Heterocyclic derivative inhibitors, methods of making and use thereof

Abstract

The present invention relates to heterocyclic derivative inhibitors, methods of making and using the same. In particular, the present invention relates to compounds of the general formula, methods of making the same, pharmaceutical compositions containing the same, and uses thereof in the treatment of cancer.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to a heterocyclic derivative inhibitor, its preparation method, and its application. Background Technology

[0002] EGFR (Epidermal Growth Factor Receptor) is a member of the ErbB family of transmembrane receptor tyrosine kinases, activated by binding to its ligands epidermal growth factor (EGF) or transforming growth factor α (TGFα). Activated EGFR forms homodimers on the cell membrane or heterodimers with other receptors in the family (such as ErbB-2, ErbB-3, or ErbB-4), leading to phosphorylation of key intracellular tyrosine residues of EGFR. This activates downstream signaling pathways, playing a crucial role in cell proliferation, survival, and anti-apoptosis. Activating mutations, overexpression, or gene amplification of EGFR can lead to excessive activation, promoting cell transformation into tumor cells and playing a vital role in tumor cell proliferation, invasion, metastasis, and angiogenesis. Therefore, EGFR is an important target for the development of anticancer drugs, particularly for lung cancer treatment.

[0003] First-generation EGFR small molecule inhibitors, including gefitinib (Iressa) and erlotinib (Tarceva), have shown good efficacy in the treatment of lung cancer and have been used as first-line drugs for the treatment of non-small cell lung cancer (NSCLC) with classic EGFR mutations (including L858R and delE746_A750). The deIE746_A750 mutation (EGFR exon 19 deletion) has a higher affinity for EGFR TKIs, thus exhibiting better downstream signal blocking effects, while the L858R mutation has a relatively lower affinity for EGFR TKIs and slightly poorer selectivity. However, after 10-12 months of treatment with first-generation small molecule EGFR inhibitors, almost all NSCLC patients develop resistance to these inhibitors, with more than half of these resistance mechanisms being due to secondary mutations in the EGFR gate gene residue T790M.

[0004] Third-generation EGFR orthoform inhibitors, represented by osimertinib (AZD9291), can efficiently and selectively inhibit classical EGFR mutations (exon 19 deletion mutations and exon 21 L858R activating mutations) and resistance mutations caused by EGFR T790M mutations. Several third-generation EGFR inhibitors have been approved for marketing as first-line or second-line treatment for patients with advanced non-small cell lung cancer with classical EGFR mutations or EGFR T790M resistance mutations. However, in clinical practice, the treatment effect for patients with EGFR L858R mutations is significantly weaker than that for patients with EGFR Del19 mutations. For example, in the FLAURA study, the progression-free survival (PFS) of patients with EGFR L858R mutations treated as first-line patients was 14.4 months, while the PFS of patients with EGFR Del19 mutations treated as first-line patients was 21.4 months. The overall survival (OS) benefit of patients with EGFR L858R mutations was also lower than that of patients with EGFR Del19 mutations. Furthermore, resistance can also develop after 1-2 years of treatment with third-generation inhibitors. The rate of EGFR C797S double mutation resistance after first-line therapy is approximately 7%, and the rate of EGFR C797S triple mutation resistance after second-line therapy is approximately 10-26%. The EGFR C797S mutation changes the cysteine ​​residue at position 797 to serine, preventing osimertinib from forming a covalent bond with the EGFR protein, thus leading to resistance. Therefore, there is unmet clinical need for treatment with EGFR L858R single mutation, EGFR L858R C797S double mutation, and EGFR L858R / T790M / C797S triple mutation.

[0005] Currently, several companies are developing fourth-generation EGFR inhibitors targeting the EGFR C797S mutation. One type is allosteric inhibitors that target the classic EGFR L858R mutation and resistance mutation. Due to their high window for EGFR wild-type, they have good development prospects. Companies with relatively fast development progress include Dana Farber and Roche.

[0006] The purpose of this invention is to develop a small molecule inhibitor targeting the EGFR L858R mutant protein, which can not only treat EGFR L858R-related drug resistance mutations, but also be used as a monotherapy or in combination with third-generation EGFR inhibitors as first-line treatment for EGFR L858R single mutations. This will improve the clinical efficacy of existing inhibitors for indications such as non-small cell lung cancer and solve drug resistance problems, and has great market potential. Summary of the Invention

[0007] The object of this invention is to provide a compound or a pharmaceutically acceptable salt thereof represented by the following general formula:

[0008]

[0009] in:

[0010] M is selected from O, C=O, C=S, N, S, -CR aa R cc -CR aa or -NR bb ;

[0011] L1, L2, or L3 are each independently selected from the bond, -(CH2). n1 O(CH2) n2 -、-(CH2) n1 C=O(CH2) n2 -、-(CH2) n1 C = S(CH2) n2 -、-(CH2) n1 C = OO(CH2) n2 -、-(CH2) n1 NR bb (CH2) n2 -、-(CH2) n1 S(CH2) n2 -、-(CH2) n1 CONH(CH2) n2 -、(CH2) n1 NHCONH(CH2) n2 -、(CH2) n1 NHC(=NH)NH(CH2) n2 -、(CH2) n1 POR bb (CH2) n2 -、O(CH2) n1 POR bb (CH2) n2 -、C 1-6 Alkylene, C 1-6 imide or C 1-6 Alynyl group; wherein the -(CH2) group is... n1 O(CH2) n2 -、-(CH2) n1 C=O(CH2) n2 -、-(CH2) n1 C = S(CH2) n2 -、-(CH2) n1 C = OO(CH2) n2 -、-(CH2) n1 NR bb (CH2) n2 -、-(CH2) n1 S(CH2) n2 -、-(CH2)n1 CONH(CH2) n2 -、(CH2) n1 NHCONH(CH2) n2 -、(CH2) n1 NHC(=NH)NH(CH2) n2 -、(CH2) n1 POR bb (CH2) n2 -、O(CH2) n1 POR bb (CH2) n2 -、C 1-6 Alkylene, C 1-6 imide and C 1-6 Alynyl group, optionally further modified by hydrogen, deuterium, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C group. 1-6 Alkyl, substituted or unsubstituted C 1-6 Deuterated alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0012] Rings A1, A2, or B are each independently selected from C. 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0013] R 1 R 2 or R 3 Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -SF3, -SF5, -(CH2) n -、-(CH2) n R aa -(CH2) n OR bb -O(CH2) n R aa -(CH2) n SR bb -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R bb -(CH2) n C(O)NR aa R bb -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R bb -(CH2) n P(O)R aa R bb -O(CH2) n P(O)R aa R bb -(CH2) n NR cc C(=NH)NR aa R bb -(CH2) n NR bb S(O) m R cc -(CH2) n S(=O)R cc =NR bb -OC(R) aa R bb ) n (CH2) m R aa -NR bb (CH2) n R aa -CH=CH(CH2)n R aa -CH=CH(CH2) n NR aa R bb -CH=CH(CH2) n NR bb C(O)R cc -CH=CH(CH2) n NR bb C(O)NR aa R bb =N-OR bb or = CR aa R cc The C mentioned therein 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Deuterated alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0014] Or, any two identical or different R 1 R 2 or R 3 Connecting them can form a ring system, which is selected from C. 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl; wherein the C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14aryl and 5-14 heteroaryl groups, optionally further bonded by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -SF3, -SF5, -(CH2) n -、-(CH2) n Raa、-(CH2) n OR bb -O(CH2) n R aa -(CH2) n SR bb -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R bb -(CH2) n C(O)NR aa R bb -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R bb -(CH2) n P(O)R aa R bb -O(CH2) n P(O)R aa R bb -(CH2) n NR cc C(=NH)NR aa R bb -(CH2) n NR bb S(O) m R cc-(CH2) n S(=O)R cc =NR bb -OC(R) aa R bb ) n (CH2) m R aa -NR bb (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R bb -CH=CH(CH2) n NR bb C(O)R cc -CH=CH(CH2) n NR bb C(O)NR aa R bb =N-OR bb or = CR aa R cc The C mentioned therein 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Deuterated alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0015] R aa R bb and R cc Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Deuterated alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0016] Or, any two identical or different R aa R bb With R cc Connecting them can form a ring system, which is selected from C. 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Deuterated alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0017] The "substitution" in "substituted or unsubstituted" mentioned above refers to substitution by 1-4 Rs. m Replace, where R m Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl;

[0018] x is an integer of 0, 1, 2, 3, 4, or 5;

[0019] y is an integer of 0, 1, 2, 3, 4, or 5;

[0020] z is an integer of 0, 1, 2, 3, 4, or 5;

[0021] m can be 0, 1, 2, or 3;

[0022] n is 0, 1, 2, or 3;

[0023] n1 and n2 are each independently 0, 1, 2 or 3.

[0024] Some embodiments of the present invention also include the following general formula:

[0025]

[0026] in:

[0027] X1, X2, X3, X4, X5, X6 and X7 are each independently selected from C, N, S, O, NH or CH.

[0028] Some embodiments of the present invention also include a compound represented by the following general formula or a pharmaceutically acceptable salt thereof:

[0029]

[0030] in:

[0031] Ring A is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 membered heteroaryl; some embodiments of the present invention also include the following general formula:

[0032]

[0033] in:

[0034] Ring A3 is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0035] R 4 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -SF3, -SF5, -(CH2) n -、-(CH2) n R aa -(CH2) n OR bb -O(CH2) n R aa -(CH2) n SR bb -(CH2) n C(O)R cc -(CH2)n C(O)OR cc 、-(CH2) n S(O) m R cc 、-(CH2) n NR aa R bb 、-(CH2) n C(O)NR aa R bb 、-(CH2) n NR bb C(O)R cc 、-(CH2) n NR cc C(O)NR aa R bb 、-(CH2) n P(O)R aa R bb 、-O(CH2) n P(O)R aa R bb 、-(CH2) n NR cc C(=NH)NR aa R bb 、-(CH2) n NR bb S(O) m R cc 、-(CH2) n S(=O)R cc =NR bb 、-OC(R aa R bb ) n (CH2) m R aa 、-NR bb (CH2) n R aa 、-CH=CH(CH2) n R aa 、-CH=CH(CH2) n NR aa R bb 、-CH=CH(CH2) n NR bb C(O)R cc 、-CH=CH(CH2) n NR bb C(O)NR aa R bb 、=N-OR bb 或=CR aa R ccThe C mentioned therein 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Deuterated alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0036] Or, any two R 4 Connecting them can form a ring system, which is selected from C. 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl; wherein the C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Deuterated alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0037] u is an integer of 0, 1, 2, 3, 4, or 5.

[0038] Some embodiments of the present invention also include a compound represented by the following general formula or a pharmaceutically acceptable salt thereof:

[0039]

[0040] in:

[0041] Each ring C is independently selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl compounds.

[0042] Some embodiments of the present invention further include the following:

[0043]

[0044] in:

[0045] X1, X2, X3, X4, X5, X6 and X7 are each independently selected from C, N, S, O, NH or CH.

[0046] The compounds or pharmaceutically acceptable salts thereof described in certain embodiments of the present invention are characterized in that ring A, ring A1, ring A2 or ring A3 are selected from monocyclic, bicyclic or polycyclic compounds;

[0047] When the ring is a single ring: Selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14-membered heteroaryl; preferably benzene or 5-8-membered heteroaryl; further preferably furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, thiadiazolyl, thiazolyl, thiophene, tetrazolyl, triazinyl or triazolyl;

[0048] When the ring is a double ring: it is selected from spiral rings, parallel rings, or bridge rings, with ring A being the preferred choice when it is a double ring.

[0049] Preferred 5-14 quinone heteroaryl 5-14 quinone heteroaryl, 5-14 quinone heteroaryl C 6-14 Aryl or C 6-14 Aryl 3-12 membered heterocyclic group; more preferably 5-6 membered heteroaryl 5-6 membered heteroaryl, 5-6 membered heteroaryl 5-6 membered aryl, 5-6 membered heterocyclic 5-6 membered heteroaryl or benzo 5-6 membered heteroaryl;

[0050] The preferred structure is as follows:

[0051]

[0052] When the ring is multi-ringed: it should be selected from a system of three or more rings, which can be a parallel ring, a spiral ring, or a bridge ring; preferably an 8-20 element multi-ring system, and preferably a three-ring system for ring A.

[0053] Preferred series: 5-6 yuan / 5-8 yuan / 5-6 yuan; even better series: 6 yuan / 5 yuan / 6 yuan, 6 yuan / 6 yuan / 6 yuan, 6 yuan / 7 yuan / 6 yuan, 5 yuan / 5 yuan / 6 yuan, 5 yuan / 5 yuan / 6 yuan, 5 yuan / 7 yuan / 6 yuan.

[0054] The preferred structure is as follows:

[0055]

[0056] In some embodiments of the present invention, ring B is selected from C. 6-14 Aryl or 5-14 membered heteroaryl; preferably phenyl or 5-10 membered bicyclic heteroaryl; specifically, the following structures are preferred:

[0057]

[0058] In some embodiments of the present invention, the ring C is selected from C 6-14 Aryl or 5-14 membered heteroaryl; preferably phenyl or 5-10 membered bicyclic heteroaryl; specifically, the following structures are preferred:

[0059]

[0060] In some embodiments of the present invention, L1 is selected from the bonds -COCH2-, -COCH2CH2-, and -CR. aa R cc -、-CO-、-NR bb -、-CONR bb -; Preferred key.

[0061] In some embodiments of the present invention, L2 is selected from the bonds -COCH2-, -COCH2CH2-, and -CR. aa R cc -、-CO-、-NR bb -、-CONR bb -;Preferred-NR bb -or-CONR bb -

[0062] The compounds described in certain embodiments of the present invention have structures represented by formula (ID-1) or formula (IH-1).

[0063]

[0064] Preferably, the compound has the structure shown in formula (ID-1-1) or formula (IH-1-1).

[0065]

[0066] Preferably, the compound has the structure shown in formula (ID-1-1-1) to (ID-1-1-4) or formula (IH-1-1-1) to (IH-1-1-4).

[0067]

[0068]

[0069] in:

[0070] R 1-1 To R 1-9 The definition is the same as R 1 ;

[0071] R' aa The definition is the same as R aa ;

[0072] Ring D is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0073] q is independently selected from 0, 1, 2, 3, 4, 5, or 6;

[0074] X1, X2, X3, X6, X7, y, z, M, L1, R 1 R 2 R 3 and R aa The definition is as described above.

[0075] In some embodiments of the present invention, L3 is selected from the bonds -COCH2-, -COCH2CH2-, and -CR. aa R cc -、-CO-、-CH2NR bb -、-CONR bb -; preferred bond or -CH2NR bb -

[0076] In some embodiments of the present invention, R 1Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -SF3, -SF5, -(CH2) n -、-(CH2) n R aa -(CH2) n OR bb -O(CH2) n R aa -C≡C(CH2) n R aa -(CH2) n SR bb -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R bb -(CH2) n C(O)NR aa R bb -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R bb -(CH2) n P(O)R aa R bb -O(CH2) n P(O)R aa R bb -(CH2) n NR cc C(=NH)NR aa R bb -(CH2) n NR bbS(O) m R cc -(CH2) n S(=O)R cc =NR bb -OC(R) aa R bb ) n (CH2) m R aa -NR bb (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R bb -CH=CH(CH2) n NR bb C(O)R cc -CH=CH(CH2) n NR bb C(O)NR aa R bb =N-OR bb or = CR aa R cc The C mentioned therein 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Deuterated alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14The aryl group is substituted with one or more substituents from a group consisting of substituted or unsubstituted 5-14 heteroaryl groups. R as described in certain embodiments of the present invention... 1-1 To R 1-9 and R 1 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10-membered heteroaryl, wherein the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further bonded by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -SF3, -SF5, -(CH2) n Raa、-(CH2) n OR bb -O(CH2) n R aa -(CH2) n SR bb -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) nS(O) m R cc -(CH2) n NR aa R bb -(CH2) n C(O)NR aa R bb -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R bb -(CH2) n P(O)R aa R bb -O(CH2) n P(O)R aa R bb -(CH2) n NR cc C(=NH)NR aa R bb -(CH2) n NR bb S(O) m R cc -(CH2) n S(O)R cc =NR bb -OC(R) aa R bb ) n (CH2) m R aa -NR bb (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R bb -CH=CH(CH2) n NR bb C(O)R cc -CH=CH(CH2) n NR bb C(O)NR aa R bb =N-OR bb or = CR aa R cc One or more substituents in it are replaced;

[0077] The following group structures are preferred:

[0078] Ring D is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 membered heteroaryl; preferably 3-12 membered heterocyclic.

[0079] In some embodiments of the present invention, R 1 Each independently selected Ring D is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 membered heteroaryl; preferably 3-12 membered heterocyclic; R' aa The definition is the same as R aa ;q is independently selected from 0, 1, 2, 3, 4, 5 or 6.

[0080] R described in certain embodiments of the present invention 2 R 3 R 4 Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10-membered heteroaryl, wherein the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further bonded by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -SF3, -SF5, -(CH2) n Raa、-(CH2) n OR bb -O(CH2) n R aa -(CH2) n SR bb -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R bb -(CH2) n C(O)NR aa R bb -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R bb -(CH2) n P(O)R aa R bb -O(CH2) n P(O)R aa R bb -(CH2) n NR cc C(=NH)NR aa R bb -(CH2) n NR bb S(O) m R cc -(CH2) n S(O)R cc =NR bb -OC(R) aa R bb ) n (CH2) m R aa -NR bb (CH2) n R aa -CH=CH(CH2) n Raa -CH=CH(CH2) n NR aa R bb -CH=CH(CH2) n NR bb C(O)R cc -CH=CH(CH2) n NR bb C(O)NR aa R bb =N-OR bb or = CR aa R cc One or more substituents in it are replaced;

[0081] Or, any two identical or different R 1 R 2 R 3 or R 4 Connecting them can form a ring system, which is selected from C. 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl; wherein the C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further bonded by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -SF3, -SF5, -(CH2) n -、-(CH2) n Raa、-(CH2) n OR bb -O(CH2) n R aa -(CH2) n SR bb -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m Rcc -(CH2) n NR aa R bb -(CH2) n C(O)NR aa R bb -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R bb -(CH2) n P(O)R aa R bb -O(CH2) n P(O)R aa R bb -(CH2) n NR cc C(=NH)NR aa R bb -(CH2) n NR bb S(O) m R cc -(CH2) n S(=O)R cc =NR bb -OC(R) aa R bb ) n (CH2) m R aa -NR bb (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R bb -CH=CH(CH2) n NR bb C(O)R cc -CH=CH(CH2) n NR bb C(O)NR aa R bb =N-OR bb or = CR aa R cc The C mentioned therein 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further bonded by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 It is substituted by one or more substituents in the aryl group and the 5-14 heteroaryl group.

[0082] R' as described in certain embodiments of the present invention aa R aa R bb and R cc Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl, wherein the C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further bonded by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0083] Or, any two identical or different R aa R bb With R cc Connecting them can form a ring system, which is selected from C. 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 quinone heteroaryl groups, optionally further bonded by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 It is substituted by one or more substituents in the aryl group and the 5-14 heteroaryl group.

[0084] In some embodiments of the present invention, R aa for Among them, ring E is selected from C 3-8 Cycloalkyl, 4-6 membered monocyclic heterocyclic groups, 6-10 membered bicyclic heterocyclic groups, C 6-10 aryl, 5-6 membered heteroaryl or 8-10 membered heteroaryl, wherein R n Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl; wherein, the C1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups may be further divided by 1-4 R groups. m replace;

[0085] w is independently selected from 0, 1, 2, 3, 4, 5 or 6.

[0086] In some embodiments of the present invention, ring E is selected from...

[0087] In some embodiments of the present invention, ring D is selected from C. 3-8 Cycloalkyl, 4-6 membered monocyclic heterocyclic groups, 6-10 membered bicyclic heterocyclic groups, C 6-10 aryl, 5-6 membered heteroaryl, or 8-10 membered heteroaryl, preferably ring D is selected from...

[0088] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of the above-described compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0089] In some embodiments of the invention, the pharmaceutical composition, based on free base, comprises 0.1% to 95% by weight of the compound, its stereoisomers, or a pharmaceutically acceptable salt thereof, preferably 90%, 85%, 80%, 75%, 70%, 60%, or 50%.

[0090] In some embodiments of the invention, the pharmaceutical composition is selected from tablets, capsules, liquid formulations or injections, preferably also containing a filler, optionally a disintegrant, or further containing one or more of a flow aid or lubricant.

[0091] The present invention further relates to the use of the compounds described above or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions described above, in the preparation of EGFR inhibitor medicaments.

[0092] In some embodiments of the present invention, the EGFR is a mutated EGFR, preferably a single or multiple mutated EGFR related to the L858R mutation; more preferably, at least one of the EGFR mutations, L858R, T790M or C797S, is present.

[0093] The present invention further relates to the use of the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above, in the preparation of a treatment for cancer; preferably, the cancer is selected from ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer, endometrial cancer, renal cancer, anaplastic large cell lymphoma, multiple myeloma, melanoma, or mesothelioma; more preferably, the cancer is non-small cell lung cancer; even more preferably, the cancer is non-small cell lung cancer with EGFR L858R, EGFR L858R / T790M, L858R / C797S, or L858R / T790M / C797S mutations.

[0094] The present invention further relates to the use of the said compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating cancer.

[0095] The present invention also provides a method for treating disease conditions using the compounds or pharmaceutical compositions of the present invention, including but not limited to conditions related to EGFR kinase dysfunction.

[0096] The present invention also relates to a method for treating, preventing and / or treating cancer, comprising administering to a patient a therapeutically effective dose of the compound as described above or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0097] In some embodiments of the present invention, the cancer is selected from 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, thyroid cancer, bile duct cancer, endometrial cancer, renal cancer, anaplastic large cell lymphoma, multiple myeloma, melanoma, or mesothelioma; more preferably, the cancer is non-small cell lung cancer; even more preferably, the cancer is non-small cell lung cancer with EGFR L858R, EGFR L858R / T790M, L858R / C797S, or L858R / T790M / C797S mutations.

[0098] Detailed description of the invention

[0099] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0100] Unless otherwise stated, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art, and in particular, the terms used in the specification and claims have the following meanings.

[0101] The term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, which may optionally be substituted with one or more substituents. In certain embodiments, alkyl refers to a group having a chain length of 1 to 20 (C1-C2). 20 ), 1 to 15 (C1-C 15 ), 1 to 12 (C1-C 12 ), 1 to 10 (C1-C 10 Straight-chain saturated hydrocarbon groups with 1 to 8 (C1-C8), 1 to 6 (C1-C6), or 1 to 3 (C1-C3) carbon atoms, or having 3 to 20 (C3-C4) carbon atoms. 20 ), 3 to 15 (C3-C) 15 ), 3 to 12 (C3-C 12 ), 3 to 10 (C3-C) 10 A branched saturated hydrocarbon group with 3 to 8 (C3-C8) or 3 to 6 (C3-C6) carbon atoms. The straight-chain C... 1- -C6 alkyl and branched C 3- -C6 alkyl groups are also called "lower alkyl groups". For example, C6 alkyl groups... 1- -C6 alkyl refers to a linear saturated monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group having 3 to 6 carbon atoms. In one embodiment, the C... 1--C6 alkyl groups contain 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. In one embodiment, the alkyl group is an optionally substituted alkyl group as described elsewhere herein.

[0102] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, wherein "alkyl" is defined as described above. Non-limiting examples of "alkylene" include methylene (-CH2-), ethylene (-(CH2)2-), propylene (-(CH2)3-), or butylene (-(CH2)4-). In one embodiment, the alkylene is an optionally substituted alkyl group as described elsewhere herein.

[0103] The term "alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond, which can be located at any position within the alkenyl group. The alkenyl group may optionally be substituted by one or more substituents. In certain embodiments, the alkenyl group has a carbon-carbon double bond of 2 to 20 (C2-C2). 20 ), 2 to 15 (C2-C 15 ), 2 to 12 (C2-C 12 ), 2 to 10 (C2-C) 10 Straight-chain unsaturated hydrocarbon groups with 2 to 8 (C2-C8), 2 to 6 (C2-C6), or 2 to 4 (C2-C4) carbon atoms, or having 3 to 20 (C3-C4) carbon atoms. 20 ), 3 to 15 (C3-C) 15), 3 to 12 (C3-C 12 ), 3 to 10 (C3-C) 10 A branched unsaturated hydrocarbon group having 2 to 8 (C3-C8) or 3 to 6 (C3-C6) carbon atoms. Unless otherwise specified, the term "alkenyl" as used herein includes both straight-chain and branched alkenyl groups. For example, a C2-C6 alkenyl group refers to a straight-chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. In one embodiment, the C2-C6 alkenyl group contains 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of alkenyl groups include: Those skilled in the art will understand that the term "alkenyl" may also include groups having "cis" and "trans" configurations, or alternatively, "E" and "Z" configurations. In one embodiment, the alkenyl is an optionally substituted alkenyl as described elsewhere herein.

[0104] The term "alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, which can be located at any position within the alkynyl group. The alkynyl group may optionally be substituted by one or more substituents. In a particular embodiment, the alkynyl group has a carbon group of 2 to 20 (C2-C2) 20 ), 2 to 15 (C2-C 15 ), 2 to 12 (C2-C 12 ), 2 to 10 (C2-C) 10 Straight-chain unsaturated hydrocarbon groups with 2 to 8 (C2-C8), 2 to 6 (C2-C6), or 2 to 4 (C2-C4) carbon atoms, or having 3 to 20 (C3-C4) carbon atoms. 20 ), 3 to 15 (C3-C) 15 ), 3 to 12 (C3-C 12 ), 3 to 10 (C3-C) 10 A branched unsaturated hydrocarbon group having 2 to 8 (C3-C8) or 3 to 6 (C3-C6) carbon atoms. Unless otherwise specified, the term "alkynyl" as used herein includes both straight-chain and branched alkynyl groups. For example, a C2-C6 alkynyl group refers to a straight-chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. In one embodiment, the C2-C6 alkynyl group contains 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of alkynyl groups include: In one embodiment, the alkynyl group is an optionally substituted alkynyl group as described elsewhere herein.

[0105] The term "cycloalkyl" refers to a monocyclic or polycyclic (two or more) cyclic group of a saturated or partially unsaturated aliphatic hydrocarbon, which may optionally be substituted with one or more substituents. In certain embodiments, the cycloalkyl ring comprises 3 to 20 (C3-C4) rings. 20 ), 3 to 12 (C3-C 12 ), 3 to 10 (C3-C) 10 3 to 8 (C3-C8) or 3 to 6 (C3-C6) carbon atoms; in one embodiment, the cycloalkyl ring comprises 6 to 14 (C6-C8) carbon atoms. 14 ) or 7 to 10 (C7-C 10 It has 10 carbon atoms; it may contain one or more double bonds, but does not have a fully conjugated π-electron system. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, or cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic alkyl, fused cycloalkyl, and bridged cycloalkyl groups in one embodiment. In one embodiment, the cycloalkyl group is an optionally substituted cycloalkyl group or an optionally fused cycloalkyl group with a heterocyclic group, aryl group, or heteroaryl group as described elsewhere herein, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.

[0106] The term "spirocycloalkyl" refers to an aliphatic hydrocarbon polycyclic group in which the monocyclic rings share a single carbon atom (called a spiro atom), and it may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. In certain embodiments, the spirocycloalkyl group comprises 5 to 20 (C5-C6) carbon atoms. 20 ), 6 to 14 (C6-C 14 ) or 7 to 10 (C7-C 10 (e.g., 7, 8, 9, 10) carbon atoms. Spirocycloalkyl groups are classified as monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between rings, with one embodiment being monospirocycloalkyl and bispirocycloalkyl. In one embodiment, it is a 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl. In one embodiment, the spirocycloalkyl group is an optionally substituted spirocycloalkyl group described elsewhere herein. Non-limiting examples of spirocycloalkyl groups include:

[0107]

[0108] The term "fused-cyclic alkyl" refers to a fully carbon polycyclic group in which each ring in a system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system. In a particular embodiment, the fused-cyclic alkyl group comprises 5 to 20 (C5-C6) atoms. 20 ), 6 to 14 (C6-C 14) or 7 to 10 (C7-C 10 (e.g., 7, 8, 9, 10) carbon atoms. Depending on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused-ring alkyl groups. In one embodiment, they are bicyclic or tricyclic, and in another embodiment, they are 3-membered / 5-membered, 4-membered / 5-membered, 5-membered / 5-membered, or 5-membered / 6-membered bicyclic alkyl groups. In one embodiment, the fused-ring alkyl group is an optionally substituted fused-ring alkyl group described elsewhere herein or an fused-ring alkyl group optionally fused with a heterocyclic group, aryl group, or heteroaryl group. Non-limiting examples of fused-ring alkyl groups include:

[0109]

[0110] The term "bridged cycloalkyl" refers to a fully carbon polycyclic group in which any two rings share two non-directly bonded carbon atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. In certain embodiments, the bridged cycloalkyl group comprises 5 to 20 (C5-C6) carbon atoms. 20 ), 6 to 14 (C6-C 14 ) or 7 to 10 (C7-C 10 (e.g., 7, 8, 9, 10) carbon atoms. Depending on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged alkyl groups, preferably bicyclic or tricyclic. In one embodiment, the bridged alkyl group is an optionally substituted bridged alkyl group described elsewhere herein. Non-limiting examples of bridged alkyl groups include:

[0111]

[0112] The term "cycloalkylene" refers to a cycloalkyl group in which one hydrogen atom is further substituted, and the definition of "cycloalkyl" is as described above.

[0113] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, wherein the nitrogen, phosphorus, or sulfur atom may optionally be oxidized, the nitrogen atom may optionally be quaternized, the ring carbon atom may optionally be substituted with oxygen but excluding the -OO-, -OS- ring moiety, and the remaining ring atoms are carbon, which may contain one or more double bonds but does not have a fully conjugated π-electron system. In a particular embodiment, the heterocyclic group comprises 3 to 20, 3 to 12, 3 to 10, 3 to 8, 4 to 10, 4 to 8, 3 to 6, or 4 to 6 ring atoms, wherein 1 to 4 are heteroatoms, such as nitrogen, oxygen, or sulfur; in one embodiment, the heterocyclic group comprises 3 to 6, 4 to 6, 3 to 8, 3 to 10, 6 to 10, or 7 to 11 ring atoms; in one embodiment, the heterocyclic group comprises 3 to 8 (e.g., 3, 4, 5, 6, 7, 8) ring atoms. Non-limiting examples of monocyclic heterocyclic groups include tetrahydropyrrole, azahexacyclic butyl, oxacyclobutyl, oxacyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrole, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and pyranyl. Polycyclic heterocyclic groups include spiroheterocyclic, fused heterocyclic, and bridged heterocyclic groups. In one embodiment, the heterocyclic group is optionally substituted as described elsewhere herein, or is a heterocyclic group further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring.

[0114] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group in which one or more ring atoms share a single atom (called a spiro atom), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. In certain embodiments, the spiroheterocyclic group comprises 5 to 20 or 6 to 14 ring atoms; in one embodiment, it comprises 7 to 11 (e.g., 7, 8, 9, 10, 11) ring atoms; spiroheterocyclic groups are classified as monospirocyclic, bispirocyclic, or multispirocyclic groups according to the number of spiro atoms shared between the rings; monospirocyclic and bispirocyclic groups are preferred; in one embodiment, the spiroheterocyclic group is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocyclic group; in one embodiment, the spiroheterocyclic group is an optionally substituted spiroheterocyclic group described elsewhere herein; non-limiting examples of spiroheterocyclic groups include:

[0115]

[0116] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in a system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, and the remaining ring atoms are carbon. In a particular embodiment, the fused heterocyclic group comprises 5 to 20 or 6 to 14 ring atoms, and in one embodiment comprises 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups depending on the number of constituent rings; bicyclic or tricyclic is preferred; in one embodiment, it is a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group; in one embodiment, the fused heterocyclic group is optionally substituted as described elsewhere herein, or a fused heterocyclic group that can be fused with cycloalkyl, heterocyclic, aryl, or heteroaryl groups; non-limiting examples of fused heterocyclic groups include:

[0117]

[0118] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, and the remaining ring atoms are carbon. In certain embodiments, the bridged heterocyclic group comprises 5 to 20 or 6 to 14 ring atoms; in one embodiment, it comprises 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group; preferably bicyclic, tricyclic, or tetracyclic; in one embodiment, it is bicyclic or tricyclic; in one embodiment, the bridged heterocyclic group is an optionally substituted bridged heterocyclic group described elsewhere herein; non-limiting examples of bridged heterocyclic groups include:

[0119]

[0120] The term "subheterocyclic group" refers to a heterocyclic group in which one hydrogen atom is further substituted, and the definition of "heterocyclic group" is as described above.

[0121] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group containing at least one conjugated π-electron system, which may optionally be substituted by one or more substituents. In certain embodiments, the aryl group comprises 6 to 20, 6 to 14, or 6 to 10 ring atoms; in one embodiment, the aryl group may further refer to a bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring is an aromatic ring, and the other rings may be saturated, partially unsaturated carbon rings, or rings containing one or more heteroatoms independently selected from O, S, and N. In one embodiment, the aryl group is selected from benzo5-10-membered heteroaryl, benzo3-10-membered cycloalkyl, or benzo3-10-membered heterocyclic groups. In one embodiment, the aryl group is selected from benzo5-6-membered heteroaryl, benzo3-6 (e.g., 5-6)-membered cycloalkyl, or benzo3-6 (e.g., 5-6)-membered heterocyclic groups, wherein the heterocyclic group is a heterocyclic group containing 1 to 3 nitrogen, oxygen, or sulfur atoms. Non-limiting examples include phenyl, naphthyl, fluorenyl, chamomilecycloyl, anthraceneyl, phenanthryl, pyrene, biphenyl, terphenyl, dihydronaphthyl, indene, tetrahydronaphthyl (naphthyl),

[0122] The term "arylene" refers to a divalent aryl group formed by further substitution of one hydrogen atom of an aryl group, wherein the arylene group may be optionally substituted or unsubstituted, as defined above for aryl groups.

[0123] The term "heteroaryl" refers to an optionally substituted monocyclic, polycyclic group or ring system comprising at least one aromatic ring having one or more heteroatoms independently selected from O, S, and N. In certain embodiments, the heteroaryl comprises 5 to 20, 5 to 15, or 5 to 10 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heteroaryl comprises 5 or 6 ring atoms; in certain embodiments, the heteroaryl may further refer to a bicyclic, tricyclic, or tetracyclic ring, wherein at least one ring is an aromatic ring having one or more heteroatoms independently selected from O, S, and N, and the other rings may be saturated, partially unsaturated carbocyclic rings, or rings comprising one or more heteroatoms independently selected from O, S, and N. In one embodiment, the heteroaryl group is selected from heteroaryl-6-10 aryl, heteroaryl-3-10 cycloalkyl, or heteroaryl-3-10 heterocyclic group; in a further embodiment, the heteroaryl group is selected from 5- or 6-membered heteroaryl-6-10 aryl, 5- or 6-membered heteroaryl-3-6 cycloalkyl, or 5- or 6-membered heteroaryl-3-6 heterocyclic group, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms. Non-limiting examples include: furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrroloyl, thiadiazolyl, thiazolyl, thiophene, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benziisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiaphenyl, benzobenzenethio, benzothiaphenyl, benzotriazolyl, imidazopyridyl, imidazothiazolyl Indazinyl, indolyl, inzolyl, isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoquinolinyl, naphridinyl, oxazolopyridyl, phthalazinyl, pteridinyl, purine, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxolinyl, quinazolinyl, thiadiazopyrimidinyl, thienenopyridyl, acridineyl, benzoindolyl, carbazole, biphenylfuranyl, phenanthrololinyl, phenanthidyl, phenpyrazinyl, phenazinyl, phenthiazinyl, phenoxazinyl, xanthonyl,

[0124] The term "heteroaryl" refers to a divalent heteroaryl group formed by further substitution of one hydrogen atom of a cycloalkyl group, wherein the heteroaryl group may be optionally substituted or unsubstituted, as defined above.

[0125] The term "heteroalkyl" refers to a stable straight-chain or branched, or cyclic, hydrocarbon group, or a combination thereof, consisting of the indicated number of carbon atoms and one or more (one to three in one embodiment) heteroatoms selected from O, N, Si, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom may optionally be quaternized. In one embodiment, the heteroatoms O, N, and S may be placed at any internal position within the heteroalkyl group. In one embodiment, the heteroatom Si may be placed at any position within the heteroalkyl group (e.g., internal or terminal positions), including positions where the alkyl group is attached to the remainder of the molecule. Non-limiting examples include: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. At most two heteroatoms can be consecutive, for example, -CH2-NH-O-CH3 and -CH2-O-Si(CH3)3. In certain embodiments, the heteroalkyl group is an optionally substituted heteroalkyl group described elsewhere herein.

[0126] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein the definition of alkyl or cycloalkyl is as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexyloxy. In one embodiment, the alkoxy group is an optionally substituted alkoxy group as described elsewhere herein.

[0127] The term "alkylacyl" refers to -C(O)-alkyl, where the definition of alkyl is as described above.

[0128] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein the definition of alkyl is as described above. Non-limiting examples of said haloalkyl groups include: trifluoromethyl, -CH2CF3,

[0129] The term “haloalkoxy” refers to an alkoxy group that has been substituted with one or more halogens, where the definition of an alkoxy group is as described above.

[0130] The term "hydroxyalkyl" refers to an alkyl group that has been substituted with a hydroxyl group, where the definition of alkyl is as described above.

[0131] The term "alkathio" refers to -S- (alkyl) and -S- (unsubstituted cycloalkyl), wherein the definition of alkyl or cycloalkyl is as described above. Non-limiting examples of alkathio groups include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, or cyclohexylthio. In one embodiment, the alkathio group is an optionally substituted alkathio group described elsewhere herein.

[0132] The term "haloalkylthio" refers to an alkylthio group substituted with one or more halogens, wherein the definition of alkylthio is as described above.

[0133] The term "alkenyl carbonyl" refers to -C(O)-(alkenyl), where alkenyl is defined as previously stated. Non-limiting examples of alkenyl carbonyl include vinyl carbonyl, propenyl carbonyl, or butenyl carbonyl. In one embodiment, the alkenyl carbonyl is an optionally substituted alkenyl carbonyl as described elsewhere herein.

[0134] The term "aminocarbonyl" refers to NH2-C(O)-.

[0135] The term "alkylaminocarbonyl" refers to an aminocarbonyl group (NH2-C(O)-) in which one or both hydrogen atoms are replaced by an alkyl group, wherein the definition of alkyl is as described above.

[0136] The term "alkylamino" refers to an amino group in which one or both of the two hydrogen atoms are replaced by an alkyl group, as defined above.

[0137] The term "carbonyl" refers to the -C(O)-, -(CO)-, or -C(=O)- group. All designations are interchangeable in the specification.

[0138] The term "hydroxyl group" refers to the -OH group.

[0139] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0140] The term "amino" refers to -NH2.

[0141] The term "cyano" refers to -CN.

[0142] The term "nitro" refers to -NO2.

[0143] The term "carboxyl group" refers to -C(O)OH.

[0144] The term "acetyl" refers to -C(O)CH3.

[0145] The term "oxo" or "side oxygen" refers to =O.

[0146] The term "thiol" refers to -SH.

[0147] The term "THF" refers to tetrahydrofuran.

[0148] The term "EtOAc" refers to ethyl acetate.

[0149] The term "MeOH" refers to methanol.

[0150] The term "DMF" refers to N,N-dimethylformamide.

[0151] The term "DIPEA" refers to diisopropylethylamine.

[0152] The term "TFA" refers to trifluoroacetic acid.

[0153] The term "TEA" refers to triethylamine.

[0154] The term "MeCN" refers to ethinylene.

[0155] The term "DMA" refers to N,N-dimethylacetamide.

[0156] The term "Et2O" refers to diethyl ether.

[0157] The term "DCE" refers to 1,2-dichloroethane.

[0158] The term "DIPEA" refers to N,N-diisopropylethylamine.

[0159] The term "NBS" refers to N-bromosuccinimide.

[0160] The term "NIS" refers to N-iodosuccinimide.

[0161] The term "Cbz-Cl" refers to benzyl chloroformate.

[0162] The term “Pd2(dba)3” refers to tris(dibenzylacetone)dipalladium.

[0163] The term "Dppf" refers to 1,1'-bis(diphenylphosphine)ferrocene.

[0164] The term "HATU" refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate.

[0165] The term "KHMDS" refers to potassium hexamethyldisilamide.

[0166] The term "LiHMDS" refers to lithium bistrimethylsilylamine.

[0167] The term "MeLi" refers to methyl lithium.

[0168] The term "n-BuLi" refers to n-butyllithium.

[0169] The term "NaBH(OAc)3" refers to sodium triacetoxyborohydride.

[0170] Group "-S(=O)R"cc =NR bb "Structure display

[0171] The term "hydrogen" includes protons ( 1 H), deuterium ( 2 H), tritium ( 3 H) and / or mixtures thereof. In certain embodiments, one or more hydrogen-occupied sites in the compound may be enriched with deuterium and / or tritium. Such isotope-enriched analogs may be prepared from suitable isotopically labeled starting materials available from commercial sources or by known literature procedures, wherein the hydrogen or hydrogen atom described in this patent comprises its isotopes (H) and / or mixtures thereof. 1 H), deuterium ( 2 H), tritium ( 3 H) and / or mixtures thereof.

[0172] This invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms with different atomic weights or mass numbers. Examples of isotopes that can be included in the compounds of this invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, respectively as follows: 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Isotope-labeled compounds can be prepared using a general method, by replacing the non-isotope reagent with an readily available isotope-labeling reagent, as described in the examples.

[0173] The alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, arylene, heteroaryl, heteroarylene, heteroalkyl, alkoxy, alkylthio, hydroxyalkyl, alkenylcarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylamino, and alkylacyl groups may be substituted or unsubstituted. In one embodiment, the substituent is selected from one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, alkylacyl, halogen, mercapto, hydroxyl, nitro, cyano, azide, oxime, phosphate ester, oxo, thio, carboxyl, carboxylic acid ester, cycloalkyl, heterocyclic, aryl, heteroaryl, heterocycloalkoxy, cycloalkylthio, or heterocycloalkylthio.

[0174] In this invention, unless otherwise specified, the term "substituted or unsubstituted" indicates that the modified substituent may optionally be further substituted by one or more of the following substituents, selected from alkyl, deuteralkyl, haloalkyl, alkenyl, alkoxy, alkylthio, alkylamino, alkylacyl, halogen, mercapto, hydroxyl, nitro, cyano, azide, oxime, phosphate ester, oxo, thio, carboxyl, carboxylic acid ester, cycloalkyl, heterocyclic, aryl, heteroaryl, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, -SF3, -SF5, -(CH2). n -、-(CH2) n R aa -(CH2) n OR bb -O(CH2) n R aa -(CH2) n SR bb -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R bb -(CH2) n C(O)NR aa R bb -(CH2) n NR bb C(O)R cc -(CH2) n NR bb S(O) m R cc -(CH2) n S(=O)R cc =NR bb -OC(R) aa R bb ) n (CH2) m R aa -NR bb (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R bb -CH=CH(CH2) n NRbb C(O)R cc -CH=CH(CH2) n NR bb C(O)NR aa R bb =N-OR bb or = CR aa R cc .

[0175] The different terms such as "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" all express the same meaning, that is, X can be any one or more of A, B, and C.

[0176] Unless otherwise specified, when a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2-, and -CONH- is equivalent to -NHCO-.

[0177] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0178] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0179] "Substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, provided that the valence state of the particular atom is normal and the substituted compound is stable in one embodiment and in another. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents can be arbitrary on a chemically feasible basis. It goes without saying that substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0180] Unless otherwise stated, the indefinite articles “a” and “an” and the definite article “the” in this specification and claims include both plural and singular forms.

[0181] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0182] "Medicinal salts" refer to the salts of the compounds of this invention, which are safe and effective when used in mammals and have the appropriate biological activity.

[0183] "Stereoisomers" encompass all enantiomers / non-corresponding isomers / stereoisomers of the present invention, as well as enantiomers / non-corresponding isomers / stereoisomers enriched in this invention.

[0184] "Stereoisopure" refers to a composition containing one stereoisomer of a compound but substantially lacking another stereoisomer of that compound. For example, a stereoisopure composition of a compound having one chiral center will substantially lack the opposing enantiomer of that compound. A stereoisopure composition of a compound having two chiral centers will substantially lack other diastereomers of that compound. A typical stereoisomeric pure compound comprises, by mass, more than about 80% of one stereoisomer of the compound and less than about 20% of another stereoisomer of the compound; more than about 90% of one stereoisomer of the compound and less than about 10% of another stereoisomer of the compound; more than about 95% of one stereoisomer of the compound and less than about 5% of another stereoisomer of the compound; more than about 97% of one stereoisomer of the compound and less than about 3% of another stereoisomer of the compound; or more than about 99% of one stereoisomer of the compound and less than about 1% of another stereoisomer of the compound.

[0185] "Stereoisomeric enrichment" refers to a composition containing a stereoisomer of a compound at a mass content greater than about 55%, about 60%, about 70%, or about 80%.

[0186] "Enantiomerically pure" refers to a stereoisomerically pure composition of a compound having a single chiral center. Similarly, the term "enantiomerically enriched" refers to a stereoisomerically enriched composition of a compound having a single chiral center.

[0187] "Optical activity" and "enantiomeric activity" refer to a molecular combination having an enantiomer excess of not less than about 50%, not less than about 70%, not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%. In a particular embodiment, the compound comprises about 95% or more of the desired enantiomer or diastereomer by weight of the racemic compound and about 5% or less of the subpreferred enantiomer or diastereomer.

[0188] In describing optically active compounds, the prefixes R and S are used to indicate the absolute configuration of the molecule relative to its chiral center. (+) and (-) are used to indicate the optical rotation of the compound, i.e., the direction of the plane of polarized light rotated by the optically active compound. The prefix (-) indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right or clockwise. However, the signs (+) and (-) for optical rotation are independent of the absolute configuration R and S of the molecule.

[0189] The compounds of this invention include all of their "stereoisomers", "stereoisomeric purity", "stereoisomeric enrichment", "enantiomeric purity", "optical activity", "enantiomeric activity" and "optical isomers". Detailed Implementation

[0190] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0191] Example

[0192] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0193] LC-MS analysis was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC analysis was performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C).18 (150×4.6mm chromatographic column).

[0194] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The standard size for TLC is 0.15mm to 0.20mm, while the standard size for separating and purifying products using TLC is 0.4mm to 0.5mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0195] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0196] Unless otherwise specified, all reactions in this invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is expressed in degrees Celsius.

[0197] Example 1

[0198] Step 1: Preparation of (S)-N-(5-fluoro-2-methoxyphenylmethylene)-2-methylpropane-2-sulfinamide

[0199]

[0200] 5-Fluoro-2-methoxybenzaldehyde (154 g, 1.0 mol) and (S)-tert-butylsulfinamide (121.2 g, 1.0 mmol) were dissolved in dichloromethane (800 mL), and cesium carbonate (652 g, 2.0 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography to give the title compound (239.3 g, 93%). MS m / z (ESI): 258.1 [M+H] + .

[0201] Step 2: Preparation of (S)-N-((S)-(5-fluoro-2-methoxyphenyl)(4-methylphenyl)methyl)-2-methylpropane-2-sulfinamide

[0202]

[0203] (S)-N-(5-fluoro-2-methoxyphenylmethylene)-2-methylpropane-2-sulfinamide (25.73 g, 100.0 mmol) and 4-methylphenylboronic acid (54.38 g, 400.0 mmol) were dissolved in a mixed solvent of dioxane (300 mL) and water (300 mL). Triethylamine (50.60 g, 500.0 mmol) and bis(acetonitrile)(1,5-cyclooctadiene)rhodium tetrafluoride (3.0 g, 8.0 mmol) were added, and the reaction mixture was stirred at room temperature for 24 hours. The mixture was concentrated under reduced pressure to remove most of the organic solvent. The residue was diluted with saturated sodium chloride solution, extracted twice with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography to give the title compound (20.3 g, 58%). MS m / z (ESI): 350.2 [M+H] + .

[0204] Step 3: Preparation of (S)-(5-fluoro-2-methoxyphenyl)(4-methylphenyl)methylamine

[0205]

[0206] (S)-N-((S)-(5-fluoro-2-methoxyphenyl)(4-methylphenyl)methyl)-2-methylpropane-2-sulfinamide (20.3 g, 58.0 mmol) was dissolved in 100 mL of 4 M hydrogen chloride / dioxane solution and stirred at room temperature for 2 hours. The solvent was removed by concentration under reduced pressure. The residue was dissolved in water, neutralized with sodium carbonate, extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate and sodium chloride solutions, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography to give the title compound (12.95 g, 91%). MS m / z (ESI): 246.2 [M+H] + .

[0207] Step 4: Preparation of 8-chloro-2-methyl-1,7-diazanaphth-4(1H)-one

[0208]

[0209] Cycloisopropyl malonate (43.24 g, 300 mmol) and trimethyl orthoacetate (48.06 g, 200 mmol) were mixed, heated to 115 °C and stirred for 2 hours. The mixture was then cooled to 50 °C, and 2-chloro-3-aminopyridine (25.72 g, 200 mmol) was added. The mixture was further heated to 115 °C and stirred for 2 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was slurried with a small amount of methanol, filtered, and the filter residue was dried under reduced pressure. The filter residue was dispersed in diphenyl ether (1.5 L), heated to 250 °C, and stirred for 2 hours. After cooling to room temperature and standing, the mixture was diluted with petroleum ether, filtered, and the insoluble matter was collected. The insoluble matter was dissolved in dichloromethane and methanol, concentrated under reduced pressure, and the residue was separated by column chromatography to give the title compound (13.62 g, 35%). MS m / z (ESI): 195.1 [M+H] + .

[0210] Step 5: Preparation of 4,8-dichloro-2-methyl-1,7-diazanaphthalene

[0211]

[0212] 13.62 g (70 mmol) of 8-chloro-2-methyl-1,7-diazanaphth-4(1H)-one was dispersed in 200 mL of phosphorus oxychloride. The mixture was heated to 120 °C and stirred for 3 hours. After cooling to room temperature, the solvent was removed by concentration under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography to give the title compound (9.1 g, 61%).

[0213] MS m / z(ESI): 213.0 [M+H] + .

[0214] Step 6: Preparation of (S)-4-chloro-N-((5-fluoro-2-methoxyphenyl)(4-methylphenyl)methyl)-2-methyl-1,7-diazanaphthalene-8-amine

[0215]

[0216] (S)-(5-fluoro-2-methoxyphenyl)(4-methylphenyl)methylamine (491 mg, 2.0 mmol) and 4,8-dichloro-2-methyl-1,7-diazanaphthalene (639 mg, 3.0 mmol) were dissolved in isoamyl alcohol (5 mL). N,N-diisopropylethylamine (1.29 g, 10.0 mmol) was added. The reaction mixture was transferred to a microwave synthesizer and heated to 160 °C with stirring for 6 hours. After cooling to room temperature, the solvent was removed by concentration under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography to give the title compound (608 mg, 72%). MS m / z (ESI): 422.2 [M+H] + .

[0217] Step 7: Preparation of (S)-2-(((4-chloro-2-methyl-1,7-diazanaphth-8-yl)amino)(4-methylphenyl)methyl)-4-fluorophenol

[0218]

[0219] (S)-4-chloro-N-((5-fluoro-2-methoxyphenyl)(4-methylphenyl)methyl)-2-methyl-1,7-diazanaphth-8-amine (608 mg, 1.44 mmol) was dissolved in dichloromethane (15 mL), cooled to 0 °C, and a 2 M boron tribromide solution in dichloromethane (1.5 mL, 3.0 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was then added dropwise to a saturated sodium bicarbonate solution pre-cooled to 0 °C, extracted with ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography to give the title compound (499 mg, 85%). MS m / z (ESI): 408.1 [M+H] + .

[0220] Step 8: Preparation of (S)-4-fluoro-2-(((4-(3-hydroxy-3-methylbut-1-yn-1-yl)-2-methyl-1,7-diazanaphth-8-yl)amino)(4-methylphenyl)methyl)phenol

[0221]

[0222] Under dry nitrogen protection, (S)-2-(((4-chloro-2-methyl-1,7-diazanaphthyl-8-yl)amino)(4-methylphenyl)methyl)-4-fluorophenol (82 mg, 0.20 mmol), 2-methyl-3-butyn-2-ol (84 mg, 1.00 mmol), palladium acetate (4.5 mg, 0.02 mmol), and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (X-Phos, 19 mg, 0.04 mmol) were dissolved in dry N,N-dimethylformamide (6 mL). Cuprous iodide (3.8 mg, 0.02 mmol) and N,N-diisopropylethylamine (130 mg, 1.0 mmol) were added. The reaction solution was heated to 100 °C and stirred for 7 hours. After cooling to room temperature, the reaction solution was filtered through a microporous membrane, and the filtrate was analyzed by HPLC to obtain the title compound (28 mg, 31%). MS m / z (ESI): 456.2 [M+H] + The following embodiments are synthesized with reference to Embodiment 1:

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230] Example 18 can also be prepared according to the following method

[0231] Step 1: Preparation of 5-(1-((2-chloropyridin-3-yl)amino)ethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0232]

[0233] 1,1,1-trimethoxyethane (4.8 g, 39.95 mmol) was added to 2,2-dimethyl-1,3-dioxane-4,6-dione (4.32 g, 29.97 mmol), the mixture was heated to 115 °C and stirred for 2 hours, then cooled to 50 °C, and 2-chloropyridine-3-amine (2.57 g, 20.01 mmol) was added. The mixture was then heated to 115 °C and stirred for another 2 hours. After cooling to room temperature, ethyl acetate (100 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered, washed with ethyl acetate (10 mL), and the filter cake was dried to give the title compound (2.5 g, 42%). MS m / z (ESI): 297.1 [M+H] + .

[0234] Step 2: Preparation of 8-chloro-2-methyl-1,7-diazanaphthalene-4-ol

[0235]

[0236] To 2.5 g (8.43 mmol) of 5-(1-((2-chloropyridin-3-yl)amino)ethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione, a diphenyl ether-biphenyl eutectic (200 mL) was added, the mixture was heated to 250 °C and stirred for 2 hours, then cooled to room temperature. Petroleum ether (1300 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the residue was washed with petroleum ether (50 mL). The filter cake was collected and separated by column chromatography to obtain the title compound (920 mg, 56%). MS m / z (ESI): 195.0 [M+H] + .

[0237] Step 3: Preparation of 8-chloro-2-methyl-1,7-diazanaphth-4-yltrifluoromethanesulfonic acid

[0238]

[0239] 8-Chloro-2-methyl-1,7-diazanaphth-4-ol (460 mg, 2.36 mmol) was dissolved in a mixed solution of dichloromethane (10 mL) and tetrahydrofuran (10 mL). DIPEA (1.75 g, 13.52 mmol) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (1.70 g, 4.76 mmol) were added sequentially, and the mixture was heated to 50 °C and stirred for 3 hours. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was separated by column chromatography to give the title compound (600 mg, 78%). MS m / z (ESI): 327.0 [M+H] + .

[0240] Step 4: Preparation of 4-(8-chloro-2-methyl-1,7-diazanaphth-4-yl)-2-methylbut-3-yn-2-ol

[0241]

[0242] Under nitrogen protection, 8-chloro-2-methyl-1,7-diazanaphth-4-yltrifluoromethanesulfonic acid (600 mg, 1.84 mmol) was dissolved in 10 mL of DMF solution. Triethylamine (931 mg, 9.20 mmol), 2-methylbut-3-yn-2-ol (172 mg, 2.04 mmol), Pd(PPh3)2Cl2 (142 mg, 202.28 μmol), and CuI (40 mg, 210.03 μmol) were added. The reaction mixture was heated to 60 °C and stirred for 3 hours. After cooling to room temperature, the mixture was diluted with water, extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by column chromatography to give the title compound (437 mg, 91%). MS m / z (ESI): 261.1 [M+H] + .

[0243] Step 5: Preparation of (R)-4-fluoro-2-(((4-(3-hydroxy-3-methylbut-1-yn-1-yl)-2-methyl-1,7-diazanaphth-8-yl)amino)(1H-indol-2-yl)methyl)phenol

[0244]

[0245] 4-(8-chloro-2-methyl-1,7-diazanaphth-4-yl)-2-methylbut-3-yn-2-ol (150 mg, 575.33 μmol) and (R)-2-(amino(1H-indol-2-yl)methyl)-4-fluorophenol (161 mg, 628.23 μmol) were dissolved in acetonitrile (5 mL). Pd(BINAP)Cl2 (54 mg, 58.63 μmol), DBU (90 mg, 591.17 μmol), and K2CO3 (165 mg, 1.20 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 18 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was subjected to column chromatography to obtain the crude product. The crude product was then reversed-phase to prepare the title compound (12 mg, 4.3%). MS m / z (ESI): 481.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ11.11(s,1H),9.89(s,1H),8.07(d,J=8.7Hz,1H),7.97(d,J=5.8Hz,1H),7.65(s,1H),7.42(d,J=7.9Hz,1H),7.32(d,J= 8.1Hz,1H),7.25-7.21(m,1H),7.12(d,J=5.8Hz,1H),7.07-6.88(m,4H) ,6.87-6.83(m,1H),6.14(s,1H),5.73(s,1H),2.65(s,3H),1.55(s,6H).

[0246] Example 75 can also be prepared according to the following method

[0247] Step 1: Preparation of methyl 3-amino-6-chloromethylpyridinium ester

[0248]

[0249] 3-Amino-6-chloro-o-pyridinecarboxylic acid (40 g, 231.79 mmol) was dissolved in methanol (800 mL), and thionyl chloride (35.85 g, 301.33 mmol) was added. The reaction mixture was heated to 75 °C and stirred for 16 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in a dichloromethane / methanol (1 L, v / v = 9 / 1) mixture, washed with saturated sodium bicarbonate solution (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (42 g, 97%). MS m / z (ESI): 187.0 [M+H] + .

[0250] Step 2: Preparation of methyl 3-amino-6-methylmethylpyridinium ester

[0251]

[0252] Under nitrogen protection, methyl 3-amino-6-chloromethylpyridinium ester (21 g, 112.54 mmol) and 2,4,6-trimethyl-cyclotriboroxane (28.26 g, 225.09 mmol) were dissolved in 1,4-dioxane (15 mL), and tetra(triphenylphosphine)palladium (13.01 g, 11.25 mmol) and potassium carbonate (46.66 g, 337.63 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 16 hours. After cooling, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give the title compound (14.19 g, 76%). MS m / z (ESI): 167.1 [M+H] + .

[0253] Step 3: Preparation of methyl 3-amino-4-bromo-6-methylmethylpyridine ester

[0254]

[0255] Methyl 3-amino-6-methylmethylpyridinium ester (9.2 g, 55.36 mmol) was dissolved in tetrahydrofuran (250 mL), and dibromohydantoin (9.5 g, 33.22 μmol) was added. The reaction mixture was stirred for 3 hours. Then, dibromohydantoin (9.5 g, 33.22 μmol) was added, and the reaction mixture was stirred for 2.5 hours. The reaction mixture was poured into water (500 L), extracted with ethyl acetate (250 mL × 2), washed with saturated sodium chloride solution (250 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the title compound (960 mg, 7%). MS m / z (ESI): 245.0 [M+H] + .

[0256] Step 4: Preparation of methyl 3-amino-4-(2-bromo-4-chlorophenyl)-6-methylmethylpyridinium ester

[0257]

[0258] Under nitrogen protection, methyl 3-amino-4-bromo-6-methylmethylpyridinium ester (300 mg, 1.22 mmol) and (2-bromo-4-chlorophenyl)boronic acid (432 mg, 1.84 mmol) were dissolved in 1,4-dioxane (15 mL) and water (3 mL). Tetra(triphenylphosphine)palladium (141 mg, 122.41 μmol) and potassium carbonate (508 mg, 3.67 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 2.5 hours under nitrogen atmosphere. After cooling, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain the title compound (300 mg, 69%). MS m / z (ESI): 355.0 [M+H] + .

[0259] Step 5: Preparation of 7-chloro-3-methyl-9H-pyrido[3,4-b]indole-1-carboxylic acid

[0260]

[0261] Methyl 3-amino-4-(2-bromo-4-chlorophenyl)-6-methylmethylpyridinium ester (275 mg, 773.31 μmol) was dissolved in dimethyl sulfoxide (5 mL), and potassium tert-butoxide (260 mg, 2.32 mmol) was added. The reaction mixture was heated to 100 °C and stirred for 3 hours. The reaction mixture was cooled to 0 °C, and the pH was adjusted to approximately 3 with dilute hydrochloric acid. The precipitated solid was collected by filtration, concentrated under reduced pressure, and dried to give the title compound (160 mg, 79%). MS m / z (ESI): 261.0 [M+H] + .

[0262] Step 6: Preparation of 3-methyl-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-9H-pyrido[3,4-b]indole-1-carboxylic acid

[0263]

[0264] Under nitrogen protection, 7-chloro-3-methyl-9H-pyrido[3,4-b]indole-1-carboxylic acid (160 mg, 566.26 μmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-1,2,3,6-tetrahydropyridine (219 mg, 982.88 μmol) were dissolved in 1,4-dioxane (10 mL) and water (1.5 mL). Then, (methanesulfonic acid {bicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine) The reaction mixture was prepared with alkyl(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (60 mg, 65.53 μmol), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (70 mg, 131.05 μmol), and cesium carbonate (320 mg, 982.88 μmol). The reaction mixture was heated to 100 °C and stirred for 4 hours under a nitrogen atmosphere. After cooling, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain the title compound (40 mg, 19%). MS m / z (ESI): 322.2 [M+H] + .

[0265] Step 7: Preparation of 3-methyl-7-(1-methylpiperidin-4-yl)-9H-pyrido[3,4-b]indole-1-carboxylic acid

[0266]

[0267] 3-Methyl-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-9H-pyrido[3,4-b]indole-1-carboxylic acid (40 mg, 124.47 μmol) was dissolved in tetrahydrofuran (3 mL) and methanol (3 mL). Wet palladium on carbon (13 mg, 12.45 μmol, 10%) and platinum dioxide (14 mg, 62.23 μmol) were added. The reaction mixture was stirred under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and dried to give the title compound (40 mg, 99%). MS m / z (ESI): 324.2 [M+H] + .

[0268] Step 8: Preparation of N-((S)-(3-fluoro-1H-indol-2-yl)((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)methyl)-3-methyl-7-(1-methylpiperidin-4-yl)-9H-pyrido[3,4-b]indol-1-carboxamide

[0269]

[0270] (S)-(3-fluoro-1H-indol-2-yl)((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)methylamine (30 mg, 104.06 μmol) and 3-methyl-7-(1-methylpiperidin-4-yl)-9H-pyrido[3,4-b]indol-1-carboxylic acid (34 mg, 104.06 μmol) were dissolved in N,N-dimethylformamide (2 mL). Diisopropylethylamine (67 mg, 520.30 μmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (43 mg, 114.47 μmol) were added at 0 °C. The reaction mixture was stirred for 30 minutes. The reaction solution was filtered through a microporous membrane, and the filtrate was subjected to high-performance liquid chromatography (HPLC) to prepare and separate the title compound (11.8 mg, 19%). MS m / z (ESI): 594.2 [M+H] + .

[0271] 1H NMR (400MHz, DMSO-d6) δ=11.50(s,1H),11.11(s,1H),9.19(d,J=7.6Hz,1H),8.16(s,1H),8.10(d,J= 8.0Hz,1H),7.68(s,1H),7.54(s,1H),7.49(d,J=8.0Hz,1H),7.35-7.31(m,1H),7.15-7.08(m,2H),7 .06-7.01(m,1H),6.55(d,J=7.6Hz,1H),5.83-5.62(m,1H),4.29-4.16(m,2H),3.00-2.83(m,3H),2. 70(s,3H),2.63-2.53(m,1H),2.46-2.39(m,1H),2.20(s,3H),2.06-1.94(m,2H),1.84-1.66(m,4H).

[0272] Other embodiments can be prepared with reference to the above embodiments, and the NMR data are shown in the table below:

[0273]

[0274]

[0275]

[0276]

[0277] Biological test evaluation

[0278] The present invention will be further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[0279] Test Example 1: In vitro cell proliferation inhibition experiment

[0280] Experimental Objective: The purpose of this test case is to evaluate the in vitro proliferation inhibitory activity of the compound against different EGFR L858R mutant cell lines: Ba / F3 EGFR L858R / T790M / C797S triple mutant, Ba / F3 EGFR L858R / C797S double mutant, Ba / F3 EGFR L858R single mutant, natural cell line NCI-H1975 (EGFR L858R / T790M), and natural cell line A431 (EGFR wild type).

[0281] Experimental apparatus:

[0282] Centrifuge (Eppendorf 5810R) and microplate reader (BioTek Synergy H1)

[0283] Pipettes (Eppendorf or Rainin) and a CO2 incubator (Thermo 311)

[0284] Life Countess II cell counter

[0285] IDOT (Dispendix) nano-level liquid separation system

[0286] Laboratory reagents and consumables:

[0287] Ba / F3 EGFR L858R / T790M / C797S cells were purchased from Nanjing Kebai Biotechnology Co., Ltd.

[0288] Ba / F3 EGFR-L858R / C797S cells were purchased from Nanjing Kebai Biotechnology Co., Ltd.

[0289] Ba / F3 EGFR L858R cells were purchased from Kangyuan Bochuang Biotechnology Co., Ltd.

[0290] NCI-H1975 cells were purchased from Nanjing Kebai Biotechnology Co., Ltd.

[0291] A431 cells were purchased from ATCC.

[0292] Cell Titer-Glo was purchased from Promega, product number G7573.

[0293] RPMI 1640 was purchased from Gibco, part number 22400089;

[0294] The DMEM was purchased from Gibco, product number 11995-065.

[0295] FBS purchased from Gibco, item number 10091148

[0296] The cell culture plates were purchased from Corning, catalog number 3610.

[0297] Experimental methods:

[0298] The Cell Titer-Glo method was used to detect the in vitro proliferation inhibitory activity of the compounds against different EGFR L858R mutant cell lines. Ba / F3 and NCI-H1975 cells were cultured in RPMI 1640 complete medium containing 10% FBS, while A431 cells were cultured in DMEM complete medium containing 10% FBS at 37°C and 5% CO2. Cells were collected by centrifugation at a certain density, counted, and adjusted to an appropriate cell density. 100 μL of cells were seeded per well in white 96-well plates and incubated overnight at 37°C and 5% CO2. Different initial compound concentrations (30 μM–370 nM) were added using an IDOT microplate, with corresponding solvent controls. After incubation at 37°C and 5% CO2 for 3 or 6 days, 50 μL of CellTiter-Glo solution was added to each well, mixed thoroughly by shaking, and incubated in the dark for 10 minutes. Readings were then performed using a BioTek Synergy H1 microplate reader.

[0299] Experimental data processing method: The inhibition rate was calculated using the emission signal value. The concentration and inhibition rate were then fitted with a nonlinear regression curve using Graphpad Prism software to obtain the IC50. 50 value.

[0300]

[0301] Note: / indicates untested.

[0302] Experimental conclusion: The above methods show that the compounds of this invention exhibit significant inhibitory activity against the proliferation of different EGFR L858R mutant cell lines.

Claims

1. A compound represented by the following general formula or a pharmaceutically acceptable salt thereof: in: M is selected from O, C=O, C=S, N, S, -CR aa R cc -CR aa or -NR bb ; L1, L2, or L3 are each independently selected from the bond, -(CH2). n1 O(CH2) n2 -、-(CH2) n1 C=O(CH2) n2 -、-(CH2) n1 C = S(CH2) n2 -、-(CH2) n1 C = OO(CH2) n2 -、-(CH2) n1 NR bb (CH2) n2 -、-(CH2) n1 S(CH2) n2 -、-(CH2) n1 CONH(CH2) n2 -、(CH2) n1 NHCONH(CH2) n2 -、(CH2) n1 NHC(=NH)NH(CH2) n2 -、(CH2) n1 POR bb (CH2) n2 -、O(CH2) n1 POR bb (CH2) n2 -、C 1-6 Alkylene, C 1-6 imide or C 1-6 Alynyl group; wherein the -(CH2) group is... n1 O(CH2) n2 -、-(CH2) n1 C=O(CH2) n2 -、-(CH2) n1 C = S(CH2) n2 -、-(CH2) n1 C = OO(CH2) n2 -、-(CH2) n1 NR bb (CH2) n2 -、-(CH2) n1 S(CH2) n2 -、-(CH2) n1 CONH(CH2) n2 -、(CH2) n1 NHCONH(CH2) n2 -、(CH2) n1 NHC(=NH)NH(CH2) n2 -、(CH2) n1 POR bb (CH2) n2 -、O(CH2) n1 POR bb (CH2) n2 -、C 1-6 Alkylene, C 1-6 imide and C 1-6 Alynyl group, optionally further modified by hydrogen, deuterium, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, substituted or unsubstituted C group. 1-6 Alkyl, substituted or unsubstituted C 1-6 Deuterated alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; Rings A1, A2, or B are each independently selected from C. 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups; R 1 R 2 Or R 3 Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -SF3, -SF5, -(CH2) n -、-(CH2) n R aa -(CH2) n OR bb -O(CH2) n R aa -(CH2) n SR bb -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R bb -(CH2) n C(O)NR aa R bb -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R bb -(CH2) n P(O)R aa R bb -O(CH2) n P(O)R aa R bb -(CH2) n NR cc C(=NH)NR aa R bb -(CH2) n NR bb S(O) m R cc -(CH2) n S(=O)R cc =NR bb -OC(R) aa R bb ) n (CH2) m R aa -NR bb (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R bb -CH=CH(CH2) n NR bb C(O)R cc -CH=CH(CH2) n NR bb C(O)NR aa R bb =N-OR bb or = CR aa R cc The C mentioned therein 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Deuterated alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; Or, any two identical or different R 1 R 2 Or R 3 Connecting them can form a ring system, which is selected from C. 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl; wherein the C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further bonded by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -SF3, -SF5, -(CH2) n -、-(CH2) n R aa -(CH2) n OR bb -O(CH2) n R aa -(CH2) n SR bb -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R bb -(CH2) n C(O)NR aa R bb -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R bb -(CH2) n P(O)R aa R bb -O(CH2) n P(O)R aa R bb -(CH2) n NR cc C(=NH)NR aa R bb -(CH2) n NR bb S(O) m R cc -(CH2) n S(=O)R cc =NR bb -OC(R) aa R bb ) n (CH2) m R aa -NR bb (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R bb -CH=CH(CH2) n NR bb C(O)R cc -CH=CH(CH2) n NR bb C(O)NR aa R bb =N-OR bb or = CR aa R cc The C mentioned therein 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Deuterated alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; R aa R bb and R cc Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Deuterated alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; Or, any two identical or different R aa R bb With R cc Connecting them can form a ring system, which is selected from C. 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 quinone heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Deuterated alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; The "substitution" in "substituted or unsubstituted" mentioned above refers to substitution by 1-4 R groups. m Replace, where R m Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl; x is an integer of 0, 1, 2, 3, 4, or 5; y is an integer of 0, 1, 2, 3, 4, or 5; z is an integer of 0, 1, 2, 3, 4, or 5; m can be 0, 1, 2, or 3; n is 0, 1, 2, or 3; n1 and n2 are each independently 0, 1, 2 or 3.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, Further, as shown in the following general formula: in: X1, X2, X3, X4, X5, X6 and X7 are each independently selected from C, N, S, O, NH or CH.

3. A compound represented by the following general formula or a pharmaceutically acceptable salt thereof: in: Ring A is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups; Other groups are as described in claim 1.

4. The compound of claim 1 or 3, or a pharmaceutically acceptable salt thereof, characterized in that, Further, as shown in the following general formula: in: Ring A3 is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups; R 4 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -SF3, -SF5, -(CH2) n -、-(CH2) n Raa、-(CH2) n OR bb -O(CH2) n R aa -(CH2) n SR bb -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R bb -(CH2) n C(O)NR aa R bb -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R bb -(CH2) n P(O)R aa R bb -O(CH2) n P(O)R aa R bb -(CH2) n NR cc C(=NH)NR aa R bb -(CH2) n NR bb S(O) m R cc -(CH2) n S(=O)R cc =NR bb -OC(R) aa R bb ) n (CH2) m R aa -NR bb (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R bb -CH=CH(CH2) n NR bb C(O)R cc -CH=CH(CH2) n NR bb C(O)NR aa R bb =N-OR bb or = CR aa R cc The C mentioned therein 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Deuterated alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; Or, any two R 4 Connecting them can form a ring system, which is selected from C. 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl; wherein the C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Deuterated alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; u is an integer of 0, 1, 2, 3, 4, or 5.

5. A compound represented by the following general formula or a pharmaceutically acceptable salt thereof: in: Each ring C is independently selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups; Other groups are as described in claim 1.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, characterized in that, Further, as shown in the following general formula: in: X1, X2, X3, X4, X5, X6 and X7 are each independently selected from C, N, S, O, NH or CH.

7. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-6, characterized in that, Ring A, ring A1, ring A2, or ring A3 are selected from single rings, double rings, or multiple rings; When the ring is a single ring: Selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14-membered heteroaryl; preferably benzene or 5-8-membered heteroaryl; further preferably furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, thiadiazolyl, thiazolyl, thiophene, tetrazolyl, triazinyl or triazolyl; When the ring is a double ring: it is selected from spiral rings, parallel rings, or bridge rings, with ring A being the preferred choice when it is a double ring. Preferred 5-14 quinone heteroaryl 5-14 quinone heteroaryl, 5-14 quinone heteroaryl C 6-14 Aryl or C 6-14 Aryl 3-12 membered heterocyclic group; more preferably 5-6 membered heteroaryl 5-6 membered heteroaryl, 5-6 membered heteroaryl 5-6 membered aryl, 5-6 membered heterocyclic 5-6 membered heteroaryl or benzo 5-6 membered heteroaryl; The preferred structure is as follows: When the ring is multi-ringed: it should be selected from a system of three or more rings, which can be a parallel ring, a spiral ring, or a bridge ring; preferably an 8-20 element multi-ring system, and preferably a three-ring system for ring A. Preferred series: 5-6 yuan / 5-8 yuan / 5-6 yuan; even better series: 6 yuan / 5 yuan / 6 yuan, 6 yuan / 6 yuan / 6 yuan, 6 yuan / 7 yuan / 6 yuan, 5 yuan / 5 yuan / 6 yuan, 5 yuan / 5 yuan / 6 yuan, 5 yuan / 7 yuan / 6 yuan. The preferred structure is as follows: and / or Ring B is selected from C 6-14 Aryl or 5-14 membered heteroaryl; preferably phenyl or 5-10 membered bicyclic heteroaryl; The preferred structure is as follows: Or; and / or ring C is selected from C 6-14 Aryl or 5-14 membered heteroaryl; preferably phenyl or 5-10 membered bicyclic heteroaryl; The preferred structure is as follows: and / or L1 is selected from the bonds -COCH2-, -COCH2CH2-, and -CR. aa R cc -、-CO-、-NR bb -、-CONR bb -; preferred key; and / or L2 is selected from the bonds -COCH2-, -COCH2CH2-, and -CR. aa R cc -、-CO-、-NR bb -、-CONR bb -;Preferred-NR bb -or-CONR bb - 8. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-7, characterized in that, The compound has the structure shown in formula (ID-1) or formula (IH-1). Preferably, the compound has the structure shown in formula (ID-1-1) or formula (IH-1-1). Preferably, the compound has the structure shown in formula (ID-1-1-1) to (ID-1-1-4) or formula (IH-1-1-1) to (IH-1-1-4). in: R 1-1 To R 1-9 The definition is the same as R 1 ; R' aa The definition is the same as R aa ; Ring D is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups; q is independently selected from 0, 1, 2, 3, 4, 5, or 6; The definitions of X1, X2, X3, X6, and X7 are as described in claim 2; y, z, M, L1, R 1 R 2 R 3 and R aa The definition is as described in claim 1.

9. The compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-8, characterized in that, L3 is selected from the bonds -COCH2-, -COCH2CH2-, and -CR. aa R cc -、-CO-、-CH2NR bb -、-CONR bb -; preferred bond or -CH2NR bb -; and / or R 1 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -SF3, -SF5, -(CH2) n -、-(CH2) n R aa -(CH2) n OR bb -O(CH2) n R aa -C≡C(CH2) n R aa -(CH2) n SR bb -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R bb -(CH2) n C(O)NR aa R bb -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R bb -(CH2) n P(O)R aa R bb -O(CH2) n P(O)R aa R bb -(CH2) n NR cc C(=NH)NR aa R bb -(CH2) n NR bb S(O) m R cc -(CH2) n S(=O)R cc =NR bb -OC(R) aa R bb ) n (CH2) m R aa -NR bb (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R bb -CH=CH(CH2) n NR bb C(O)R cc -CH=CH(CH2) n NR bb C(O)NR aa R bb =N-OR bb or = CR aa R cc The C mentioned therein 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Deuterated alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; Preferably, R 1-1 To R 1-9 and R 1 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10-membered heteroaryl, wherein the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further bonded by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -SF3, -SF5, -(CH2) n Raa、-(CH2) n OR bb -O(CH2) n R aa -(CH2) n SR bb -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R bb -(CH2) n C(O)NR aa R bb -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R bb -(CH2) n P(O)R aa R bb -O(CH2) n P(O)R aa R bb -(CH2) n NR cc C(=NH)NR aa R bb -(CH2) n NR bb S(O) m R cc -(CH2) n S(O)R cc =NR bb -OC(R) aa R bb ) n (CH2) m R aa -NR bb (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R bb -CH=CH(CH2) n NR bb C(O)R cc -CH=CH(CH2) n NR bb C(O)NR aa R bb =N-OR bb or = CR aa R cc One or more substituents in it are replaced; The following group structures are preferred: Ring D is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 membered heteroaryl; preferably 3-12 membered heterocyclic; R' aa The definition is the same as R aa ;q is independently selected from 0, 1, 2, 3, 4, 5, or 6; More preferably, the following functional group structure is preferred: Ring D is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 membered heteroaryl; preferably 3-12 membered heterocyclic; Or, two adjacent or non-adjacent R 1 Connecting them can form a ring system, which is selected from C. 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl, wherein the C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further bonded by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -SF3, -SF5, -(CH2) n -、-(CH2) n Raa、-(CH2) n OR bb -O(CH2) n R aa -(CH2) n SR bb -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R bb -(CH2) n C(O)NR aa R bb -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R bb -(CH2) n P(O)R aa R bb -O(CH2) n P(O)R aa R bb -(CH2) n NR cc C(=NH)NR aa R bb -(CH2) n NR bb S(O) m R cc -(CH2) n S(=O)R cc =NR bb -OC(R) aa R bb ) n (CH2) m R aa -NR bb (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R bb -CH=CH(CH2) n NR bb C(O)R cc -CH=CH(CH2) n NR bb C(O)NR aa R bb =N-OR bb or = CR aa R cc The C mentioned therein 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further bonded by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted with one or more substituents of the 5-14 heteroaryl group; and / or R 2 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10-membered heteroaryl, wherein the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further bonded by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -SF3, -SF5, -(CH2) n Raa、-(CH2) n OR bb -O(CH2) n R aa -(CH2) n SR bb -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R bb -(CH2) n C(O)NR aa R bb -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R bb -(CH2) n P(O)R aa R bb -O(CH2) n P(O)R aa R bb -(CH2) n NR cc C(=NH)NR aa R bb -(CH2) n NR bb S(O) m R cc -(CH2) n S(O)R cc =NR bb -OC(R) aa R bb ) n (CH2) m R aa -NR bb (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R bb -CH=CH(CH2) n NR bb C(O)R cc -CH=CH(CH2) n NR bb C(O)NR aa R bb =N-OR bb or = CR aa R cc One or more substituents in it are replaced; Or, two adjacent or non-adjacent R 2 Connecting them can form a ring system, which is selected from C. 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl, wherein the C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further bonded by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -SF3, -SF5, -(CH2) n -、-(CH2) n Raa、-(CH2) n OR bb -O(CH2) n R aa -(CH2) n SR bb -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R bb -(CH2) n C(O)NR aa R bb -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R bb -(CH2) n P(O)R aa R bb -O(CH2) n P(O)R aa R bb -(CH2) n NR cc C(=NH)NR aa R bb -(CH2) n NR bb S(O) m R cc -(CH2) n S(=O)R cc =NR bb -OC(R) aa R bb ) n (CH2) m R aa -NR bb (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R bb -CH=CH(CH2) n NR bb C(O)R cc -CH=CH(CH2) n NR bb C(O)NR aa R bb =N-OR bb or = CR aa R cc The C mentioned therein 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further bonded by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted with one or more substituents of the 5-14 heteroaryl group; and / or R 3 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10-membered heteroaryl, wherein the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further bonded by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -SF3, -SF5, -(CH2) n Raa、-(CH2) n OR bb -O(CH2) n R aa -(CH2) n SR bb -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R bb -(CH2) n C(O)NR aa R bb -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R bb -(CH2) n P(O)R aa R bb -O(CH2) n P(O)R aa R bb -(CH2) n NR cc C(=NH)NR aa R bb -(CH2) n NR bb S(O) m R cc -(CH2) n S(O)R cc =NR bb -OC(R) aa R bb ) n (CH2) m R aa -NR bb (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R bb -CH=CH(CH2) n NR bb C(O)R cc -CH=CH(CH2) n NR bb C(O)NR aa R bb =N-OR bb or = CR aa R cc One or more substituents in it are replaced; Or, two adjacent or non-adjacent R 3 Connecting them can form a ring system, which is selected from C. 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl, wherein the C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further bonded by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -SF3, -SF5, -(CH2) n -、-(CH2) n Raa、-(CH2) n OR bb -O(CH2) n R aa -(CH2) n SR bb -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R bb -(CH2) n C(O)NR aa R bb -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R bb -(CH2) n P(O)R aa R bb -O(CH2) n P(O)R aa R bb -(CH2) n NR cc C(=NH)NR aa R bb -(CH2) n NR bb S(O) m R cc -(CH2) n S(=O)R cc =NR bb -OC(R) aa R bb ) n (CH2) m R aa -NR bb (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R bb -CH=CH(CH2) n NR bb C(O)R cc -CH=CH(CH2) n NR bb C(O)NR aa R bb =N-OR bb or = CR aa R cc The C mentioned therein 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further bonded by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted with one or more substituents of the 5-14 heteroaryl group; and / or R 4 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10-membered heteroaryl, wherein the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further bonded by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -SF3, -SF5, -(CH2) n Raa、-(CH2) n OR bb -O(CH2) n R aa -(CH2) n SR bb -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R bb -(CH2) n C(O)NR aa R bb -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R bb -(CH2) n P(O)R aa R bb -O(CH2) n P(O)R aa R bb -(CH2) n NR cc C(=NH)NR aa R bb -(CH2) n NR bb S(O) m R cc -(CH2) n S(O)R cc =NR bb -OC(R) aa R bb ) n (CH2) m R aa -NR bb (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R bb -CH=CH(CH2) n NR bb C(O)R cc -CH=CH(CH2) n NR bb C(O)NR aa R bb =N-OR bb or = CR aa R cc One or more substituents in Or, two adjacent or non-adjacent R 4 Connecting them can form a ring system, which is selected from C. 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl, wherein the C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further bonded by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -SF3, -SF5, -(CH2) n -、-(CH2) n Raa、-(CH2) n OR bb -O(CH2) n R aa -(CH2) n SR bb -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R bb -(CH2) n C(O)NR aa R bb -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R bb -(CH2) n P(O)R aa R bb -O(CH2) n P(O)R aa R bb -(CH2) n NR cc C(=NH)NR aa R bb -(CH2) n NR bb S(O) m R cc -(CH2) n S(=O)R cc =NR bb -OC(R) aa R bb ) n (CH2) m R aa -NR bb (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R bb -CH=CH(CH2) n NR bb C(O)R cc -CH=CH(CH2) n NR bb C(O)NR aa R bb =N-OR bb or = CR aa R cc The C mentioned therein 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further bonded by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted with one or more substituents of the 5-14 heteroaryl group; and / or R' aa R aa R bb and R cc Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl, wherein the C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further bonded by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group; Or, any two identical or different R aa R bb With R cc Connecting them can form a ring system, which is selected from C. 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further bonded by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group; Preferably, R aa for Among them, ring E is selected from C 3-8 Cycloalkyl, 4-6 membered monocyclic heterocyclic groups, 6-10 membered bicyclic heterocyclic groups, C 6-10 aryl, 5-6 membered heteroaryl or 8-10 membered heteroaryl, wherein R n Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl; wherein, the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups may be further divided by 1-4 R groups. m replace; w is independently selected from 0, 1, 2, 3, 4, 5, or 6; Preferably, ring E is selected from and / or Ring D is selected from C 3-8 Cycloalkyl, 4-6 membered monocyclic heterocyclic groups, 6-10 membered bicyclic heterocyclic groups, C 6-10 aryl, 5-6 membered heteroaryl, or 8-10 membered heteroaryl, preferably ring D is selected from...

10. The compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-9, characterized in that, The compound is selected from the following compounds:

11. A pharmaceutical composition comprising a therapeutically effective dose of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

12. The use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-10, or the pharmaceutical composition of claim 11, in the preparation of an EGFR inhibitor drug; preferably the EGFR is a mutated and / or overexpressed EGFR, more preferably a single-mutated or multi-mutated EGFR; further preferably, at least one of the EGFR mutations, L858R, T790M or C797S, is present.

13. The use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-10, or the pharmaceutical composition according to claim 11, in the preparation of a treatment for cancer; preferably, the cancer is selected from ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer, endometrial cancer, renal cancer, anaplastic large cell lymphoma, multiple myeloma, melanoma, or mesothelioma; more preferably, the cancer is non-small cell lung cancer; More preferably, the cancer is non-small cell lung cancer with EGFR L858R, EGFR L858R / T790M, L858R / C797S or L858R / T790M / C797S mutations.

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