Compounds that inhibit EGFR kinase and induce its degradation

Abstract

The present invention relates to novel EGFR kinase inhibitors represented by general formula (I), and pharmaceutical compositions containing said inhibitors, which are used in the treatment of diseases associated with EGFR kinase, such as cancer. The present invention also relates to the preparation and use of said inhibitors. [Formula 1] JPEG2023506086000126.jpg30100

Description

[Technical Field]

[0001] The present invention relates to the pharmaceutical field, more particularly, the present invention provides compounds that can inhibit EGFR kinase or induce the degradation of EGFR, as well as their preparation methods and applications. [Background technology]

[0002] Lung cancer is one of the most common malignancies. In 2018, there were 2.1 million new cases of lung cancer worldwide, accounting for 11.6% of all new tumor cases, and 1.8 million deaths, accounting for 18.4% of all tumor deaths. Non-small cell lung cancer (NSCLC) accounted for 80%-85% of all lung cancer cases. The epithelial growth factor receptor (EGFR) is the most common driver gene for NSCLC. Approximately 50% of NSCLC patients in China and 11-16% of NSCLC patients in Western countries have EGFR gene mutations. The most common mutation types are exon 19 deletion mutations (del E746-A750) and exon 21 L858R point mutations, accounting for approximately 90% of all EGFR mutations.

[0003] EGFR small molecule inhibitors are the standard first-line treatment for non-small cell lung cancer (NSCLC) with EGFR gene mutations and have been widely used in the field of lung cancer treatment. They competitively bind to EGFR with endogenous ligands, inhibit tyrosine kinase activation, and block the EGFR signaling pathway, inhibiting tumor cell proliferation and metastasis and promoting a series of biological effects, including tumor cell apoptosis.

[0004] The first-generation EGFR small molecule inhibitors, gefitinib and erlotinib, have been used to treat advanced non-small cell lung cancer (NSCLC) with activating EGFR mutations (L858R, del E746-A750). However, patients can develop drug resistance after 10–12 months of treatment with gefitinib and erlotinib. More than 50% of these drug-resistant patients experience secondary EGFR T790M mutations. Afatinib, a second-generation irreversible EGFR inhibitor, is effective in patients with advanced NSCLC with activating EGFR mutations (L858R, del E746-A750), but cannot resolve clinical drug resistance due to the EGFR T790M mutation. Furthermore, afatinib lacks selectivity over wild-type EGFR and is associated with significant toxicity. Osimertinib, a third-generation irreversible inhibitor, overcomes EGFR T790M drug resistance and effectively treats patients with advanced non-small cell lung cancer (NSCLC) with drug resistance due to the EGFR T790M mutation. Osimertinib has shown great success in the clinical treatment of EGFR T790M-associated NSCLC. However, some treated patients develop drug resistance again after 9–14 months of treatment (Nature Medicine, 2015, 21(6), 560–562). Research has shown that 22% of patients with drug resistance experience osimertinib resistance due to the EGFR C797S mutation (JAMA Oncol. 2018;4(11):1527–1534). The EGFR C797S mutation mutates cysteine ​​797 to serine, preventing osimertinib from covalently binding to EGFR, ultimately resulting in drug resistance. Currently, there is no single effective EGFR inhibitor for EGFR C797S in clinical practice, so the development of a new generation of EGFR inhibitors to meet clinical treatment needs is an urgent issue to be resolved.

[0005] The ubiquitin-proteasome system (UPS) is a multi-component intracellular protein degradation system involved in important physiological and biochemical processes, such as cell growth, differentiation, DNA replication and repair, cellular metabolism, and immune response. Protein degradation mediated by the ubiquitin-proteasome pathway is an important mechanism for regulating the levels and function of intracellular proteins and plays a key role in maintaining protein homeostasis in vivo. Inducing EGFR degradation via the intracellular ubiquitin-proteasome pathway offers a novel approach for the treatment of non-small cell lung cancer.

[0006] The present invention provides compounds capable of inhibiting EGFR kinase or inducing the degradation of EGFR, as well as methods for their preparation and application. Summary of the Invention

[0007]

[0008] The compounds of general formula (I) provided by the present invention are used in the treatment of diseases mediated by EGFR kinase, such as cancer.

[0009] In one aspect, the present invention provides a compound represented by the following general formula (I), its pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof: [ka] however, [ka] represents a single or double bond; [ka] indicates that the attachment site to the remainder of the molecule may be located at any available site on the ring; Z1 is one or two R Z1 or Z1 is absent, so Z4 is connected to a C atom of the aromatic ring to which Z1 is bonded, Z2 or Z3, and Z2 and the C atom of the aromatic ring bonded to Z1 are each connected to R; or Z1, Z2 and Z3 are all absent, so Z4 is connected to one of the C atoms of the aromatic ring to which Z1 or Z3 is bonded, and another C atom of the aromatic ring is connected to R; Z2 is one or two R Z2 is an O, S, N or C atom optionally substituted with; Z3 is one or two R Z3 is an O, S, N or C atom optionally substituted with [ka] represents a double bond, Z2 is an N or C atom and Z3 is an N or C atom; Z4 is N or CR Z4 and; Z5 is N or CR Z5 and; R a , R b and R c are independently H, halogen, -OR', NR'R'', C 1-6 Alkyl, or C 1-6 haloalkyl; or R a , R b and the C atoms to which they are attached, C=O, C 3-7 forms a cycloalkyl or a 4- to 8-membered heterocyclyl; or R a , R c and the C atoms to which they are attached, C 3-7 forms a cycloalkyl or a 4- to 8-membered heterocyclyl; or R a and R c forms chemical bonds; R N1 is H, C 1-6 Alkyl, or C 1-6 is haloalkyl; RZ1 is absent or is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, or -(CH2) 0-5 -4 to 8-membered heterocyclyl; or two R Z1 Together with Z1, C=O, C 3-7 forming a cycloalkyl or 4- to 8-membered heterocyclyl; R Z2 is absent or is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, or -(CH2) 0-5 -4 to 8-membered heterocyclyl; or two R Z2 Together with Z2, C=O, C 3-7 forming a cycloalkyl or 4- to 8-membered heterocyclyl; R Z3 is absent or is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, or -(CH2) 0-5 -4 to 8-membered heterocyclyl; or two R Z3 Together with Z3, C=O, C 3-7 forming a cycloalkyl or 4- to 8-membered heterocyclyl; R Z4 is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, or C 1-6 is haloalkyl; R Z5 is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, or -(CH2) 0-5 -4 to 8-membered heterocyclyl; Alternatively, the ring in which Z4 is located is absent; where R is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, -(CH2) 0-5 -4-8 membered heterocyclyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) 0-5 -C 3-10 Halocycloalkyl, -(CH2) 0-5 -C 6-10 Aryl, or -(CH2) 0-5 - 5 to 14 membered heteroaryl; R' is H, C 1-6 Alkyl, C 1-6 Haloalkyl, or -(CH2) 0-5 -C 3-7 is cycloalkyl; R'' is H, C 1-6 Alkyl, or C 1-6 is haloalkyl; L1 is a chemical bond, -O-, -S(O) p -, -S(O)(=NR * )-, -NR # -, -CR # R # '-, -C a R # R # '-C b R # R # '-, -N=S(O)(R* )-, or -S(O)(R * )=N-; L2 is a chemical bond, -O-, -S(O) p -, -S(O)(=NR * )-, -NR # -, -CR # R # '-, -C a R # R # '-C b R # R # '-, -N=S(O)(R * )-, or -S(O)(R * )=N-; where C a R # R # ' or C b R # R # ' is O, S(O) p , S(O)(=NR * ) or NR # can be replaced by C a R # R # ' or C b R # R # ' is O, S or NR # If replaced by C a R # R # ' or C b R # R # ', another one is S(O) q can be replaced by; E is independently a chemical bond, -C c R # R # '-C d R # R # '-C e R # R # ', [ka] selected from the group consisting of: where C c R # R # ', C d R # R # ' or C e R # R # ' or C c R # R # ' and C e R # R # 'Both O and S(O) p , S(O)(=NR * ) or NR # can be replaced by C c R # R # ', C d R # R # ' or C e R # R # ' is O, S or NR # If replaced by one or two adjacent Cs, c R # R # ', C d R # R # ' or C e R # R # ', S(O) q can be replaced by; Alternatively, two E units may be -CH2CH2OCH2CH2-, -OCH2CH2CH2CH2-, -CH2CH2CH2CH2O-, [ka] can be formed; where: [ka] represents the attachment site to L1 or L2; H1 and H2 are N or C atoms, H3 is O, S, N or C atom, and H1 and H3, H2 and H3 are not heteroatoms at the same time; H4 and H5 are N or C atoms; H6, H7, H8 and H9 are C or N atoms; p is 0, 1 or 2; q is 1 or 2; R * is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Halocycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5- to 14-membered heteroaryl; R # H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Halocycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5- to 14-membered heteroaryl; R # ' is H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Halocycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5- to 14-membered heteroaryl; Alternatively, R on the adjacent atom # and R # can form chemical bonds, R on adjacent atoms # ' and R # ' can form chemical bonds; Alternatively, R on the same or different atoms # and R# ' is both, =O, C 3-7 Cycloalkyl, 4-8 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl, wherein C 3-7 Cycloalkyl, 4-8 membered heterocyclyl, C 6-10 Aryl or 5-6 membered heteroaryl is R x and may be substituted with the above-mentioned R x H, CN, halogens, C 1-6 Alkyl, or C 1-6 is haloalkyl; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; X1 is a C or N atom; X2 is a C or N atom; X3 is a C or N atom; X4 is an O, S, C or N atom optionally substituted with one or two R2; X5 is an O, S, C or N atom; X6 is a C or N atom; X7 is an O, S, C or N atom; R1 is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, -(CH2) 0-5 -C 3-10 Halocycloalkyl, -(CH2) 0-5 -4 to 8-membered heterocyclyl, -(CH2) 0-5 -C 6-10 Aryl, -(CH2) 0-5 - 5 to 14 membered heteroaryl, -C(O)R, -S(O)R, or -S(O)R; R2 is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, -(CH2) 0-5 -C 3-10 Halocycloalkyl, -(CH2) 0-5 -4 to 8-membered heterocyclyl, -(CH2) 0-5 -C 6-10 Aryl, -(CH2) 0-5 - 5 to 14 membered heteroaryl, -C(O)R, -S(O)R, or -S(O)R; R N2 is H, C 1-6 Alkyl, or C 1-6 is haloalkyl; The definition of L1' is the same as the definition of L1; The definition of L2' is the same as that of L2; The definition of E' is the same as the definition of E; The definition of m' is the same as the definition of m; R s1 is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -4-8 membered heterocyclyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, -(CH2) 0-5 -C 3-10 Halocycloalkyl, -(CH2) 0-5 -C 6-10 Aryl, -(CH2) 0-5 - selected from the group consisting of 5- to 14-membered heteroaryl, -C(O)R, -S(O)R, or -S(O)R; R s2 H, CN, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6Alkynyl, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', -(CH2) 0-5 -C 3-7 Cycloalkyl, -(CH2) 0-5 -C 3-10 Halocycloalkyl, -(CH2) 0-5 -4 to 8-membered heterocyclyl, -(CH2) 0-5 -C 6-10 Aryl, -(CH2) 0-5 - selected from the group consisting of 5- to 14-membered heteroaryl, -C(O)R, -S(O)R, or -S(O)R; R s3 is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, -(CH2) 0-5 -4-8 membered heterocyclyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) 0-5 -C 3-10 Halocycloalkyl, -(CH2) 0-5 -C 6-10 Aryl, -(CH2) 0-5 - selected from the group consisting of 5- to 14-membered heteroaryl, -C(O)R, -S(O)R, or -S(O)R; R s4 H, CN, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', -(CH2) 0-5 -C 3-7 Cycloalkyl, -(CH2) 0-5 -4 to 8-membered heterocyclyl, -(CH2) 0-5 -C 3-10 Halocycloalkyl, -(CH2) 0-5 -C 6-10Aryl, -(CH2) 0-5 - selected from the group consisting of 5- to 14-membered heteroaryl, -C(O)R, -S(O)R, or -S(O)R; s1 is 0, 1, 2 or 3; s2 is 0, 1, 2 or 3; s3 is 0, 1 or 2; s4 is 0, 1, 2, 3, 4 or 5; The alkyl, alkylene, haloalkyl, alkenyl, alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl, or groups containing OH, NH, NH, CH, CH, CH in L1, E, L2, L1', E', L2' may each be one, two, three or more R s and may be substituted with the above-mentioned R s are independently halogen, hydroxyl, amino, cyano, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Halocycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, -OR a’ , -OC(O)R a’ , -C(O)R a’ , -C(O)OR a’ , -C(O)NR a’ R b’ , -S(O) n R a’ , -S(O) n OR a’ , -S(O) n NR a’ R b’ , -NR a’ R b’ , -NR a’ C(O)R b’ , -NR a’ -C(O)OR b’ , -NR a’ -S(O) n -R b’ , -NRa’ C(O)NR a’ R b’ , -C 1-6 Alkylene-R a’ , -C 1-6 Alkylene-OR a’ , -C 1-6 Alkylene-OC(O)R a’ , -C 1-6 Alkylene-C(O)OR a’ , -C 1-6 Alkylene-S(O) n R a’ , -C 1-6 Alkylene-S(O) n OR a’ , -C 1-6 Alkylene-OC(O)NR a’ R b’ , -C 1-6 Alkylene-C(O)NR a’ R b’ , -C 1-6 Alkylene-NR a’ -C(O)NR a’ R b’ , -C 1-6 Alkylene-OS(O) n R a’ , -C 1-6 Alkylene-S(O) n NR a’ R b’ , -C 1-6 Alkylene-NR a’ -S(O) n NR a’ R b’ , -C 1-6 Alkylene-NR a’ R b’ and -OC 1-6 Alkylene-NR a’ R b’ wherein the substituent R s The hydroxyl, amino, alkyl, alkylene, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl mentioned above are independently selected from halogen, OH, amino, cyano, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C3-6 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 may be further substituted with one, two, three or more substituents selected from the group consisting of aralkyl; n is independently 1 or 2; R a’ and R b’ are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl-O-, C 1-6 Alkyl-S-, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 aralkyl.

[0010] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and any pharmaceutically acceptable excipient.

[0011] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition further comprises another therapeutic agent.

[0012] In another aspect, the invention provides a kit comprising a compound of the invention, another therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0013] In another aspect, the present invention provides the use of a compound of the present invention for the preparation of a medicament for treating and / or preventing a disease mediated by EGFR kinase.

[0014] In another aspect, the present invention provides a method for treating and / or preventing a disease mediated by EGFR kinase in a subject, comprising administering to the subject a compound of the present invention or a composition of the present invention.

[0015] In another aspect, the present invention provides the compound of the present invention or the composition of the present invention for the treatment and / or prevention of a disease mediated by EGFR kinase.

[0016] In certain embodiments, diseases treated by the present invention include cancers such as, for example, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, stomach cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, endometrial cancer, kidney cancer, anaplastic large cell lymphoma, acute myeloid leukemia (AML), multiple myeloma, melanoma, mesothelioma, and the like.

[0017] Other objects and advantages of the present invention will become apparent to those skilled in the art from the following specific embodiments, examples, and claims. [Brief explanation of the drawings]

[0018] [Figure 1] FIG. 1 shows the effect of Compound D3 on EGFRL858R / T790M / C797S protein levels.

[0019] definition chemistry definition Specific functional groups and chemical term definitions are explained in more detail below.

[0020] When a numerical range is recited, it includes each value and subrange within the range. For example, "C 1-6 "Alkyl group" 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, C 5-6 Contains an alkyl group.

[0021] "C 1-6 An "alkyl group" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, 1-4 Alkyl groups are preferred. 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), n-hexyl (C6), and the like. 1-6 The term "alkyl group" also includes heteroalkyl groups 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). An alkyl group may be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Common abbreviations for alkyl include Me(-CH), Et(-CHCH), iPr(-CH(CH)), nPr(-CHCHCH), n-Bu(-CHCHCHCHCH), or i-Bu(-CHCH(CH)).

[0022] "C 2-6 An "alkenyl group" refers to 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 groups are preferred. 2-6 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. 1-6The term "alkenyl group" also includes heteroalkenyl groups 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). Alkenyl groups can be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0023] "C 2-6 An "alkynyl group" refers to a straight- or branched-chain 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 groups are preferred. 2-6 Examples of alkynyl groups 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. 2-6 The term "alkynyl group" also includes heteroalkynyl groups 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). The alkynyl group may be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0024] "Halogenated" or "halogen" means fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0025] Therefore, "C 1-6 Haloalkyl refers to any of the above "C" groups substituted with one or more halogen groups. 1-6 In some embodiments, C 1-4 Haloalkyl is particularly preferred, C 1-2Haloalkyl is more preferred. 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. Exemplary haloalkoxyl groups include, but are not limited to, -OCH2F, -OCHF2, -OCF3, and the like. The haloalkyl group is substituted at any available bonding site with, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0026] "C 3-10 A "cycloalkyl group" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and 0 heteroatoms. In some embodiments, C 3-7 Cycloalkyl groups and C 3-6 Cycloalkyl groups are particularly preferred, C 5-6 Cycloalkyl groups are more preferred. Cycloalkyl groups further include ring systems in which the cycloalkyl ring is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the cycloalkyl ring, and 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 (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), and the like. Cycloalkyl groups may be substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0027] "C 3-10 "Halocycloalkyl" refers to the above "C" substituted with one or more halogens. 3-10 It refers to "cycloalkyl."

[0028] A "3- to 12-membered heterocyclyl group" is a 3- to 12-membered non-aromatic ring system group having ring carbon atoms and 1 to 5 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the linking site may be a carbon or nitrogen atom, as long as the valence allows. In some embodiments, 4- to 12-membered heterocyclyl groups are preferred, which are 4- to 12-membered non-aromatic ring systems having ring carbon atoms and 1 to 5 ring heteroatoms. In some embodiments, 3- to 10-membered heterocyclyl groups are preferred, which are 3- to 10-membered non-aromatic ring systems having ring carbon atoms and 1 to 5 ring heteroatoms. In some embodiments, 3- to 8-membered heterocyclyl groups are preferred, which are 3- to 8-membered non-aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms. In some embodiments, 3- to 6-membered heterocyclyl groups are preferred, which are 3- to 6-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms. Preferred are 4- to 8-membered heterocyclyl groups, which are 4- to 8-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms. More preferred are 5- to 6-membered heterocyclyl groups, which are 5- to 6-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms. Furthermore, heterocyclyl groups include ring systems in which the heterocyclyl ring is fused with one or more cycloalkyl groups, where the point of attachment is on the cycloalkyl ring; or ring systems in which the heterocyclyl ring is fused with one or more aryl or heteroaryl groups, where the point of attachment is on the heterocyclyl ring. In these contexts, the number of ring members still refers to the number of ring members in the heterocyclyl group. Exemplary 3-membered heterocyclyls containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione.Exemplary 5-membered heterocyclyls 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, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyls 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 to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclyls) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, and benzoxazolinonyl. Exemplary 6-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl groups) include, but are not limited to, tetrahydroquinolinyl and tetrahydroisoquinolinyl. Heterocyclyl groups may be substituted with one or more substituents, such as, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0029] The terms "4- to 12-membered heterocyclylene" and "5- to 6-membered heterocyclylene" refer to divalent groups obtained by removing another hydrogen atom from the aforementioned "4- to 12-membered heterocyclyl" and "5- to 6-membered heterocyclyl", respectively, and may be substituted or unsubstituted.

[0030] "C6-10 An "aryl group" refers to a group of monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring systems (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having 6 to 10 ring carbon atoms and 0 heteroatoms. In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., a phenyl group). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 "Aryl"; e.g., naphthyl, such as 1-naphthyl, 2-naphthyl, etc.). Aryl groups also include ring systems in which the aryl ring is fused with one or more cycloalkyl or heterocyclyl groups, and the linkage site is located on the aryl ring, in which case the number of carbon atoms still refers to the number of carbon atoms in the aryl ring system. Aryl groups may be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0031] "C 6-12 "Aralkyl" refers to the group -R-R' where R is alkyl and R' is aryl, and the alkyl and aryl have a total of 6 to 12 carbon atoms.

[0032] A "5- to 14-membered heteroaryl group" is a group having a 5- to 14-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π-electrons shared in a cyclic arrangement) with ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, where valence allows. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. Heteroaryl groups also include ring systems in which the heteroaryl ring is fused with one or more cycloalkyl or heterocyclyl groups, and the attachment site is located on the heteroaryl ring, in which case the number of carbon atoms still refers to the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5- to 10-membered heteroaryl groups that are 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring systems with ring carbon atoms and 1-4 ring heteroatoms are preferred. In some other embodiments, 5- to 6-membered heteroaryl groups that are 5- to 6-membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms are particularly preferred. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,4-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, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl.Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and 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, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. A heteroaryl group may be optionally substituted with one or more substituents, such as, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0033] "Oxo" stands for =O.

[0034] The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups defined herein may be optionally substituted.

[0035] Exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(OR cc)2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa)2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(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, carbocyclic group, heterocyclyl group, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl group, heterocyclyl group, aryl, and heteroaryl each independently have 0, 1, 2, 3, 4, or 5 R dd substituted with a group;

[0036] Or, the two geminal hydrogens on the carbon atom can be =O, =S, or =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 substituted with a group;

[0037] Each R aa are independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl groups, heterocyclyl groups, aryl, and heteroaryl, or two R aagroups linked to form a heterocyclyl group or a heteroaryl ring, wherein the alkyl, alkenyl, alkynyl, cycloalkyl group, heterocyclyl group, aryl, and heteroaryl each independently contain 0, 1, 2, 3, 4, or 5 R dd substituted with a group;

[0038] Each R bb are independently hydrogen, -OH, or -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 group, heterocyclyl group, aryl, and heteroaryl, or two R bb groups linked to form a heterocyclyl group or a heteroaryl ring, wherein the alkyl, alkenyl, alkynyl, cycloalkyl group, heterocyclyl group, aryl, and heteroaryl each independently contain 0, 1, 2, 3, 4, or 5 R dd substituted with a group;

[0039] Each R ccare independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl group, heterocyclyl group, aryl, and heteroaryl, or two R cc groups linked to form a heterocyclyl group or a heteroaryl ring, where the alkyl, alkenyl, alkynyl, cycloalkyl group, heterocyclic group, aryl, and heteroaryl each independently contain 0, 1, 2, 3, 4, or 5 R dd substituted with a group;

[0040] Each R dd are independently 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, -NR ff C(=NR ff )N(R ff )2, -NRff 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 group, heterocyclyl group, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl group, heterocyclyl group, aryl, and heteroaryl are each independently selected from 0, 1, 2, 3, 4, or 5 R gg or two geminal R dd the substituents may be linked to form =O or =S;

[0041] Each R ee are independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl group, aryl, heterocyclyl group, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl group, heterocyclyl group, aryl, and heteroaryl are each independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group;

[0042] Each R ff are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl group, heterocyclyl group, aryl, and heteroaryl, or two R ffgroups linked to form a heterocyclyl group or a heteroaryl ring, wherein the alkyl, alkenyl, alkynyl, cycloalkyl group, heterocyclyl group, aryl, and heteroaryl each independently have 0, 1, 2, 3, 4, or 5 R gg substituted with a group;

[0043] Each R gg are independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl group, -ON(C 1-6 alkyl group)2, -N(C 1-6 alkyl group)2, -N(C 1-6 alkyl group)3 + X - , -NH(C 1-6 alkyl group)2 + X - , -NH2(C 1-6 alkyl group) + X - , -NH3 + X - , -N(OC 1-6 alkyl group)(C 1-6 alkyl group), -N(OH)(C 1-6 alkyl group), -NH(OH), -SH, -SC 1-6 Alkyl group, -SS(C 1-6 alkyl group), -C(=O)(C 1-6 alkyl group), -CO2H, -CO2(C 1-6 alkyl group), -OC(=O)(C 1-6 alkyl group), -OCO2(C 1-6 alkyl group), -C(=O)NH2, -C(=O)N(C 1-6 alkyl group)2, -OC(=O)NH(C 1-6 alkyl group), -NHC(=O)(C 1-6 alkyl group), -N(C 1-6 alkyl group)C(=O)(C 1-6 alkyl group), -NHCO2(C 1-6 alkyl group), -NHC(=O)N(C 1-6 alkyl group)2, -NHC(=O)NH(C 1-6alkyl group), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl group), -OC(=NH)(C 1-6 alkyl group), -OC(=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 alkyl group)2, -C(=NH)NH(C 1-6 alkyl group), -C(=NH)NH2, -OC(=NH)N(C 1-6 alkyl group)2, -OC(NH)NH(C 1-6 alkyl group), -OC(NH)NH2, -NHC(NH)N(C 1-6 alkyl group), -NHC(=NH)NH, -NHSO(C 1-6 alkyl group), -SO2N(C 1-6 alkyl group)2, -SO2NH(C 1-6 alkyl group), -SO2NH2, -SO2C 1-6 Alkyl group, -SO2OC 1-6 Alkyl group, -OSO2C 1-6 Alkyl group, -SOC 1-6 Alkyl group, -Si(C 1-6 alkyl group)3, -OSi(C 1-6 alkyl group)3, -C(=S)N(C 1-6 alkyl group), C(=S)NH(C 1-6 alkyl group), C(=S)NH2, -C(=O)S(C 1-6 alkyl group), -C(=S)SC 1-6 Alkyl group, -SC(=S)SC 1-6 Alkyl group, -P(=O)2(C 1-6 alkyl group), -P(=O)(C 1-6 alkyl group)2, -OP(=O)(C 1-6 alkyl group)2, -OP(=O)(OC 1-6 Alkyl group)2, C 1-6 Alkyl group, C 1-6 Haloalkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C7 cycloalkyl groups, C6-C 10 Aryl groups, C3-C7 heterocyclyl groups, C5-C 10 a heteroaryl group; or two geminal R ggThe substituents may be linked to form =O or =S; where X - is the counter ion.

[0044] Exemplary nitrogen atom substituents 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, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl group, heterocyclyl group, aryl, and heteroaryl, or two R bonded to a nitrogen atom cc The groups are linked to form a heterocyclyl group or a heteroaryl ring, where the alkyl, alkenyl, alkynyl, cycloalkyl group, heterocyclyl group, aryl, and heteroaryl each independently contain 0, 1, 2, 3, 4, or 5 R dd group, where R aa , R bb , R cc and R dd is as described above.

[0045] Other definitions The term "cancer" includes, but is not limited to, cancers of the breast, ovary, cervix, prostate, testicle, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, biliary tract, buccal cavity and pharynx (mouth), lip, tongue, mouth, pharynx, small intestine, colorectal, large intestine, rectum, brain and central nervous system, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, adenoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer, kidney cancer, bone marrow disorders, lymphatic disorders, Hodgkin's disease, hairy cell carcinoma, and leukemia.

[0046] The term "treatment" as used herein relates to the reversal, alleviation, suppression of the disorder or condition to which the term applies, or the progression or prevention of one or more symptoms of such disorder or condition. The noun "treatment" as used herein relates to the act of treating, which is a verb, as defined above.

[0047] As used herein, the term "pharmaceutically acceptable salts" refers to carboxylate salts, amino acid salt addition salts of the present invention that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, and are effective for their desired application, commensurate with a reasonable benefit / risk ratio, including, where possible, zwitterionic forms of the compounds of the present invention.

[0048] Pharmaceutically acceptable base addition salts are formed with metals or amines, such as, for example, alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, calcium, etc. Examples of preferred amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.

[0049] 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 the conventional manner. The free acid is regenerated by contacting the salt form with an acid in the conventional manner and isolating the free acid. The free acid forms may differ somewhat from their respective salt forms in physical properties, such as solubility in polar solvents. However, for purposes of this invention, the salts are equivalent to the respective free acids.

[0050] Salts may be prepared from inorganic acids, such as sulfate, pyrosulfate, bisulfite, sulfite, 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 may be prepared from organic acids, such as 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, methylbenzoate, dinitrobenzoate, naphthoate, besylate, tosylate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Pharmaceutically acceptable salts include, for example, alkali and alkaline earth metal cations 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, gluconate, galacturonate, and the like (see, e.g., Berge SM et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19).

[0051] The "subject" to be administered includes, but is not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) 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" are used interchangeably herein.

[0052] "Disease," "disorder," and "condition" are used interchangeably herein.

[0053] Unless otherwise specified, the term "treatment" as used herein contemplates actions taken while a subject is suffering from a particular disease, disorder, or condition to reduce the severity of the disease, disorder, or condition or to delay or slow the progression of the disease, disorder, or condition ("therapeutic treatment"), and also actions taken before a subject begins to suffer from a particular disease, disorder, or condition ("prophylactic treatment").

[0054] 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 invention may vary depending on factors such as the desired biological goal, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age, health and condition of the subject. The effective amount includes a therapeutically effective amount and a prophylactically effective amount.

[0055] Unless otherwise specified, a "therapeutically effective amount" of a compound, as used herein, is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with that disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of that disease, disorder, or condition. The term "therapeutically effective amount" includes an amount that improves overall treatment, an amount that reduces or avoids the symptoms or causes of a disease or condition, or an amount that enhances the therapeutic effect of another therapeutic agent.

[0056] Unless otherwise specified, a "prophylactically effective amount" of a compound, as used herein, is an amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with that disease, disorder, or condition, or to prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of that disease, disorder, or condition. The term "prophylactically effective amount" includes an amount that improves overall prophylaxis or enhances the prophylactic effect of another prophylactic agent.

[0057] "Combination" and related terms refer to simultaneous or sequential administration of a compound of the invention and another therapeutic agent. For example, the compound of the invention can be administered simultaneously or sequentially with the other therapeutic agent in separate unit dosage forms or simultaneously with the other therapeutic agent in a single unit dosage form. DETAILED DESCRIPTION OF THE INVENTION

[0058] As used herein, the term "compound of the invention" refers to a compound represented by the following formula (I) (including subgeneric formulas such as formula (II')), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof.

[0059] In this specification, compounds are generally named in a standard manner. For compounds having asymmetric centers, it should be understood that all optical isomers and mixtures thereof are included unless otherwise specified. Furthermore, all isomeric compounds and carbon-carbon double bonds included in the present invention may appear in Z and E forms unless otherwise specified. For compounds that exist in different tautomeric forms, the compounds are not limited to a specific tautomer, but are intended to include all tautomeric forms.

[0060] In one embodiment, the present invention relates to a compound represented by general formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof. [ka] however, [ka] represents a single or double bond; [ka] indicates that the attachment site to the remainder of the molecule may be located at any available site on the ring; Z1 is one or two R Z1 or Z1 is absent, so Z4 is connected to a C atom of the aromatic ring to which Z1 is bonded, Z2 or Z3, and Z2 and the C atom of the aromatic ring bonded to Z1 are each connected to R; or Z1, Z2 and Z3 are all absent, so Z4 is connected to one of the C atoms of the aromatic ring to which Z1 or Z3 is bonded, and another C atom of the aromatic ring is connected to R; Z2 is one or two R Z2 is an O, S, N or C atom optionally substituted with; Z3 is one or two R Z3 is an O, S, N or C atom optionally substituted with [ka] represents a double bond, Z2 is an N or C atom and Z3 is an N or C atom; Z4 is N or CR Z4 and; Z5 is N or CR Z5 and; R a , R b and R c are independently H, halogen, -OR', NR'R'', C 1-6 Alkyl, or C 1-6 haloalkyl; or R a , R b and the C atoms to which they are attached, C=O, C 3-7 forms a cycloalkyl or a 4- to 8-membered heterocyclyl; or R a , R c and the C atoms to which they are attached, C 3-7 forms a cycloalkyl or a 4- to 8-membered heterocyclyl; or R a and R c forms chemical bonds; R N1 is H, C 1-6 Alkyl, or C 1-6 is haloalkyl; R Z1 is absent or is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, or -(CH2) 0-5 -4 to 8-membered heterocyclyl; or two R Z1 Together with Z1, C=O, C 3-7 forming a cycloalkyl or 4- to 8-membered heterocyclyl; R Z2 is absent or is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2)0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, or -(CH2) 0-5 -4 to 8-membered heterocyclyl; or two R Z2 Together with Z2, C=O, C 3-7 forming a cycloalkyl or 4- to 8-membered heterocyclyl; R Z3 is absent or is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, or -(CH2) 0-5 -4 to 8-membered heterocyclyl; or two R Z3 Together with Z3, C=O, C 3-7 forming a cycloalkyl or 4- to 8-membered heterocyclyl; R Z4 is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, or C 1-6 is haloalkyl; R Z5 is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, or -(CH2) 0-5 -4 to 8-membered heterocyclyl; Alternatively, the ring in which Z4 is located is absent; where R is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6Haloalkyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, -(CH2) 0-5 -4-8 membered heterocyclyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) 0-5 -C 3-10 Halocycloalkyl, -(CH2) 0-5 -C 6-10 Aryl, or -(CH2) 0-5 - 5 to 14 membered heteroaryl; R' is H, C 1-6 Alkyl, C 1-6 Haloalkyl, or -(CH2) 0-5 -C 3-7 is cycloalkyl; R'' is H, C 1-6 Alkyl, or C 1-6 is haloalkyl; L1 is a chemical bond, -O-, -S(O) p -, -S(O)(=NR * )-, -NR # -, -CR # R # '-, -C a R # R # '-C b R # R # '-, -N=S(O)(R * )-, or -S(O)(R * )=N-; L2 is a chemical bond, -O-, -S(O) p -, -S(O)(=NR * )-, -NR # -, -CR # R # '-, -C a R # R # '-C b R # R # '-, -N=S(O)(R * )-, or -S(O)(R * )=N-; where C a R# R # ' or C b R # R # ' is O, S(O) p , S(O)(=NR * ) or NR # can be replaced by C a R # R # ' or C b R # R # ' is O, S or NR # If replaced by C a R # R # ' or C b R # R # ', another one is S(O) q can be replaced by; E is independently a chemical bond, -C c R # R # '-C d R # R # '-C e R # R # ', [ka] selected from the group consisting of: where C c R # R # ', C d R # R # ' or C e R # R # ' or C c R # R # ' and C e R # R # 'Both O and S(O) p , S(O)(=NR * ) or NR # can be replaced by C cR # R # ', C d R # R # ' or C e R # R # ' is O, S or NR # If replaced by one or two adjacent Cs, c R # R # ', C d R # R # ' or C e R # R # ', S(O) q can be replaced by; Alternatively, two E units may be -CH2CH2OCH2CH2-, -OCH2CH2CH2CH2-, -CH2CH2CH2CH2O-, [ka] can be formed; where: [ka] represents the attachment site to L1 or L2; H1 and H2 are N or C atoms, H3 is O, S, N or C atom, and H1 and H3, H2 and H3 are not heteroatoms at the same time; H4 and H5 are N or C atoms; H6, H7, H8 and H9 are C or N atoms; p is 0, 1 or 2; q is 1 or 2; R * is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Halocycloalkyl, 3-10 membered heterocyclyl, C 6-10aryl, or 5- to 14-membered heteroaryl; R # H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Halocycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5- to 14-membered heteroaryl; R # ' is H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Halocycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5- to 14-membered heteroaryl; Alternatively, R on the adjacent atom # and R # can form chemical bonds, R on adjacent atoms # ' and R # ' can form chemical bonds; Alternatively, R on the same or different atoms # and R # ' is both, =O, C 3-7 Cycloalkyl, 4-8 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl, wherein C 3-7 Cycloalkyl, 4-8 membered heterocyclyl, C 6-10 Aryl or 5-6 membered heteroaryl is R x and may be substituted with the above-mentioned R x H, CN, halogens, C 1-6 Alkyl, or C 1-6 is haloalkyl; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; X1 is a C or N atom; X2 is a C or N atom; X3 is a C or N atom; X4 is an O, S, C or N atom optionally substituted with one or two R2; X5 is an O, S, C or N atom; X6 is a C or N atom; X7 is an O, S, C or N atom; R1 is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, -(CH2) 0-5 -C 3-10 Halocycloalkyl, -(CH2) 0-5 -4 to 8-membered heterocyclyl, -(CH2) 0-5 -C 6-10 Aryl, -(CH2) 0-5 - 5 to 14 membered heteroaryl, -C(O)R, -S(O)R, or -S(O)R; R2 is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, -(CH2) 0-5 -C 3-10 Halocycloalkyl, -(CH2) 0-5 -4 to 8-membered heterocyclyl, -(CH2) 0-5 -C 6-10 Aryl, -(CH2) 0-5 - 5 to 14 membered heteroaryl, -C(O)R, -S(O)R, or -S(O)R; R N2 is H, C 1-6 Alkyl, or C 1-6 is haloalkyl; The definition of L1' is the same as the definition of L1; The definition of L2' is the same as that of L2; The definition of E' is the same as the definition of E; The definition of m' is the same as the definition of m; R s1 is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -4-8 membered heterocyclyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, -(CH2) 0-5 -C 3-10 Halocycloalkyl, -(CH2) 0-5 -C 6-10 Aryl, -(CH2) 0-5 - selected from the group consisting of 5- to 14-membered heteroaryl, -C(O)R, -S(O)R, or -S(O)R; R s2 H, CN, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', -(CH2) 0-5 -C 3-7 Cycloalkyl, -(CH2) 0-5 -C 3-10 Halocycloalkyl, -(CH2) 0-5 -4 to 8-membered heterocyclyl, -(CH2) 0-5 -C 6-10 Aryl, -(CH2) 0-5 - selected from the group consisting of 5- to 14-membered heteroaryl, -C(O)R, -S(O)R, or -S(O)R; R s3 is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, -(CH2) 0-5 -4-8 membered heterocyclyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) 0-5 -C 3-10 Halocycloalkyl, -(CH2) 0-5 -C 6-10 Aryl, -(CH2) 0-5 - selected from the group consisting of 5- to 14-membered heteroaryl, -C(O)R, -S(O)R, or -S(O)R; R s4 H, CN, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', -(CH2) 0-5 -C 3-7 Cycloalkyl, -(CH2) 0-5 -4 to 8-membered heterocyclyl, -(CH2) 0-5 -C 3-10 Halocycloalkyl, -(CH2) 0-5 -C 6-10 Aryl, -(CH2) 0-5 - selected from the group consisting of 5- to 14-membered heteroaryl, -C(O)R, -S(O)R, or -S(O)R; s1 is 0, 1, 2 or 3; s2 is 0, 1, 2 or 3; s3 is 0, 1 or 2; s4 is 0, 1, 2, 3, 4 or 5; The alkyl, alkylene, haloalkyl, alkenyl, alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl, or groups containing OH, NH, NH, CH, CH, CH in L1, E, L2, L1', E', L2' may each be one, two, three or more R sand may be substituted with the above-mentioned R s are independently halogen, hydroxyl, amino, cyano, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Halocycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, -OR a’ , -OC(O)R a’ , -C(O)R a’ , -C(O)OR a’ , -C(O)NR a’ R b’ , -S(O) n R a’ , -S(O) n OR a’ , -S(O) n NR a’ R b’ , -NR a’ R b’ , -NR a’ C(O)R b’ , -NR a’ -C(O)OR b’ , -NR a’ -S(O) n -R b’ , -NR a’ C(O)NR a’ R b’ , -C 1-6 Alkylene-R a’ , -C 1-6 Alkylene-OR a’ , -C 1-6 Alkylene-OC(O)R a’ , -C 1-6 Alkylene-C(O)OR a’ , -C 1-6 Alkylene-S(O) n R a’ , -C 1-6 Alkylene-S(O) n OR a’ , -C 1-6 Alkylene-OC(O)NR a’ R b’, -C 1-6 Alkylene-C(O)NR a’ R b’ , -C 1-6 Alkylene-NR a’ -C(O)NR a’ R b’ , -C 1-6 Alkylene-OS(O) n R a’ , -C 1-6 Alkylene-S(O) n NR a’ R b’ , -C 1-6 Alkylene-NR a’ -S(O) n NR a’ R b’ , -C 1-6 Alkylene-NR a’ R b’ and -OC 1-6 Alkylene-NR a’ R b’ wherein the substituent R s The hydroxyl, amino, alkyl, alkylene, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl mentioned above are independently selected from halogen, OH, amino, cyano, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 may be further substituted with one, two, three or more substituents selected from the group consisting of aralkyl; n is independently 1 or 2; R a’ and R b’ are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl-O-, C 1-6 Alkyl-S-, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C6-10 Aryl, 5-14 membered heteroaryl and C 6-12 aralkyl. [ka] In certain embodiments, [ka] represents a single bond; in another particular embodiment, [ka] represents a double bond.

[0061] Z1 In certain embodiments, Z1 is an O atom; in another particular embodiment, Z1 is an S atom; in another particular embodiment, Z1 is an N atom; in another particular embodiment, Z1 is a C atom; in another particular embodiment, Z1 is one R Z1 In another particular embodiment, is substituted with two R Z1 In another particular embodiment, Z1 is absent.

[0062] Z2 In certain embodiments, Z2 is an O atom; in another particular embodiment, Z2 is an S atom; in another particular embodiment, Z2 is an N atom; in another particular embodiment, Z2 is a C atom; in another particular embodiment, Z2 is one R Z2 In another particular embodiment, Z2 is substituted with two R Z2 is replaced by

[0063] Z3 In certain embodiments, Z3 is an O atom; in another particular embodiment, Z3 is an S atom; in another particular embodiment, Z3 is an N atom; in another particular embodiment, Z3 is a C atom; in another particular embodiment, Z3 is one R Z3 In another particular embodiment, Z is substituted with two RZ3 is replaced by

[0064] In certain embodiments, Z1, Z2 and Z3 are all absent.

[0065] Z4 In certain embodiments, Z4 is N; in other certain embodiments, Z4 is CR Z4 is.

[0066] Z5 In certain embodiments, Z5 is N; in other certain embodiments, Z5 is CR Z5 is.

[0067] R a , R b and R c In certain embodiments, R a is H; in another particular embodiment, R a is halogen; in another particular embodiment, R a is OR'; in another particular embodiment, R a is NR'R''; in another particular embodiment, R a is C 1-6 alkyl; in another particular embodiment, R a is C 1-6 It is haloalkyl.

[0068] In certain embodiments, R b is H; in another particular embodiment, R b is halogen; in another particular embodiment, R b is OR'; in another particular embodiment, R b is NR'R''; in another particular embodiment, R b is C 1-6 alkyl; in another particular embodiment, R b is C 1-6 It is haloalkyl.

[0069] In certain embodiments, Rc is H; in another particular embodiment, R c is halogen; in another particular embodiment, R c is OR'; in another particular embodiment, R c is NR'R''; in another particular embodiment, R c is C 1-6 alkyl; in another particular embodiment, R c is C 1-6 It is haloalkyl.

[0070] In certain embodiments, R a , R b and together with the C atom to which they are attached form C=O; in another particular embodiment, R a , R b and the C atoms to which they are attached, C 3-7 In another particular embodiment, R a , R b and together with the C atom to which they are attached form a 4-8 membered heterocyclyl; in another particular embodiment, R a and R c forms a chemical bond; in another particular embodiment, R a and R c and the C atoms to which they are attached, C 3-7 It forms a cycloalkyl or a 4- to 8-membered heterocyclyl.

[0071] R Z1 In certain embodiments, R Z1 is absent; in another particular embodiment, R Z1 is H; in another particular embodiment, R Z1 is CN; in another particular embodiment, R Z1 is halogen; in another particular embodiment, R Z1 Ha-(CH2) 0-5 -OR'; in another particular embodiment, R Z1 Ha-(CH2) 0-5-NR'R''; in another particular embodiment, R Z1 is C 1-6 alkyl; in another particular embodiment, R Z1 is C 1-6 haloalkyl; in another particular embodiment, R Z1 Ha-(CH2) 0-5 -C 3-7 cycloalkyl; in another particular embodiment, R Z1 Ha-(CH2) 0-5 -4- to 8-membered heterocyclyl; in another particular embodiment, two R Z1 together with Z1 form C=O; in another particular embodiment, two R Z1 Along with Z1, C 3-7 In another particular embodiment, two R Z1 forms a 4- to 8-membered heterocyclyl together with Z1.

[0072] R Z2 In certain embodiments, R Z2 is absent; in another particular embodiment, R Z2 is H; in another particular embodiment, R Z2 is CN; in another particular embodiment, R Z2 is halogen; in another particular embodiment, R Z2 Ha-(CH2) 0-5 -OR'; in another particular embodiment, R Z2 Ha-(CH2) 0-5 -NR'R''; in another particular embodiment, R Z2 is C 1-6 alkyl; in another particular embodiment, R Z2 is C 1-6 haloalkyl; in another particular embodiment, R Z2 Ha-(CH2) 0-5 -C 3-7 cycloalkyl; in another particular embodiment, R Z2 Ha-(CH2) 0-5 -4- to 8-membered heterocyclyl; in another particular embodiment, two RZ2 together with Z2 form C=O; in another particular embodiment, two R Z2 C with Z2 3-7 In another particular embodiment, two R Z2 forms a 4- to 8-membered heterocyclyl together with Z2.

[0073] R Z3 In certain embodiments, R Z3 is absent; in another particular embodiment, R Z3 is H; in another particular embodiment, R Z3 is CN; in another particular embodiment, R Z3 is halogen; in another particular embodiment, R Z3 Ha-(CH2) 0-5 -OR'; in another particular embodiment, R Z3 Ha-(CH2) 0-5 -NR'R''; in another particular embodiment, R Z3 is C 1-6 alkyl; in another particular embodiment, R Z3 is C 1-6 haloalkyl; in another particular embodiment, R Z3 Ha-(CH2) 0-5 -C 3-7 cycloalkyl; in another particular embodiment, R Z3 Ha-(CH2) 0-5 -4- to 8-membered heterocyclyl; in another particular embodiment, two R Z3 together with Z3 form C=O; in another particular embodiment, two R Z3 But Z3 and C 3-7 In another particular embodiment, two R Z3 forms a 4- to 8-membered heterocyclyl together with Z3.

[0074] R Z4 In certain embodiments, R Z4 is H; in another particular embodiment, R Z4is CN; in another particular embodiment, R Z4 is halogen; in another particular embodiment, R Z4 Ha-(CH2) 0-5 -OR'; in another particular embodiment, R Z4 Ha-(CH2) 0-5 -NR'R''; in another particular embodiment, R Z4 is C 1-6 alkyl; in another particular embodiment, R Z4 is C 1-6 It is haloalkyl.

[0075] R Z5 In certain embodiments, R Z5 is H; in another particular embodiment, R Z5 is CN; in another particular embodiment, R Z5 is halogen; in another particular embodiment, R Z5 Ha-(CH2) 0-5 -OR'; in another particular embodiment, R Z5 Ha-(CH2) 0-5 -NR'R''; in another particular embodiment, R Z5 is C 1-6 alkyl; in another particular embodiment, R Z5 is C 1-6 haloalkyl; in another particular embodiment, R Z5 Ha-(CH2) 0-5 -C 3-7 cycloalkyl; in another particular embodiment, R Z5 Ha-(CH2) 0-5 -4 to 8-membered heterocyclyl.

[0076] In certain embodiments, the ring in which Z4 is located is absent.

[0077] L1 In certain embodiments, L1 is a chemical bond; in other particular embodiments, L1 is -O-; in other particular embodiments, L1 is -S(O) p-; in another particular embodiment, L is -S(O)(=NR * )-; in another particular embodiment, L1 is -NR # In another particular embodiment, L is -CR # R # In another particular embodiment, L is -C a R # R # '-C b R # R # In another particular embodiment, L is -N=S(O)(R * )-; in another particular embodiment, L is -S(O)(R * )=N-.

[0078] L2 In certain embodiments, L2 is a chemical bond; in other particular embodiments, L2 is -O-; in other particular embodiments, L2 is -S(O) p -; in another particular embodiment, L2 is -S(O)(=NR * )-; in another particular embodiment, L2 is -NR # In another particular embodiment, L2 is -CR # R # In another particular embodiment, L2 is -C a R # R # '-C b R # R # In another particular embodiment, L2 is -N=S(O)(R * )—; in another particular embodiment, L2 is —S(O)(R * )=N-.

[0079] In another particular embodiment, C in L1 or L2 a R # R # ' or C b R # R # ' is O, S(O) p, S(O)(=NR * ) or NR # can be replaced by C a R # R # ' or C b R # R # ' is O, S or NR # If replaced by C a R # R # ' or C b R # R # ', another one is S(O) q can be replaced by

[0080] E In certain embodiments, E is a chemical bond; in other certain embodiments, E is -C c R # R # '-C d R # R # '-C e R # R # In another particular embodiment, E is [ka] In another particular embodiment, E is [ka] In another particular embodiment, E is [ka] In another particular embodiment, E is [ka] In another particular embodiment, E is [ka] is.

[0081] In another particular embodiment, C c R # R # ', C d R # R # ' or C e R # R # ' or C c R # R # ' and C e R # R # 'Both O and S(O) p , S(O)(=NR * ) or NR # can be replaced by C c R # R # ', C d R # R # ' or C e R # R # ' is O, S or NR # If replaced by one or two adjacent Cs, c R # R # ', C d R # R # ' or C e R # R # ', S(O) q can be replaced by

[0082] In another particular embodiment, two E units can form -CH2CH2OCH2CH2-; in another particular embodiment, two E units can form -OCH2CH2CH2CH2-; in another particular embodiment, two E units can form -CH2CH2CH2CH2O-; in another particular embodiment, two E units can form [ka] In another particular embodiment, two E units can form [ka] In another particular embodiment, two E units can form [ka] In another particular embodiment, two E units can form [ka] In another particular embodiment, two E units can form [ka] In another particular embodiment, two E units can form [ka] can be formed.

[0083] In another particular embodiment, in the embodiment of L, L or E, R on adjacent atoms # and R # can form chemical bonds, R on adjacent atoms # ' and R # ' is capable of forming chemical bonds.

[0084] In another particular embodiment, in the embodiments of L, L or E, R on the same atom # and R # ' are both =O or R x C optionally substituted with 3-7 Cycloalkyl, 4-8 membered heterocyclyl, C 6-10 In another particular embodiment, in the embodiment of L, L or E, R on different atoms form an aryl or a 5- to 6-membered heteroaryl. # and R # ' is both Rx C optionally substituted with 3-7 Cycloalkyl, 4-8 membered heterocyclyl, C 6-10 Forms an aryl or a 5- to 6-membered heteroaryl.

[0085] m In certain embodiments, m is 0; in other particular embodiments, m is 1; in other particular embodiments, m is 2; in other particular embodiments, m is 3; in other particular embodiments, m is 4; in other particular embodiments, m is 5; in other particular embodiments, m is 6; in other particular embodiments, m is 7; in other particular embodiments, m is 8; in other particular embodiments, m is 9; in other particular embodiments, m is 10.

[0086] X1 In certain embodiments, X 1 is a C atom; in other particular embodiments, X 1 is an N atom.

[0087] X2 In certain embodiments, X2 is a C atom; in other particular embodiments, X2 is an N atom.

[0088] X3 In certain embodiments, X3 is a C atom; in another particular embodiment, X3 is an N atom.

[0089] X4 In certain embodiments, X4 is an O atom; in another particular embodiment, X4 is an S atom; in another particular embodiment, X4 is a C atom; in another particular embodiment, X4 is an N atom; in another particular embodiment, X4 is substituted with one R2; in another particular embodiment, X4 is substituted with two R2.

[0090] X5 In certain embodiments, X5 is an O atom; in another particular embodiment, X5 is an S atom; in another particular embodiment, X5 is a C atom; in another particular embodiment, X5 is an N atom.

[0091] X6 In certain embodiments, X6 is a C atom; in other particular embodiments, X6 is an N atom.

[0092] X7 In certain embodiments, X7 is an O atom; in another particular embodiment, X7 is an S atom; in another particular embodiment, X7 is a C atom; in another particular embodiment, X7 is an N atom.

[0093] In certain embodiments, the ring in which X4, X5, X6, and X7 are located is a pyrazole ring; in another particular embodiment, the ring in which X4, X5, X6, and X7 are located is an imidazole ring; in another particular embodiment, the ring in which X4, X5, X6, and X7 are located is a thiazole ring; in another particular embodiment, the ring in which X4, X5, X6, and X7 are located is an oxazole ring; in another particular embodiment, the ring in which X4, X5, X6, and X7 are located is a triazole ring; in another particular embodiment, the ring in which X4, X5, X6, and X7 are located is a tetrazole ring; [ka] In another particular embodiment, the ring in which X4, X5, X6 and X7 are located is [ka] In another particular embodiment, the ring in which X4, X5, X6 and X7 are located is [ka] In another particular embodiment, the ring in which X4, X5, X6 and X7 are located is [ka] In another particular embodiment, the ring in which X4, X5, X6 and X7 are located is [ka] In another particular embodiment, the ring in which X4, X5, X6 and X7 are located is [ka] In another particular embodiment, the ring in which X4, X5, X6 and X7 are located is [ka] In another particular embodiment, the ring in which X4, X5, X6 and X7 are located is [ka] In another particular embodiment, the ring in which X4, X5, X6 and X7 are located is [ka] In another particular embodiment, the ring in which X4, X5, X6 and X7 are located is [ka] In another particular embodiment, the ring in which X4, X5, X6 and X7 are located is [ka] In another particular embodiment, the ring in which X4, X5, X6 and X7 are located is [ka] In another particular embodiment, the ring in which X4, X5, X6 and X7 are located is [ka] In another particular embodiment, the ring in which X4, X5, X6 and X7 are located is [ka] In another particular embodiment, the ring in which X4, X5, X6 and X7 are located is [ka] is.

[0094] Any one or any combination of the technical features in the above specific embodiments can be combined with any one or any combination of the technical features in other specific embodiments, and the present invention includes all combinations of such technical features that are not listed here.

[0095] In a more specific embodiment, the present invention provides a compound represented by general formula (I), its pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof. [ka] however, [ka] represents a single or double bond; [ka] indicates that the attachment site to the remainder of the molecule may be located at any available site on the ring; Z1 is one or two R Z1 is an O, S, N or C atom optionally substituted with; Z2 is one or two R Z2 is an O, S, N or C atom optionally substituted with; Z3 is one or two R Z3is an O, S, N or C atom optionally substituted with [ka] represents a double bond, Z2 is an N or C atom and Z3 is an N or C atom; Z4 is N or CR Z4 and; Z5 is N or CR Z5 and; R a , R b and R c are independently H, halogen, C 1-6 Alkyl, or C 1-6 Haloalkyl; R N1 is H, C 1-6 Alkyl, or C 1-6 is haloalkyl; R Z1 is absent or H, CN, halogen, C 1-6 Alkyl, or C 1-6 haloalkyl; or two R Z1 forms C=O with Z1; R Z2 is absent or H, CN, halogen, C 1-6 Alkyl, or C 1-6 is haloalkyl; R Z3 is absent or H, CN, halogen, C 1-6 Alkyl, or C 1-6 haloalkyl; or two R Z3 forms C=O with Z3; R Z4 H, CN, halogens, C 1-6 Alkyl, or C 1-6 is haloalkyl; R Z5 H, CN, halogens, C 1-6 Alkyl, or C 1-6 is haloalkyl; L1 is a chemical bond, -O-, -S(O) p -, -NR # -, -CR# R # '-or-C a R # R # '-C b R # R # '- selected from the group consisting of; L2 is a chemical bond, -O-, -S(O) p -, -NR # -, -CR # R # '-or-C a R # R # '-C b R # R # '- selected from the group consisting of; where C a R # R # ' or C b R # R # ' is O, S(O) p or NR # can be replaced by C a R # R # ' or C b R # R # ' is O, S or NR # If replaced by C a R # R # ' or C b R # R # ', another one is S(O) q can be replaced by; E is independent, -C c R # R # '-C d R # R # '-C e R # R # 'or [ka] selected from the group consisting of: where C c R # R # ', C d R # R # ' or C e R # R # ' or C c R # R # ' and C e R # R # 'Both O and S(O) p or NR # can be replaced by C c R # R # ', C d R # R # ' or C e R # R # ' is O, S or NR # If replaced by one or two adjacent Cs, c R # R # ', C d R # R # ' or C e R # R # ', S(O) q can be replaced by; H4 and H5 are N or C atoms; p is 0, 1 or 2; q is 1 or 2; R # H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, or C 2-6 is alkynyl; R # ' is H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, or C 2-6 is alkynyl; Alternatively, R on the adjacent atom # and R # can form chemical bonds, R on adjacent atoms # ' and R # ' can form chemical bonds; Alternatively, R on the same or different atoms # and R # ' together form =O; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; X1 is a C or N atom; X2 is a C or N atom; X3 is a C or N atom; X4 is an O, S, C or N atom optionally substituted with one or two R2; X5 is an O, S, C or N atom; X6 is a C or N atom; X7 is an O, S, C or N atom; R1 is H, CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, or C 2-6 is alkynyl; R2 is H, CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, or C 2-6 is alkynyl; R N2 is H, C 1-6 Alkyl, or C 1-6 is haloalkyl; The definition of L1' is the same as the definition of L1; The definition of L2' is the same as that of L2; The definition of E' is the same as the definition of E; The definition of m' is the same as the definition of m; R s1 H, CN, halogens, C 1-6 Alkyl, or C 1-6 haloalkyl; R s2H, CN, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, or C 2-6 alkynyl; R s3 H, CN, halogens, C 1-6 Alkyl, or C 1-6 haloalkyl; R s4 H, CN, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, or C 2-6 alkynyl; s1 is 0, 1, 2 or 3; s2 is 0, 1, 2 or 3; s3 is 0, 1 or 2; s4 is 0, 1, 2, 3, 4 or 5.

[0096] In a more specific embodiment, the present invention provides a compound represented by general formula (II), its pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof: [ka] wherein all groups are as defined above; Preferably, [ka] represents a single or double bond; [ka] indicates that the attachment site to the remainder of the molecule may be located at any available site on the ring;

[0097] Z1 is one or two R Z1or Z1 is absent, so that Z2 bonded to Z1 and the C atom on the aromatic ring are bonded to R to form a compound represented by general formula (II'): [ka] Z2 is R Z2 is an N or C atom optionally substituted with; Z3 is one or two R Z3 is an N or C atom optionally substituted with; Z4 is N or CR Z4 and; Z5 is N or CR Z5 and; R Z1 is absent or is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, or -(CH2) 0-5 -4 to 8-membered heterocyclyl; or two R Z1 Together with Z1, C=O, C 3-7 forming a cycloalkyl or 4- to 8-membered heterocyclyl; R Z2 is absent or is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, or -(CH2) 0-5 -4 to 8-membered heterocyclyl; R Z3 is absent or is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5-C 3-7 Cycloalkyl, or -(CH2) 0-5 -4 to 8-membered heterocyclyl; or two R Z3 Together with Z3, C=O, C 3-7 forming a cycloalkyl or 4- to 8-membered heterocyclyl; R Z4 is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, or C 1-6 is haloalkyl; R Z5 is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, or -(CH2) 0-5 -4 to 8-membered heterocyclyl; and the other groups are as defined above.

[0098] In a more specific embodiment, the present invention provides a compound represented by general formula (III), its pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof: [ka] wherein all groups are as defined above; Preferably, [ka] represents a single or double bond; [ka] indicates that the attachment site to the remainder of the molecule may be located at any available site on the ring; Z1 is R Z1is an N or C atom optionally substituted with; Z2 is one or two R Z2 is an N or C atom optionally substituted with; Z3 is one or two R Z3 is an N or C atom optionally substituted with; Z4 is N or CR Z4 and; Z5 is N or CR Z5 and; R Z1 is absent or is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, or -(CH2) 0-5 -4 to 8-membered heterocyclyl; R Z2 is absent or is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, or -(CH2) 0-5 -4 to 8-membered heterocyclyl; or two R Z2 Together with Z2, C=O, C 3-7 forming a cycloalkyl or 4- to 8-membered heterocyclyl; R Z3 is absent or is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, or -(CH2) 0-5 -4 to 8-membered heterocyclyl; or two R Z3 Together with Z3, C=O, C 3-7forming a cycloalkyl or 4- to 8-membered heterocyclyl; R Z4 is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, or C 1-6 is haloalkyl; R Z5 is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, or -(CH2) 0-5 -4 to 8-membered heterocyclyl; and the other groups are as defined above.

[0099] In a more specific embodiment, the present invention provides a compound represented by general formula (IV) or (IV'), its pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof: [ka] wherein all groups are as defined above; Preferably, [ka] represents a single or double bond; [ka] indicates that the attachment site to the remainder of the molecule may be located at any available site on the ring; Z2 is one or two R Z2 is an N or C atom optionally substituted with; Z3 is one or two R Z3 is an O, S, N or C atom optionally substituted with [ka] If represents a double bond, Z3 is a N or C atom; Z4 is N or CR Z4 and; Z5 is N or CR Z5 and; R Z2 is absent or is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, or -(CH2) 0-5 -4 to 8-membered heterocyclyl; or two R Z2 Together with Z2, C=O, C 3-7 forming a cycloalkyl or 4- to 8-membered heterocyclyl; R Z3 is absent or is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, or -(CH2) 0-5 -4 to 8-membered heterocyclyl; or two R Z3 Together with Z3, C=O, C 3-7 forming a cycloalkyl or 4- to 8-membered heterocyclyl; R Z4 is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, or C 1-6 is haloalkyl; R Z5 is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, or -(CH2) 0-5 -4 to 8-membered heterocyclyl; R is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, or -(CH2) 0-5 -4 to 8-membered heterocyclyl; and the other groups are as defined above.

[0100] In a more specific embodiment, the present invention provides a compound represented by general formula (V), its pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof: [ka] wherein all groups are as defined above; Preferably, [ka] represents a single or double bond; [ka] indicates that the attachment site to the remainder of the molecule may be located at any available site on the ring; Z1 is one or two R Z1 is an O, S, N or C atom optionally substituted with; Z2 is one or two R Z2 is an O, S, N or C atom optionally substituted with; Z3 is one or two R Z3 is an O, S, N or C atom optionally substituted with [ka] represents a double bond, Z2 is an N or C atom and Z3 is an N or C atom; Z5 is N or CR Z5 and; R Z1 is absent or is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, or -(CH2) 0-5 -4 to 8-membered heterocyclyl; or two R Z1 Together with Z1, C=O, C 3-7 forming a cycloalkyl or 4- to 8-membered heterocyclyl; R Z2 is absent or is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, or -(CH2) 0-5 -4 to 8-membered heterocyclyl; or two R Z2 Together with Z2, C=O, C 3-7 forming a cycloalkyl or 4- to 8-membered heterocyclyl; R Z3 is absent or is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, or -(CH2) 0-5 -4 to 8-membered heterocyclyl; or two R Z3 Together with Z3, C=O, C 3-7forming a cycloalkyl or 4- to 8-membered heterocyclyl; R Z5 is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, or -(CH2) 0-5 -4 to 8-membered heterocyclyl; and the other groups are as defined above.

[0101] In a more specific embodiment, the present invention provides a compound represented by general formula (VI) or (VI'), its pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof: [ka] wherein all groups are as defined above; Preferably, in the general formula (VI) or (VI'), X1 is a C or N atom; X2 is a C or N atom; X3 is a C or N atom; X4 is an O, S, C, or N atom; when X4 is a C or N atom, it may be substituted with one or two R2; X5 is a C or N atom; X6 is a C or N atom; X7 is an O, S, C or N atom; R1 is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, -(CH2) 0-5 -4 to 8-membered heterocyclyl, -(CH2)0-5 -C 6-10 Aryl, -(CH2) 0-5 - 5 to 14 membered heteroaryl, -C(O)R, -S(O)R, or -S(O)R; R2 is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, -(CH2) 0-5 -4-8 membered heterocyclyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) 0-5 -C 3-10 Halocycloalkyl, -(CH2) 0-5 -C 6-10 Aryl, -(CH2) 0-5 - 5 to 14 membered heteroaryl, -C(O)R, -S(O)R, or -S(O)R; and the other groups are as defined above.

[0102] In a more specific embodiment, the present invention provides a compound represented by general formula (VII) or (VII'), a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof: [ka] wherein all groups are as defined above; Preferably, in the general formula (VII) or (VII'), X1 is a C or N atom; X2 is a C or N atom; X3 is a C or N atom; X4 is a C or N atom; when X4 is a C atom, it may be substituted with R2; X5 is an O, S, C or N atom; X6 is a C or N atom; X7 is an O, S, C or N atom; R1 is H, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, -(CH2) 0-5 -4 to 8-membered heterocyclyl, -(CH2) 0-5 -C 6-10 Aryl, -(CH2) 0-5 - 5 to 14 membered heteroaryl, -C(O)R, -S(O)R, or -S(O)R; R2 is H, CN, halogen, -(CH2) 0-5 -OR', -(CH2) 0-5 -NR'R'', C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-5 -C 3-7 Cycloalkyl, -(CH2) 0-5 -4 to 8-membered heterocyclyl, -(CH2) 0-5 -C 6-10 Aryl, -(CH2) 0-5 - 5 to 14 membered heteroaryl, -C(O)R, -S(O)R, or -S(O)R; and the other groups are as defined above.

[0103] In more specific embodiments, the present invention provides the aforementioned compounds, pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants thereof, and mixtures thereof. [ka] teeth, [ka] [ka] selected from the group consisting of: Preferably, wherein: [ka] teeth, [ka] [ka] is selected from the group consisting of:

[0104] In more specific embodiments, the present invention provides the aforementioned compounds, pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants thereof, and mixtures thereof. L1, L2, L1' and L2' are independently a chemical bond, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NH)-, -S(O)(=NMe)-, [ka] -NH-, -N(Me)-, [ka] -N(CF3)-, -CH2-, -CH(OMe)-, -CH(Cl)-, -CH(F)-, -CF2-, -CH(CF3)-, -C(O)-, -CH2CH2-, -CH=CH-, -C≡C-, -OCH2-, -CH2O-, -SCH2-, -CH2S-, -S(O)CH2-, -CH2S(O)-, -S(O)2CH2-, -CH2S(O)2-, -NHCH2-, -N(Me)CH2-, -CH2NH-, -CH2N(Me)-, -C(O)CH2-, -CH2C(O)-, -C(O)CMe2-, -CMe2C(O)-, -OC(O)-, -C(O)O-, -SC(O)-, -C( O)S-, -NHC(O)-, -N(Me)C(O)-, -C(O)N(Me)-, -C(O)NH-, -S(O)=NH-, -NH=S(O)-, -N=S(O)Me-, -S(O)Me=N-, [ka] selected from the group consisting of:

[0105] Preferably, L1, L2, L1' and L2' are each independently a chemical bond, -O-, -S-, -S(O)-, -S(O)2-, -NH-, -N(Me)-, -N(CF3)-, -CH2-, -CH(Cl)-, -CH(F)-, -CF2-, -CH(CF3)-, -C(O)-, -CH2CH2-, -CH=CH-, -C≡C-, -OCH2-, -CHO-, -SCH2-, -CH2S-, -S(O)CH2-, -CH is selected from the group consisting of 2S(O)-, -S(O)2CH2-, -CH2S(O)2-, -NHCH2-, -N(Me)CH2-, -CH2NH-, -CH2N(Me)-, -C(O)CH2-, -CH2C(O)-, -C(O)CMe2-, -CMe2C(O)-, -OC(O)-, -C(O)O-, -SC(O)-, -C(O)S-, -NHC(O)-, -N(Me)C(O)-, -C(O)NH- or -C(O)N(Me)-.

[0106] In more specific embodiments, the present invention provides the aforementioned compounds, pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants thereof, and mixtures thereof. E and E' are independently a chemical bond, -CH2CH2CH2-, -CH2CH=CH-, -CH=CHCH2-, -CH2C≡C-, -C≡CCH2-, -CH2CH2C(O)-, -CH2C(O)CH2-, -C(O)CH2CH2-, -CH2CH2S(O)2-, -CH2S(O)2CH2-, -S(O)2CH2CH2-, -C(O)CH=CH-, -C(O)C≡C-, -CH2CH2O-, -CH2OCH2-, -OCH2CH2-, -CH2CH2S-, -CH2SCH2-, -SCH2CH2-, -C(O)CH2O-, -OCH2C(O) -, -CH2C(O)O-, -C(O)CH2S-, -SCH2C(O)-, -CH2C(O)S-, -OC(O)CH2-, -C(O)OCH2-, -CH2OC(O)-, -SC(O)CH2-, -C(O)SCH2-, -CH2SC(O)-, -CH2CH2NH-, -CH 2NHCH2-, -NHCH2CH2-, -CH2CH2NMe-, -CH2NMeCH2-, -NMeCH2CH2-, -C(O)CH2NH-, -NHCH2C(O)-, -CH2C(O)NH-, -NHC(O)CH2-, -C(O)NHCH2-, -CH2NHC(O)-, [ka] selected from the group consisting of: Alternatively, two E units or two E' units may be -CH2CH2OCH2CH2-, -OCH2CH2CH2CH2-, -CH2CH2CH2CH2O-, [ka] can be formed.

[0107] In more specific embodiments, the present invention provides the aforementioned compounds, pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof, wherein the ring in which X4, X5, X6, and X7 are located is [ka] and; Preferably, wherein E and E' independently represent a chemical bond, -CH2CH2CH2-, -CH2CH=CH-, -CH=CHCH2-, -CH2C≡C-, -C≡CCH2-, -CH2CH2C(O)-, -CH2C(O)CH2-, -C(O)CH2CH2-, -CH2CH2S(O)2-, -CH2S(O)2CH2-, -S(O)2CH2CH2-, -C(O)CH=CH-, -C(O)C≡C-, -CH2CH2O-, -CH2OCH2-, -OCH2CH2-, -CH2CH2S-, -CH2SCH2-, -SCH2CH2-, -C(O)CH2O-, -OCH2C( O)-, -CH2C(O)O-, -C(O)CH2S-, -SCH2C(O)-, -CH2C(O)S-, -OC(O)CH2-, -C(O)OCH2-, -CH2OC(O)-, -SC(O)CH2-, -C(O)SCH2-, -CH2SC(O)-, -CH2CH2NH-, -C H2NHCH2-, -NHCH2CH2-, -CH2CH2NMe-, -CH2NMeCH2-, -NMeCH2CH2-, -C(O)CH2NH-, -NHCH2C(O)-, -CH2C(O)NH-, -NHC(O)CH2-, -C(O)NHCH2-, -CH2NHC(O)-, [ka] is selected from the group consisting of:

[0108] In more specific embodiments, the present invention provides the aforementioned compounds, pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants thereof, and mixtures thereof. [ka] teeth, [ka] [ka] selected from the group consisting of:

[0109] Preferably, wherein: [ka] teeth, [ka] [ka] is selected from the group consisting of:

[0110] In more specific embodiments, the present invention provides the above-mentioned compound, its pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein the compound is represented by the following general formula (VIII): [ka] however, Z1 is one or two R Z1 is an O, S, N or C atom optionally substituted with; where R Z1 H, CN, halogens, C 1-6 Alkyl, or C 1-6 haloalkyl; or two R Z1 forms C=O with Z1; L1 is a chemical bond, -O-, -NR # -, -CR # R #’ -or- C a R # R #’ C b R # R #’ - selected from the group consisting of; L3 is a chemical bond, -O-, -NR # -, -CR # R #’ -or- C a R # R #’ C b R # R#’ - selected from the group consisting of; where C a R # R # ' or C b R # R # ' is O, S(O) p or NR # can be replaced by C a R # R # ' or C b R # R # ' is O, S or NR # If replaced by C a R # R # ' or C b R # R # ', another one is S(O) q can be replaced by; E is independently -C c R # R # '-C d R # R # '-C e R # R # 'And; where C c R # R # ', C d R # R # ' or C e R # R # ' or C c R # R # ' and C e R # R # 'Both O and S(O) p or NR # can be replaced by C c R # R # ', C d R # R# ' or C e R # R # ' is O, S or NR # If replaced by one or two adjacent Cs, c R # R # ', C d R # R # ' or C e R # R # ', S(O) q can be replaced by; p is 0, 1 or 2; q is 1 or 2; R # H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, or C 2-6 is alkynyl; R # ' is H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, or C 2-6 is alkynyl; Alternatively, R on the adjacent atom # and R # can form chemical bonds, R on adjacent atoms # ' and R # ' can form chemical bonds; Or, R on the same atom # and R # ' together form =O; m is 1, 2 or 3.

[0111] In a more specific embodiment, the present invention provides a compound represented by the general formula (VIII) above, a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof. wherein Z1 is -CH2- or -C(O)-; L1 is selected from the group consisting of a chemical bond, -O-, -NH-, -CH2-, -CH2CH2-, -CH=CH- or -C≡C-; E independently represents -CH2CH2CH2-, -CH2CH=CH-, -CH=CHCH2-, -CH2C≡C-, -C≡CCH2-, -CH2CH2O-, -CH2OCH2-, -OCH2CH2-, -CH2CH2NH-, -CH2NHCH2-, -NHCH2CH2-, -CH2CH2C(O)-, -CH2C(O)CH2-, -C(O )CH2CH2-, -CH2OC(O)-, -CH2C(O)O-, -OC(O)CH2-, -C(O)OCH2-, -CH2NHC(O)-, -CH2C(O)NH- , -NHC(O)CH2-, -C(O)NHCH2-, -OCH2C(O)-, -C(O)CH2O-, -NHCH2C(O)-, or -C(O)CH2NH-; L3 is selected from the group consisting of a chemical bond, -O-, -NH-, -CH2-, -C(O)-, -CH2CH2-, -C(O)CH2- or -CH2C(O)-; m is 1, 2 or 3.

[0112] In a more specific embodiment, the present invention provides a compound represented by the general formula (VIII) above, a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof. wherein Z1 is -CH2- or -C(O)-; L1 is selected from the group consisting of a chemical bond, -O-, -NH-, -CH2-, -CH2CH2-, -CH=CH- or -C≡C-; E is independently -CH2CH2CH2-, -CH2CH=CH-, -CH=CHCH2-, -CH2C≡C-, or -C≡CCH2-; L3 is selected from the group consisting of a chemical bond, -O-, -NH-, -CH2-, or -C(O)-; m is 1, 2 or 3.

[0113] In a more specific embodiment, the present invention provides a compound represented by the general formula (VIII) above, a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof. wherein Z1 is -CH2- or -C(O)-; L1 is selected from the group consisting of a chemical bond, -O-, -NH-, -CH2-, -CH2CH2- or -C≡C-; E is independently -CHCHCH-; L3 is selected from the group consisting of a chemical bond, -CH2-, or -C(O)-; m is 1 or 2.

[0114] In a more specific embodiment, the present invention provides a compound represented by the general formula (VIII) above, a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof. where Z1 is -CH2-; L1 is selected from the group consisting of a chemical bond, -CH2-, -CH2CH2-, or -C≡C-; E is independently -CH2CH2CH2-; L3 is selected from a chemical bond or -CH2-; m=1 or 2.

[0115] In more specific embodiments, the present invention provides the above-mentioned compound, its pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein the compound is represented by the following general formula (VIII): [ka] however, Z1 is one or two R Z1 is an O, S, N or C atom optionally substituted with; R Z1 H, CN, halogens, C 1-6 Alkyl, or C 1-6 haloalkyl; or two R Z1 forms C=O with Z1; L1 is a chemical bond, -O-, -NR # -, -CR # R #’ -or- C a R # R #’ C b R # R #’ - selected from the group consisting of; L3 is a chemical bond, -O-, -NR # -, -CR # R #’ -or- C a R # R #’ C b R # R #’ - selected from the group consisting of; E is -C c R # R # '-C d R # R # '-C e R # R # 'And; where C c R # R # ' or C e R # R # ' is O, S(O) p or NR # can be replaced by; p is 0, 1 or 2; R # H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, or C 2-6 is alkynyl; R # ' is H, halogen, C 1-6 Alkyl, C 1-6Haloalkyl, C 2-6 Alkenyl, or C 2-6 is alkynyl; Alternatively, R on the adjacent atom # and R # can form chemical bonds, R on adjacent atoms # ' and R # ' can form chemical bonds; Or, R on the same atom # and R # ' together form =O; m is 1.

[0116] In a more specific embodiment, the present invention provides a compound represented by the general formula (VIII) above, a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof. wherein Z1 is -CH2- or -C(O)-; L1 is selected from the group consisting of a chemical bond, -O-, -NH-, -CH2-, -CH2CH2-, -CH=CH- or -C≡C-; E is -CH2CH2CH2-, -CH2CH=CH-, -CH=CHCH2-, -CH2C≡C-, -C≡CCH2-, -CH2CH2C(O)-, -CH2C(O)CH2-, -C(O)CH2CH2-, -OCH2C(O)-, -C(O)CHO-, -NHCH2C(O)-, or -C(O)CH2NH-; L3 is selected from the group consisting of a chemical bond, -O-, -NH-, -CH2-, -C(O)-, -CH2CH2-, -C(O)CH2- or -CH2C(O)-; m is 1.

[0117] In a more specific embodiment, the present invention provides a compound represented by the general formula (VIII) above, a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof. wherein Z1 is -CH2- or -C(O)-; L1 is selected from the group consisting of a chemical bond, -O-, -NH-, -CH2-, -CH2CH2-, -CH=CH- or -C≡C-; E is -CH2CH2CH2-, -CH2CH=CH-, -CH=CHCH2-, -CH2C≡C- or -C≡CCH2-; L3 is selected from the group consisting of a chemical bond, -O-, -NH-, -CH2-, or -C(O)-; m is 1.

[0118] In a more specific embodiment, the present invention provides a compound represented by the general formula (VIII) above, a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof. wherein Z1 is -CH2- or -C(O)-; L1 is selected from the group consisting of a chemical bond, -O-, -NH-, -CH2-, -CH2CH2- or -C≡C-; E is -CH2CH2CH2-; L3 is selected from the group consisting of a chemical bond, -CH2-, or -C(O)-; m is 1.

[0119] In a more specific embodiment, the present invention provides a compound represented by the general formula (VIII) above, a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof. where Z1 is -CH2-; L1 is selected from the group consisting of a chemical bond, -CH2-, -CH2CH2-, or -C≡C-; E is -CH2CH2CH2-; L3 is selected from a chemical bond or -CH2-; m=1.

[0120] In more specific embodiments, the present invention provides the aforementioned compounds, pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants thereof, and mixtures thereof, wherein the aforementioned compounds are [ka] [ka] is selected from the group consisting of:

[0121] The compounds of the present invention may contain one or more asymmetric centers, and therefore may exist as various isomers, for example, enantiomers and / or diastereomers.For example, the compounds of the present invention may be in the form of individual enantiomers, diastereomers or geometric isomers (for example, cis and trans isomers), or may be in the form of a mixture of stereoisomers (including racemic mixtures and mixtures enriched with one or more stereoisomers).Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis.

[0122] Those skilled in the art will recognize that organic compounds may form complexes with solvents when reacted in or precipitated or crystallized from such solvents. These complexes are called "solvates." When the solvent is water, the complex is called a "hydrate." The present invention includes all solvates of the compounds of the present invention.

[0123] The term "solvate" generally refers to a form of a compound or its salt combined with a solvent, formed by solvolysis. This physical association involves hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds of the present invention can be prepared, for example, as crystals, and solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include stoichiometric and non-stoichiometric solvates. In certain embodiments, the solvates are isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" includes solvates in solution and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0124] The term "hydrate" refers to a compound in combination with water. Typically, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of that compound in the hydrate is constant. Thus, a hydrate of a compound may be, for example, a compound of the general formula R x HO, where R is the compound and x is a number greater than 0. A given compound may form multiple types of hydrates, such as monohydrates (x is 1), lower hydrates (x is a number greater than 0 but less than 1, e.g., hemihydrates (R 0.5 HO), and polyhydrates (where x is greater than 1, e.g., dihydrate (RHO) and hexahydrate (RHO)).

[0125] The compounds of the present invention may be in either amorphous or crystalline (polymorphic) form. They may also exist as one or more crystals. Therefore, the present invention encompasses all amorphous or crystalline forms of the compounds of the present invention. The term "polymorph" refers to a crystalline form of a compound (or its salts, hydrates, or solvates) that is a specific crystalline arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, photoelectric properties, stability, and solubility. The recrystallization solvent, crystallization rate, storage temperature, and other factors may result in a predominant crystalline form. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0126] The present invention also includes isotopically labeled compounds (isotopic variants) equivalent to those described in formula (I), but in which one or more atoms have been replaced by atoms whose atomic mass or mass number differs from the atomic mass or mass number typically found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively. 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 Examples of such isotopes include Cl. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or said prodrugs that contain the above isotopes and / or other isotopes of other atoms are included within the scope of the present invention. 3 H and 14 Some isotopically labeled compounds of the present invention, such as those incorporating tritium (i.e., C), are useful in determining the tissue distribution of drugs and / or substrates. 3 H) and carbon-14 (i.e. 14C) isotopes are particularly preferred due to their ease of preparation and detectability. 2 Substitution with heavier isotopes such as H can be advantageous in therapy due to superior metabolic stability. For example, it may be possible to increase in vivo half-life or reduce dosage, which may be considered preferred depending on the circumstances. In general, isotopically labeled compounds of formula (I) of the present invention and prodrugs thereof can be prepared by using readily available isotopically labeled reagents in place of non-isotopically labeled reagents when the processes disclosed in the following schemes and / or examples and preparations are carried out.

[0127] Furthermore, prodrugs are also included in the present specification. As used herein, the term "prodrug" refers to a compound that is converted into an active form having medical effects in vivo, 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.

[0128] A prodrug is any covalently bonded compound of the present invention that releases the parent compound in vivo upon administration to a patient. Prodrugs are typically prepared by modifying functional groups so that they can be cleaved, either by routine manipulation or in vivo, to yield the parent compound. Prodrugs include, for example, compounds of the present invention in which a hydroxyl, amino, or mercapto group is bonded to any group that, upon administration to a patient, can be cleaved to form a hydroxyl, amino, or mercapto group. Thus, representative examples of prodrugs include, but are not limited to, acetate / acetamide, formate / formamide, and benzoate / benzamide derivatives of the hydroxyl, amino, or mercapto group of a compound of Formula (I). Additionally, in the case of carboxylic acids (—COOH), esters such as methyl esters and ethyl esters can be used. The esters themselves may be active and / or may be hydrolyzed under conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those that readily decompose in the human body to release the parent acid or its salt.

[0129] The present invention also provides pharmaceutical formulations comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient, all of which forms are encompassed by the present invention.

[0130] Pharmaceutical Compositions and Kits In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the present invention.

[0131] The pharmaceutically acceptable excipient of the present invention refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound that is incorporated.The pharmaceutically acceptable carrier, adjuvant or vehicle that can be used in the composition of the present invention includes, but is not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum albumin (e.g., human serum albumin), buffer substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0132] The present invention further includes kits (e.g., pharmaceutical packs). The provided kits include a compound of the invention, another therapeutic agent, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersion packages, or other suitable containers) containing the compound of the invention and the other therapeutic agent. In some embodiments, the provided kits may also include a third container containing a pharmaceutically acceptable excipient for diluting or suspending the compound of the invention and / or the other therapeutic agent. In some embodiments, the compound of the invention in the first container and the second container are provided in combination with the other therapeutic agent to form a unit dosage form.

[0133] Administration The pharmaceutical compositions provided by the present invention can be administered by a variety of routes, including, but not limited to, oral, parenteral, inhalation, topical, rectal, nasal, buccal, vaginal, implant, or other administration methods. For example, parenteral administration used in the present invention includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection and infusion techniques.

[0134] The compounds provided by the present invention are typically administered in an effective amount, and the amount of compound actually administered will be determined by a physician depending on the circumstances, including the condition being treated, the selected administration method, the compound actually administered, the age, weight, and response of the patient, the severity of the patient's symptoms, etc.

[0135] When used to prevent the conditions described herein, the compounds provided by the present invention are administered to subjects at risk of developing the condition, typically at dosage levels as described above, based on a physician's recommendation. Subjects at risk of developing a particular condition typically include subjects with a family history of the condition or subjects predisposed to developing the condition by genetic testing or screening.

[0136] The pharmaceutical compositions provided by the present invention ("long-term administration") can also be administered chronically. Long-term 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 administered continuously indefinitely, for example, for the rest of the subject's life. For example, in some embodiments, long-term administration is intended to provide a constant level of the compound in the blood over an extended period of time, e.g., within a therapeutic window.

[0137] The pharmaceutical composition of the present invention can also be delivered using various administration methods.For example, in some embodiments, pharmaceutical compositions can be administered by bolus injection, for example, to increase the concentration of compound in blood to an effective level.The placement of bolus dose depends on the target systemic level of active ingredient through the body, for example, intramuscular or subcutaneous bolus dose allows for slow release of active ingredient, while bolus delivered directly into the vein (for example, by IV drip) allows for faster delivery, which quickly increases the concentration of active ingredient in blood to an effective level.In other embodiments, the pharmaceutical composition can be administered as continuous infusion, for example, by IV drip, to provide the maintenance of steady-state concentration of active ingredient in the subject's body.

[0138] Compositions for oral administration can take the form of bulk liquid solutions or suspensions or bulk powders. However, compositions are typically provided in unit dosage forms to allow for precise dosage administration. The term "unit dosage form" refers to physically discrete units suitable as unit dosages for human subjects and other mammals, each unit containing a predetermined amount of active ingredient calculated to produce a desired therapeutic effect, along with suitable pharmaceutical excipients. Typical unit dosage forms include pre-measured, pre-filled ampoules or syringes for liquid compositions, or pills, tablets, capsules, etc. for solid compositions. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various carriers or excipients and processing aids that serve to form the desired dosage form.

[0139] For oral administration, a typical regimen is 1 to 5, particularly 2 to 4, and typically 3 oral doses per day. Using these dosing patterns, each dose provides about 0.01 to about 20 mg / kg of the compound of the invention, with preferred doses providing about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg, respectively.

[0140] Transdermal doses are generally selected to provide blood levels similar to or lower than those achieved using injection doses, and generally range from about 0.01% to about 20% by weight, preferably from about 0.1% to about 20% by weight, preferably from about 0.1% to about 10% by weight, and more preferably from about 0.5% to about 15% by weight.

[0141] Injectable dose levels range from about 0.1 mg / kg / hour to at least 10 mg / kg / hour, all over a period of about 1 to about 120 hours, particularly 24 to 96 hours. A preloading bolus 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 will not exceed about 2 g / day for a 40-80 kg human patient.

[0142] 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: binders (e.g., microcrystalline cellulose, gum tragacanth, or gelatin); excipients (e.g., starch or lactose); disintegrating agents (e.g., alginic acid, Primogel, or corn starch); lubricants (e.g., magnesium stearate); glidants (e.g., colloidal silicon dioxide); sweetening agents (e.g., sucrose or saccharin); or flavoring agents (e.g., peppermint, methyl salicylate, or orange flavor).

[0143] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline or other injectable excipients known in the art. Conventionally, 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.

[0144] Transdermal compositions are typically formulated as topical ointments or creams containing active ingredient(s).When formulated as an ointment, the active ingredient is typically mixed with a paraffin ointment base or a water-miscible ointment base.Alternatively, the active ingredient can be formulated as a cream, for example, containing an oil-in-water cream base.Such transdermal formulations are well known in the art and generally contain additional ingredients that enhance the skin penetration or stability of the active ingredient or formulation.All such known transdermal formulations and ingredients are included within the scope provided by the present invention.

[0145] The compounds of this invention 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.

[0146] The components described above for orally administrable, injectable, or topically administrable compositions are merely representative. Other materials and processing techniques are set forth in Part 8 of Remington's Pharmaceutical Sciences, 17th Edition, 1985, Mack Publishing Company, Easton, Pennsylvania (incorporated herein by reference).

[0147] The compounds of this invention 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.

[0148] The present invention also relates to pharmaceutically acceptable formulations of the compounds of the present invention. In one embodiment, the formulation contains water. In another embodiment, the formulation contains a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, which consist of 6, 7, and 8 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 a specific embodiment, 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 some embodiments, the formulation contains hexapropyl-β-cyclodextrin (e.g., 10-50% in water).

[0149] treatment As mentioned above, EGFR kinase is known to play a role in tumorigenesis as well as many other diseases. The compounds of the present invention exhibit potent antitumor activity, which is believed to be achieved by inhibiting EGFR kinase.

[0150] The compounds of the present invention are valuable as antitumor agents. In particular, the compounds of the present invention are valuable as antiproliferative, apoptotic, and / or anti-invasive agents in the prevention and / or treatment of solid and / or liquid tumor diseases. In particular, the compounds of the present invention are expected to be useful in the prevention or treatment of tumors sensitive to ATR inhibition. Furthermore, the compounds of the present invention are expected to be useful in the prevention or treatment of tumors mediated solely or in part by EGFR. Thus, the compounds are useful for producing EGFR enzyme inhibitory effects in warm-blooded animals in need of such treatment.

[0151] As noted above, inhibitors of EGFR kinase are useful in the treatment of cancers such as, for example, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute myeloid leukemia (AML), multiple myeloma, melanoma, and mesothelioma.

[0152] Therefore, anti-cancer effects useful in treating cancer in patients include, but are not limited to, anti-tumor effects, response rates, time to disease progression, and survival rates. Anti-tumor effects of the therapeutic methods of the present invention include, but are not limited to, inhibition of tumor growth, delay of tumor growth, tumor regression, tumor reduction, increasing the time until tumor regrowth after treatment is stopped, and delay of disease progression. Anti-cancer effects include not only preventative treatment, but also treatment of existing disease.

[0153] Furthermore, EGFR kinase inhibitors, or pharmaceutically acceptable salts thereof, are useful for treating cancer patients, including hematological malignancies such as leukemia and multiple myeloma; lymphomas such as Hodgkin's disease, non-Hodgkin's lymphoma (including mantle cell lymphoma), and myelodysplastic syndrome; and solid tumors and their metastases, such as breast cancer, lung cancer (non-small cell lung cancer (NSCL), small cell lung cancer (SCLC), non-small cell lung cancer (NSCL)), endometrial cancer, central nervous system tumors (e.g., glioma, dysembryoplastic neuroepithelial tumor, glioblastoma multiforme, mixed glioma, medulloblastoma, retinoblastoma, neuroblastoma, germinoma, and teratoma), gastrointestinal cancer. Cancers that may be affected include, but are not limited to, cancers of the esophagus (e.g., stomach cancer), esophageal cancer, hepatocellular (liver) cancer, bile duct cancer, colorectal cancer, small intestine cancer, pancreatic cancer, skin cancer such as melanoma (especially metastatic melanoma), thyroid cancer, head and neck and salivary gland cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, uterine cancer, vulvar cancer, bladder cancer, kidney cancer (including renal cell carcinoma, clear cell carcinoma, and renal oncocytoma), squamous cell carcinoma, sarcomas such as osteosarcoma, chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, Ewing's sarcoma, gastrointestinal stromal tumor (GIST), Kaposi's sarcoma, and childhood cancers such as rhabdomyosarcoma and neuroblastoma.

[0154] An effective amount of the compound of the present invention is typically 0.01 mg to 50 mg of compound / kg of patient body weight per day, preferably 0.1 mg to 25 mg of compound / kg of patient body weight, administered in one or more doses. Typically, the compound of the present invention can be administered to a patient in need of this treatment at a daily dose ranging from about 1 mg to about 3500 mg per patient, preferably 10 mg to 1000 mg per patient. For example, the daily dose per patient can be 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 500, 600, 700, 800, 900, or 1000 mg. The compound can be administered in one or more doses daily, weekly (or every few days), or on an intermittent schedule. For example, the compound can be administered weekly (e.g., every Monday), once or multiple times daily, irregularly, or continuously for several weeks, e.g., 4 to 10 weeks. Alternatively, the compound can be administered daily for several days (e.g., 2 to 10 days), followed by no administration for several days (e.g., 1 to 30 days), and this cycle can be repeated at random or a predetermined number of times, e.g., 4 to 10 times. For example, the compound of the present invention can be administered continuously daily for 5 days, followed by a 9-day break, followed by another 5 days of continuous daily administration, followed by a 9-day break, and this cycle can be repeated irregularly or a total of 4 to 10 times.

[0155] Combination therapy The treatments defined herein may be applied as the sole treatment or may include, in addition to the compounds of the present invention, conventional surgery or radiotherapy or chemotherapy. Thus, the compounds of the present invention may also be used in combination with existing therapeutic agents for treating cancer.

[0156] Combination therapy also refers to conventional surgery, radiation therapy, chemotherapy, or immunotherapy in addition to the compounds of the present invention. Such chemotherapy may be administered simultaneously, sequentially, or separately from the compounds of the present invention and may include one or more of the following types of anti-tumor agents:

[0157] (i) Antiproliferative and antitumor agents and their combinations used in medical oncology, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolomide, nitrosoureas); antimetabolites (e.g., gemcitabine and folate antagonists, such as fluoropyrimidines (5-fluorouracil and tegafur), raltitrexate, methotrexate, cytosine arabinoside, hydroxyurea); antitumor antibiotics (e.g., adriamycin, anthracyclines such as vincristine, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin; mitotic inhibitors (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine; taxoids such as paclitaxel, taxotere, and polo-kinase inhibitors); and topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide, teniposide, amsacrine, topotecan, and camptothecin);

[0158] (ii) cell proliferation inhibitors, such as antiestrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxifene), antiandrogens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or agonists (e.g., goserelin, leuprorelin, and buserelin), progestogens (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorazole, and exemestane), and 5α-reductase inhibitors (e.g., finasteride);

[0159] (iii) anti-invasion agents: for example, c-Src kinase family inhibitors (e.g., 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline [AZD0530 (saracatinib)], N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825) and bosutinib (SKI-606), as well as metalloproteinase inhibitors (e.g., marimastat), inhibitors of urokinase plasminogen activator receptor function or antibodies against heparanase);

[0160] (iv) Growth factor function inhibitors: for example, growth factor antibodies and growth factor receptor antibodies (e.g., the anti-erbB2 antibody trastuzumab [Herceptin], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225]); further, tyrosine kinase inhibitors, for example, inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors, such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinylpropoxy)-quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774), 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinylpropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors (e.g., lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family, such as imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (e.g., Ras / Raf signaling inhibitors such as farnesyltransferase inhibitors, e.g., sorafenib (BAY43-9006), tipifarnib (R115777), lonafarnib (SCH66336)), inhibitors of mEK and / or AKT kinase-mediated cell signaling, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase (aurora kinase) inhibitors (e.g., AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528, AX39459), including cyclin-dependent kinase inhibitors such as CDK2 and / or CDK4 inhibitors;

[0161] (v) Antiangiogenic agents: for example, those that inhibit the effects of vascular endothelial growth factor (e.g., the anti-vascular endothelial growth factor antibody bevacizumab (Avastin)); and VEGF receptor tyrosine kinase inhibitors, such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW786034), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171), and compounds that act by other mechanisms (e.g., linomide, integrin ανβ3 function inhibitors, and angiostatin);

[0162] (vi) vascular damaging agents: e.g., combretastatin A4;

[0163] (vii) endothelin receptor antagonists: for example, zibotentan (ZD4054) or atrasentan;

[0164] (viii) Antisense therapy: for example, directed against the above targets, such as ISIS2503 (antisense therapeutic agent);

[0165] (ix) Gene therapy approaches, including approaches that replace abnormal genes (e.g., abnormal p53 or abnormal BRCA1 or BRCA2); GDEPT (gene-directed enzyme prodrug therapy) approaches, such as approaches that use cytosine deaminase, thymidine kinase, or bacterial nitroreductase; and approaches that increase a patient's resistance to chemotherapy or radiation therapy (e.g., multidrug resistance gene therapy);

[0166] (x) Immunotherapy approaches: ex-vivo and in-vivo approaches to increase the immunogenicity of a patient's tumor cells, such as transfection with cytokines (e.g., interleukin-2, interleukin-4, or granulocyte-macrophage colony-stimulating factor); approaches to reduce T cell anergy; approaches using transfected immune cells (e.g., cytokine-transfected dendritic cells); approaches using cytokine-transfected tumor cell lines; approaches using anti-idiotypic antibodies; approaches to reduce the function of immunosuppressive cells (e.g., regulatory T cells, myeloid-derived immunosuppressive cells, or IDO (indoleamine 2,3-deoxygenase)-expressing dendritic cells); and approaches using cancer vaccines consisting of proteins or peptides derived from tumor-associated antigens (e.g., NY-ESO-1, mAGE-3, WT1, or Her2 / neu).

[0167] Example The materials or reagents used in the present invention are either commercially available or prepared by synthetic methods generally known in the art.

[0168] Preparation of 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (C1-1) [ka]

[0169] Methyl 3-bromo-2-methylbenzoate (1.14 g, 5.0 mmol) was dissolved in 20.0 mL of CCl4. Under nitrogen gas protection, NBS (1.34 g, 7.5 mmol) and AIBN (164 mg, 1.0 mmol) were added, and the mixture was heated to 85 °C and refluxed for 20 h. TLC showed no remaining starting material. The reaction mixture was cooled to room temperature, filtered under suction, and the filtrate was concentrated under reduced pressure to obtain the crude product. Purification by flash chromatography afforded 1.35 g of a pale yellow oil. This oil (1.35 g, 4.41 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (941 mg, 5.74 mmol) were dispersed in 25.0 mL of anhydrous MeCN. TEA (580 mg, 5.74 mmol) was added, and the mixture was heated to 80 °C and refluxed for 16 h. LCMS showed that the reaction was complete. After cooling to room temperature, the reaction mixture was filtered under suction, the filter cake was washed three times with MeCN, and the solid was dried to give compound D1-1 (1.31 g, 92.3% yield). LCMS: [M+H] + =323,325.

[0170] Preparation of target compounds 3-(1-oxo-4-(4-(4-(((R,E)-1 1 ,2 6 ,7-trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-2(2,4)-pyridine-1(4,5)-pyrazolecyclododecane-5 6 Preparation of (1-yl)methyl)piperazin-1-yl)butyl)isoindol-2-yl)piperidine-2,6-dione (D1) [ka]

[0171] Step 1: D1-1 (644 mg, 2.0 mmol), CuI (38 mg, 0.2 mmol), and Pd(dppf)Cl2 (146.2 mg, 0.2 mmol) were dispersed in 20.0 mL of anhydrous DMF. Under N2 protection, D1-2 (280.4 mg, 4.0 mmol) and TEA (606 mg, 6.0 mmol) were added sequentially. The mixture was heated to 70 °C and reacted for 20 h. LCMS showed the reaction was complete. The reaction mixture was cooled to room temperature and purified by RP-Flash to give crude product D1-3 (450 mg, 72.1% yield) as a pale yellow solid. LCMS: [M+H] + =313.

[0172] Step 2: D1-3 (450 mg, 1.44 mmol) was dissolved in 90.0 mL of anhydrous MeOH, and 10% Pd / C (225 mg) was added to the mixture. H2 (0.4 atm) was added to the reaction mixture, and the mixture was reacted at room temperature for 2 h. LCMS showed the reaction was complete. The reaction mixture was filtered under suction to remove the solid catalyst, and the filtrate was decompressed to remove the solvent, yielding crude product D1-4 (450 mg, 98.9% yield) as a white solid. This crude product was used directly in the next reaction. LCMS: [M+H] + =317.

[0173] Step 3: D1-4 (420 mg, 1.33 mmol) was dissolved in 150 mL of anhydrous DCM, and Dess-Martin reagent (1010 mg, 2.39 mmol) was added under N2 protection. The mixture was heated to 50 °C and refluxed for 2.0 h. Completion of the reaction was confirmed by TLC. After cooling to room temperature, 30 mL of saturated NaHCO3 solution and 30 mL of saturated Na2S2O3 solution were added to the reaction mixture and stirred at room temperature for 5 min. The organic layer was separated, dried over anhydrous sodium sulfate, and suction filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. This crude product was purified by flash filtration to obtain product D1-5 (350 mg, 83.3% yield) as a white solid. LCMS: [M+H] + =315.

[0174] Step 4: D1-5 (47.1 mg, 0.15 mmol) and D1-6 (63.4 mg, 0.12 mmol) were dissolved in a mixture of 5.0 mL of anhydrous DCM and 0.5 mL of anhydrous MeOH. CH3COOH (13.5 mg, 0.225 mmol) was added under nitrogen gas protection and stirred at room temperature for 0.5 h. Next, solid NaBH3CN (18.84 mg, 0.3 mmol) was added to the reaction mixture, and the mixture was allowed to react at room temperature for an additional 2 h. Completion of the reaction was confirmed by LCMS and TLC. The reaction mixture was purified by prep-TLC to give the crude product. This crude product was further purified by prep-HPLC to give the pure product D1 (10.5 mg, 10.61% yield) as a white solid. LCMS: [M+H] + =827.

[0175] 3-(1-oxo-4-(5-(4-(((R,E)-1 1 ,2 6 ,7-trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-2(2,4)-pyridine-1(4,5)-pyrazolecyclododecane-5 6 Preparation of (1-yl)methyl)piperazin-1-yl)pent-1-yn-1-yl)isoindol-2-yl)piperidine-2,6-dione (D2) [ka]

[0176] Step 1: D2-1 (or D1-1) (322 mg, 1.0 mmol), CuI (19 mg, 0.1 mmol), and Pd(dppf)Cl2 (73.1 mg, 0.1 mmol) were dispersed in 10.0 mL of anhydrous DMF. Under N2 protection, pent-4-yn-1-ol (210 mg, 2.5 mmol) and TEA (303 mg, 3.0 mmol) were added sequentially. The mixture was heated to 70 °C and reacted for 20 h. LCMS showed the reaction was complete. The reaction mixture was cooled to room temperature and purified by RP-Flash to obtain crude product D2-3 (410 mg, 94.1% yield) as a white solid. LCMS: [M+H] + =327.

[0177] Step 2: D2-3 (400 mg, 0.920 mmol) was dissolved in a mixture of 150 mL of anhydrous DCM and 10 mL of anhydrous THF. Dess-Martin reagent (1.04 g, 2.454 mmol) was added under N2 protection, and the mixture was heated to 50 °C and refluxed for 2.0 h. Completion of the reaction was confirmed by TLC. After cooling to room temperature, 20 mL of saturated NaHCO3 solution and 20 mL of saturated Na2S2O3 solution were added to the reaction mixture and stirred vigorously at room temperature for 5 min. The organic layer was separated, dried over anhydrous sodium sulfate, and suction filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. This crude product was purified by flash filtration to obtain product D2-4 (280 mg, 93.3% yield) as a pale yellow solid. LCMS: [M+H] + =325.

[0178] Step 3: D2-4 (48.6 mg, 0.15 mmol) and D1-6 (63.4 mg, 0.12 mmol) were dissolved in a mixture of 50 mL of anhydrous DCM and 0.5 mL of anhydrous MeOH. CH3COOH (13.5 mg, 0.225 mmol) was added under nitrogen gas protection and stirred at room temperature for 0.5 h. Next, solid NaBH3CN (18.84 mg, 0.3 mmol) was added to the reaction mixture, and the mixture was allowed to react at room temperature for an additional 2 h. Completion of the reaction was confirmed by LCMS and TLC. The reaction mixture was purified by prep-TLC to obtain the crude product. This crude product was further purified by prep-HPLC to obtain the pure product D2 (20 mg, 20.0% yield) as a white solid. LCMS: [M+H] + =837.

[0179] 3-(1-oxo-4-(5-(4-(((R,E)-1 1 ,2 6 ,7-trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-2(2,4)-pyridine-1(4,5)-pyrazolecyclododecane-5 6 Preparation of (-yl)methyl)piperazin-1-yl)pentyl)isoindol-2-yl)piperidine-2,6-dione (D3) [ka]

[0180] Starting from 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (D1-1) and pent-4-yn-1-ol, D3 was prepared in the same manner as D1 to give a white solid. LCMS: [M+H] + =841.

[0181] 3-(1-oxo-4-(6-(4-(((R,E)-1 1 ,2 6 ,7-trimethyl-3-oxo-5 2 ,5 3-dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-2(2,4)-pyridine-1(4,5)-pyrazolecyclododecane-5 6 Preparation of (1-yl)methyl)piperazin-1-yl)hexyl)isoindol-2-yl)piperidine-2,6-dione (D4) [ka] Starting from 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (D1-1) and hex-5-yn-1-ol, D4 was prepared in the same manner as D1 to give a white solid. LCMS: [M+H] + =855.

[0182] 3-(1-oxo-4-(7-(4-(((R,E)-1 1 ,2 6 ,7-trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-2(2,4)-pyridine-1(4,5)-pyrazolecyclododecane-5 6 Preparation of (1-yl)methyl)piperazin-1-yl)heptyl)isoindol-2-yl)piperidine-2,6-dione (D5) [ka] Starting from 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (D1-1) and hept-6-yn-1-ol, D5 was prepared in the same manner as D1 to give a white solid. LCMS: [M+H] + =869.

[0183] EGFR inhibitory activity assay 1. Experimental Method (1) Compound stock solutions were prepared and diluted 3x to obtain compound dilutions. 10 nL of the compound dilutions were transferred to a 384-well plate (784075, Greiner) using an Echo550. (2) The plate was sealed and centrifuged at 1,000 g for 1 minute. (3) 2x EGFR using 1x kinase buffer L858R / T790M / C797S Protein working solutions were prepared for each. (4) 5 μl of the 2×EGFR protein working solution was added to the 384-well plate from step (2), centrifuged at 1,000 g for 30 seconds, and allowed to stand (mix thoroughly) at room temperature for 10 minutes. (5) A mixture of 2×TK-substrate-biotin (2 μM) and ATP was prepared using 1×Kinase buffer. (6) 5 μl of TK-substrate-biotin and ATP (the mixture prepared in step (5)) was added to the 384-well plate from step (4) to initiate the reaction. (7) After centrifugation at 1,000 g for 30 seconds, the plate was sealed and allowed to stand (react) at room temperature for 40 minutes. (8) 4XSa-XL 665 and TK-antibody-Cryptate were prepared using detection buffer. (9) 5 μl of Sa-XL 665 and 5 μl of TK-antibody-Cryptate were added sequentially to the 384-well plate from step (7). (10) The mixture was centrifuged at 1,000 g for 30 seconds and allowed to stand (react) at room temperature for 1 hour. (11) Fluorescence values ​​were read at 615 nm and 665 nm using a microplate reader (PerkinElmer, 74785).

[0184] 2. Data Analysis The ratio (665 / 615) for each well was calculated. Formula for % inhibition:

number

number

number

number

[0185] 3. Experimental Results Mutant EGFR L858R / T790M / C797S Inhibitory activity IC of the compounds of the present invention against 50 The values ​​are shown in the table below. [Table 1]

[0186] Conclusion: The compounds of the present invention inhibit the mutated EGFR L858R / T790M / C797S It has strong inhibitory activity against

[0187] Ba / F3(EGFR L858R / T790M / C797S ) and Ba / F3 (EGFR Del19 / T790M / C797S ) Cell activity assay 1. Experimental Method (1) Ba / F3 (EGFR L858R / T790M / C797S ) and Ba / F3 (EGFR Del19 / T790M / C797S) Cells were cultured according to ATCC requirements and incubated in an incubator at 37°C under 5% CO2. Cells were analyzed by index analysis. Cells with a viability of >90% were used for experiments. Cells were seeded into 384-well plates (PerkinElmer, 6007680) at 700 cells / well, 30 μl / well. (2) Compound stock solutions were prepared and diluted 3x to obtain compound dilutions. 30 nL of compound dilutions were added to a 384-well plate using an Echo (Labcyte, Echo 550) microscope. The plate was incubated at 37°C in a 5% CO2 incubator for 72 hours. (3) 30 μl of CTG was added to each well, and the 384-well plate was shaken using a plate shaker (QILINBEIER, QB-9002). The 384-well plate was incubated in the dark at 37°C and 5% CO for 30 minutes, and the chemiluminescence readings were then measured using Envision (PerkinElmer, EnVision 2104).

[0188] 2. Data Analysis The percentage of inhibition (% inhibition) was calculated by the following formula:

number

number

number

number

[0189] 3. Experimental Results Ba / F3(EGFR L858R / T790M / C797S ) and Ba / F3 (EGFR Del19 / T790M / C797S ) Inhibitory activity IC of the compounds of the present invention against cells 50 The values ​​are shown in the table below. [Table 2]

[0190] Conclusion: The compounds of the present invention inhibit the mutant Ba / F3 (EGFR L858R / T790M / C797S ) and Ba / F3 (EGFR Del19 / T790M / C797S ) It has strong inhibitory activity against cells.

[0191] Compound EGFR L858R / T790M / C797S Assay for proteolysis-inducing activity The compounds of the present invention are Ba / F3 (EGFR L858R / T790M / C797S To further explain why they have inhibitory activity against EGFR cells, a typical compound, D3, was selected to study the mechanism of action of the compound. L858R / T790M / C797S The effect on protein levels was examined.

[0192] (1) Cell culture: Ba / F3(EGFR L858R / T790M / C797S ) Cells were cultured according to the culture conditions recommended by ATCC and analyzed by index. Complete medium: 1640 medium, 10% FBS, 1x glutamine, 1x penicillin-streptomycin. Culture conditions: Incubated at 37°C in an incubator with 95% air and 5% CO2.

[0193] (2) Compound stock solution: 10 mm DMSO stock solution, stored at -20°C.

[0194] (3) Preparation of cell suspension: Cells in the cell culture bottle were harvested, and cells with a viability of >90% were used for the assay. 40 μL of cells were diluted to 1*10 5 Cells / well were seeded into 96-well plates.

[0195] (4) Compound treatment: The compounds were diluted with DMSO to an initial concentration of 1.0 mM, and diluted 3 times to prepare a working solution with a 10-concentration gradient.

[0196] (5) The compounds were added to a 96-well plate, and the cells were incubated in an incubator at 37°C, 95% air, and 5% CO2 for 6 hours.

[0197] (6) Measurement: 1) Cells were activated with 1 μg / ml EGF and treated for 10 min. 2) After compound treatment, cells were lysed by adding lysis buffer. 10 μL of the cell lysate was added to a 384-well plate, and simultaneously, 5 μL of the acceptor mix was added to the 384-well plate, followed by shaking for 1 to 2 minutes on a shaker. 3) 5 μL of donor mix was added to each well, the 384-well plate was sealed, shaken on a shaker for 1-2 minutes, left at room temperature in the dark overnight, and then read using a microplate reader.

[0198] (7) Data analysis: Alpha Counts were fitted by logarithmic processing of compound concentrations using Graphpad Prism 8.0. Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)) X: logarithm of compound concentration; Y: Alpha Counts.

[0199] (8) Experimental results: Mutant EGFR L858R / T790M / C797S The effect of compounds of the invention on protein levels is shown in FIG. As shown in Figure 1, the experimental results showed that EGFR L858R / T790M / C797S The protein level decreased with increasing concentrations of Compound D3, indicating that Compound D3 inhibits EGFR L858R / T790M / C797S significantly reduced protein levels, and that DC 50 The compound of the present invention dose-dependently inhibited EGFR L858R / T790M / C797S It was demonstrated to have a significant decomposition effect on proteins. Conclusion: The compounds of the present invention inhibit EGFR in cells in a dose-dependent manner. L858R / T790M / C797S It can induce protein degradation.

[0200] The above is a detailed description of the present invention with reference to preferred embodiments, but the present invention is not limited to the above description. It will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the present invention.

Claims

1. A compound represented by general formula (I), its pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, or isotopic variants, and mixtures thereof, 【Chemistry 1】 however, 【Chemistry 2】 represents a single or double bond; 【Transformation 3】 indicates that the attachment site to the remainder of the molecule may be located at any available site on the ring; 【Chemistry 4】 teeth, 【Transformation 5】 selected from the group consisting of: L １ is a chemical bond, -O-, -S(O) ｐ -, -NR ＃ -, -CR ＃ R ＃ '- or -C ａ R ＃ R ＃ '-C ｂ R ＃ R ＃ '- selected from the group consisting of; L ２ is -CR # R # '-; Here, C ａ R ＃ R ＃ ' or C ｂ R ＃ R ＃ ' is O, S(O) ｐ or NR ＃ and C ａ R ＃ R ＃ ' or C ｂ R ＃ R ＃ ' is O, S or NR ＃ When replaced with ａ R ＃ R ＃ ' or C ｂ R ＃ R ＃ Another one of ' is S(O) ｑ can be replaced by; E is independently -C ｃ R ＃ R ＃ '-C ｄ R ＃ R ＃ '-C ｅ R ＃ R ＃ 'or 【Transformation 6】 selected from the group consisting of: Here, C ｃ R ＃ R ＃ ', C ｄ R ＃ R ＃ ' or C ｅ R ＃ R ＃ ' or C ｃ R ＃ R ＃ ' and C ｅ R ＃ R ＃ ' both O, S(O) ｐ or NR ＃ and C ｃ R ＃ R ＃ ', C ｄ R ＃ R ＃ ' or C ｅ R ＃ R ＃ ' is O, S or NR ＃ If replaced by one or two adjacent Cs, ｃ R ＃ R ＃ ', C ｄ R ＃ R ＃ ' or C ｅ R ＃ R ＃ ', S(O) ｑ can be replaced by; H ４ and H ５ is a N or C atom; p is 0, 1 or 2; q is 1 or 2; R ＃ is H, halogen, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ alkenyl, or C ２－６ is alkynyl; R ＃ ' is H, halogen, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ alkenyl, or C ２－６ is alkynyl; Alternatively, R on an adjacent atom ＃ and R ＃ can form a chemical bond, and R on adjacent atoms ＃ ' and R ＃ ' is capable of forming a chemical bond; Alternatively, R on the same or different atoms ＃ and R ＃ ' together form =O; m is 2; 【Transformation 7】 teeth, 【Transformation 8】 selected from the group consisting of Compounds represented by general formula (I), pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, or isotopic variants thereof, and mixtures thereof.

2. Z ４ and Z ２ are bonded to form a compound represented by the following general formula (II): 【Chemistry 9】 where: 【Chemistry 10】 but, 【Chemistry 11】 selected from the group consisting of: the other groups are as defined in claim 1.

10. The compound of claim 1, its pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, or isotopic variants, and mixtures thereof.

3. The compound is a compound represented by the following general formula (VI) or (VI'): 【Chemistry 12】 wherein all groups are as defined in claim 1; 10. The compound of claim 1, its pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, or isotopic variants, and mixtures thereof.

4. L 1 is a chemical bond, —O—, —S—, —S(O)—, —S(O) ２ -, -NH-, -N(Me)-, -N(CF ３ ) -, -CH ２ -, -CH(Cl)-, -CH(F)-, -CF ２ -, -CH(CF ３ )-, -C(O)-, -CH ２ CH ２ -, -CH=CH-, -C≡C-, -OCH ２ -, -CH ２ O-, -SCH ２ -, -CH ２ S-, -S(O)CH ２ -, -CH ２ S(O)-, -S(O) ２ CH ２ -, -CH ２ S (O) ２ --NHCH ２ -, -N(Me)CH ２ -, -CH ２ NH-, -CH ２ N(Me)-, -C(O)CH ２ -, -CH ２ C(O)-, -C(O)CMe ２ --, --CMe ２ selected from the group consisting of —C(O)—, —OC(O)—, —C(O)O—, —SC(O)—, —C(O)S—, —NHC(O)—, —N(Me)C(O)—, —C(O)NH—, or —C(O)N(Me)—; L 2 is selected from the group consisting of —CH 2 —, —CH(Cl)—, —CH(F)—, —CF 2 —, —CH(CF 3 )—, and —C(O)—; A compound according to any one of claims 1 to 3, its pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, or isotopic variants, and mixtures thereof.

5. E is a chemical bond, -CH ２ CH ２ CH ２ -, -CH ２ CH=CH-, -CH=CHCH ２ -, -CH ２ C≡C-, -C≡CCCH ２ -, -CH ２ CH ２ C(O)-, -CH ２ C(O)CH ２ -, -C(O)CH ２ CH ２ -, -CH ２ CH ２ S(O) ２ -, -CH ２ S(O) ２ CH ２ -, -S(O) ２ CH ２ CH ２ -, -C(O)CH=CH-, -C(O)C≡C-, -CH ２ CH ２ O-, -CH ２ OCH ２ -, -OCH ２ CH ２ -, -CH ２ CH ２ S-, -CH ２ SCH ２ -, -SCH ２ CH ２ -, -C(O)CH ２ O-, -OCH ２ C(O)-, -CH ２ C(O)O-, -C(O)CH ２ S-, -SCH ２ C(O)-, -CH ２ C(O)S-, -OC(O)CH ２ -, -C(O)OCH ２ -, -CH ２ OC(O)-, -SC(O)CH ２ -, -C(O)SCH ２ -, -CH ２ SC(O)-, -CH ２ CH ２ NH-, -CH ２ NHCH ２ -, -NHCH ２ CH ２ -、-CH ２ CH ２ NMe-、-CH ２ NMeCH ２ -、-NMeCH ２ CH ２ -、-C(O)CH ２ NH-、-NHCH ２ C(O)-、-CH ２ C(O)NH-、-NHC(O)CH ２ -、-C(O)NXCH ２ -、-CH ２ NXC(O)-、 【Chemistry 13】 selected from the group consisting of 10. The compound of claim 1, its pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, or isotopic variants, and mixtures thereof.

6. A compound represented by general formula (VIII): 【Chemistry 14】 however, Z １ But one or two R Ｚ１ is a C atom optionally substituted with Here, R Ｚ１ is H; or two R Ｚ１ Z １ together to form C=O; L １ is a chemical bond, -O-, -NR ＃ -, -CR ＃ R ＃’ -or-C ａ R ＃ R ＃’ C ｂ R ＃ R ＃’ - selected from the group consisting of; L ３ is a chemical bond, -O-, -NR ＃ - or -CR ＃ R ＃’ - selected from the group consisting of; Here, C ａ R ＃ R ＃ ' or C ｂ R ＃ R ＃ ' is O, S(O) ｐ or NR ＃ and C ａ R ＃ R ＃ ' or C ｂ R ＃ R ＃ ' is O, S or NR ＃ When replaced with ａ R ＃ R ＃ ' or C ｂ R ＃ R ＃ Another one of ' is S(O) ｑ can be replaced by; E is independently -C ｃ R ＃ R ＃ '-C ｄ R ＃ R ＃ '-C ｅ R ＃ R ＃ ' and; Here, C ｃ R ＃ R ＃ ', C ｄ R ＃ R ＃ ' or C ｅ R ＃ R ＃ ' or C ｃ R ＃ R ＃ ' and C ｅ R ＃ R ＃ ' both O, S(O) ｐ or NR ＃ and C ｃ R ＃ R ＃ ', C ｄ R ＃ R ＃ ' or C ｅ R ＃ R ＃ ' is O, S or NR ＃ If replaced by one or two adjacent Cs, ｃ R ＃ R ＃ ', C ｄ R ＃ R ＃ ' or C ｅ R ＃ R ＃ ', S(O) ｑ can be replaced by; p is 0, 1 or 2; q is 1 or 2; R ＃ H, halogen, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ alkenyl, or C ２－６ is alkynyl; R ＃ ' is H, halogen, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ alkenyl, or C ２－６ is alkynyl; Alternatively, R on an adjacent atom ＃ and R ＃ can form a chemical bond, and R on adjacent atoms ＃ ' and R ＃ ' is capable of forming a chemical bond; Alternatively, R on the same atom ＃ and R ＃ ' together form =O; m is 1; The compound, its pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, or isotopic variants, and mixtures thereof.

7. Z １ But -CH ２ - or -C(O)-; L １ is a chemical bond, -O-, -NH-, -CH ２ -, -CH ２ CH ２ selected from the group consisting of -, -CH=CH-, or -C≡C-; E is, independently, -CH ２ CH ２ CH ２ -, -CH ２ CH=CH-, -CH=CHCH ２ -, -CH ２ C≡C-, -C≡CCH ２ -, -CH ２ CH ２ O-, -CH ２ OCH ２ -, -OCH ２ CH ２ -, -CH ２ CH ２ NH-, -CH ２ NHCH ２ -, -NHCH ２ CH ２ -, -CH ２ CH ２ C(O)-, -CH ２ C(O)CH ２ -, -C(O)CH ２ CH ２ -, -CH ２ OC(O)-, -CH ２ C(O)O-, -OC(O)CH ２ -, -C(O)OCH<X ２ -, -CH ２ NH C(O)-, -CH ２ C(O)NH-, -NH C(O)CH ２ -, -C(O)NHCH ２ -, -OCH ２ C(O)-, -C(O)CH ２ O-, -NHCH ２ C(O)-, or -C(O)CH ２ NH-; L ３ is a chemical bond, -O-, -NH-, -CH ２ -, or -C(O)-; m is 1; A compound represented by the general formula (VIII) according to claim 6, its pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, or isotopic variants, and mixtures thereof.

8. A compound represented by general formula (VIII): 【Chemistry 15】 however, Z １ But one or two R Ｚ１ is a C atom optionally substituted with R Ｚ１ is H; or two R Ｚ１ Z １ together to form C=O; L １ is a chemical bond, -O-, -NR ＃ -, -CR ＃ R ＃’ -or-C ａ R ＃ R ＃’ C ｂ R ＃ R ＃’ - selected from the group consisting of; L ３ is a chemical bond, -O-, -NR ＃ -, -CR ＃ R ＃’ -or-C ａ R ＃ R ＃’ C ｂ R ＃ R ＃’ - selected from the group consisting of; E is -C ｃ R ＃ R ＃ '-C ｄ R ＃ R ＃ '-C ｅ R ＃ R ＃ ' and; Here, C ｃ R ＃ R ＃ ' or C ｅ R ＃ R ＃ ' is O, S(O) ｐ or NR ＃ can be replaced by; p is 0, 1 or 2; R ＃ H, halogen, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ alkenyl, or C ２－６ is alkynyl; R ＃ ' is H, halogen, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ alkenyl, or C ２－６ is alkynyl; Alternatively, R on an adjacent atom ＃ and R ＃ can form a chemical bond, and R on adjacent atoms ＃ ' and R ＃ ' is capable of forming a chemical bond; Alternatively, R on the same atom ＃ and R ＃ ' together form =O; m is 1; The compound, its pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, or isotopic variants, and mixtures thereof.

9. Z １ But -CH ２ - or -C(O)-; L １ is a chemical bond, -O-, -NH-, -CH ２ -, -CH ２ CH ２ selected from the group consisting of -, -CH=CH-, or -C≡C-; Eが、-CH ２ CH ２ CH ２ -、-CH ２ CH=CH-、-CH=CHCH ２ -、-CH ２ C≡C-、-C≡CCH ２ -、-CH ２ CH ２ C(O)-、-CH ２ C(O)CH ２ -、-C(O)CH ２ CH ２ -、-OCH ２ C(O)-、-C(O)CH ２ O-、-NHCH ２ C(O)-、または-C(O)CH ２ NH-であり; L ３ is a chemical bond, -O-, -NH-, -CH ２ -, -C(O)-, -CH ２ CH ２ -, -C(O)CH ２ - or -CH ２ C(O)—; m is 1; A compound represented by the general formula (VIII) according to claim 8, its pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, or isotopic variant, and mixtures thereof.

10. A compound according to claim 1, wherein Z 1 is —CH 2 — or —C(O)—; L 1 is selected from the group consisting of a chemical bond, —O—, —NH—, —CH 2 —, —CH 2 CH 2 —, —CH═CH—, or —C≡C—; E is —CH 2 CH 2 CH 2 —, —CH 2 CH═CH—, —CH═CHCH 2 —, —CH 2 C≡C— or —C≡CCH 2 —; L 3 is selected from the group consisting of a chemical bond, —O—, —NH—, —CH 2 —, or —C(O)—; m is 1; A compound represented by the general formula (VIII) according to claim 8, its pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, or isotopic variant, and mixtures thereof.

11. A compound according to claim 1, wherein Z 1 is —CH 2 — or —C(O)—; L 1 is selected from the group consisting of a chemical bond, —O—, —NH—, —CH 2 —, —CH 2 CH 2 —, or —C≡C—; E is —CH 2 CH 2 CH 2 —; L 3 is selected from the group consisting of a chemical bond, —CH 2 —, or —C(O)—; m is 1; A compound represented by the general formula (VIII) according to claim 8, its pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, or isotopic variant, and mixtures thereof.

12. The compound according to claim 1, wherein Z 1 is —CH 2 —; L 1 is selected from the group consisting of a chemical bond, —CH 2 —, —CH 2 CH 2 —, or —C≡C—; E is —CH 2 CH 2 CH 2 —; L 3 is selected from a chemical bond or —CH 2 —; m=1, A compound represented by the general formula (VIII) according to claim 8, its pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, or isotopic variant, and mixtures thereof.

13. The compound is 【Chemistry 16】 selected from the group consisting of 10. The compound of claim 1, its pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, or isotopic variants, and mixtures thereof.

14. A compound according to any one of claims 1 to 13, its pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, or isotopic variant, and mixtures thereof; a pharmaceutically acceptable excipient; Alternatively, the pharmaceutical composition further comprises other therapeutic agents.

15. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition according to claim 14, in the preparation of a medicament for treating and / or preventing a disease mediated by EGFR kinase.

16. 16. The use of claim 15, wherein the disease mediated by EGFR kinase comprises cancer such as ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, endometrial cancer, kidney cancer, anaplastic large cell lymphoma, acute myeloid leukemia (AML), multiple myeloma, melanoma, mesothelioma, etc.

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