereoisomer, tautomer, cis-trans isomer, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition according to claim 10.

15. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, stereoisomer, tautomer, cis-trans isomer, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition according to claim 10, for use in the treatment of tumor diseases.

16. 16. The use according to claim 13 or the method according to claim 14 or the use of the compound or composition according to claim 15, wherein the tumor disease is selected from hematological tumors and solid tumor diseases.

17. 17. The use or method or use of the compound or composition according to claim 16, wherein the hematological tumor or solid tumor disease is selected from solid tumors such as breast cancer, lung cancer, neuroblastoma, oral squamous cell carcinoma, colorectal tumor, ovarian cancer, cervical cancer, prostate cancer and pancreatic cancer, hematological tumor diseases such as myeloid leukemia and lymphoid leukemia, and other relapsed and refractory advanced solid and hematological tumors.

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