EGFR (epidermal growth factor receptor) allosteric inhibitor as well as preparation method and pharmaceutical application thereof

Abstract

The invention provides an EGFR (epidermal growth factor receptor) allosteric inhibitor as shown in a formula I, and preparation, a pharmaceutical composition and application thereof. The compound provided by the invention can be used as an EGFR allosteric inhibitor for treating or preventing EGFR protein mutation related diseases. I

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry and drug synthesis technology, specifically relating to a class of EGFR allosteric inhibitors, their preparation methods, and their pharmaceutical applications. Background Technology

[0002] Epidermal growth factor receptor (EGFR), a member of the HER family, is a transmembrane glycoprotein essential for cell signaling pathways regulating cell proliferation, differentiation, and apoptosis. EGFR overexpression is present in at least 70% of human cancers and can be observed in various types of solid tumors, such as non-small cell lung cancer (NSCLC), breast cancer, glioma, head and neck squamous cell carcinoma, and prostate cancer. Therefore, EGFR tyrosine kinase inhibitors are considered an effective clinical therapy for patients with EGFR-mutant NSCLC.

[0003] The most common mutation in non-small cell lung cancer (NSCLC) is EGFR (L858R), which activates kinases and promotes abnormal cell growth. First-generation small-molecule tyrosine kinase inhibitors are reversible, competing with ATP for binding sites to selectively inhibit L858R variants; representative drugs include gefitinib and erlotinib. In most cases, after a period of treatment with first-generation drugs, patients develop secondary EGFR mutations such as T790M, leading to resistance. Second-generation irreversible small-molecule tyrosine kinase inhibitors emerged to address this. Second-generation drugs, such as afatinib, can inhibit the T790M variant of EGFR, but they lack specificity and indiscriminately attack WT-EGFR, causing severe toxic side effects. Based on first- and second-generation drugs, third-generation irreversible inhibitors were further investigated, resulting in the widely used irreversible inhibitor osimertinib. Furthermore, osimertinib in combination with chemotherapy has been approved as a first-line treatment for patients with EGFR-mutant advanced NSCLC. Similarly, regarding the issue of drug resistance mutations, clinical studies have found that patients using osimertinib for a period of time develop resistance variants characterized by the C797S mutation, preventing third-generation drugs from exerting their anti-cancer effects. The fourth generation is epidermal growth factor receptor tyrosine kinase inhibitors, a new class of targeted drugs developed to address the resistance problem of third-generation inhibitors. This class of drugs aims to solve the drug resistance problem that arises in EGFR-mutant non-small cell lung cancer (NSCLC) patients after treatment with third-generation EGFR-TKIs, particularly targeting the C797S mutation, a resistance mutation point in third-generation drugs. EAI045 is an allosteric inhibitor that targets specific resistant EGFR mutants without affecting the wild-type receptor. This compound inhibited the L858R / T790M mutant EGFR with low nanomolar potency in biochemical analysis, but due to the different efficiencies of the two subunits of the dimer receptor, it could not effectively block EGFR-driven proliferation in cells as a single drug (WO2019164945 A1) (10.1038 / nature17960) (10.1038 / nature08622). Currently, research on fourth-generation inhibitors is stalled, and no drugs have been successfully approved for clinical use. Summary of the Invention

[0004] Objectives of this invention: The first objective is to provide a class of EGFR allosteric inhibitors that can effectively inhibit the proliferation of tumor cells; the second objective is to provide a method for preparing such EGFR allosteric inhibitors; and the third objective is the pharmaceutical application of these EGFR allosteric inhibitors. The compounds of this invention overcome the ineffectiveness of third-generation EGFR inhibitors against drug-resistant C797S point-mutant EGFR and exhibit high selectivity for wild-type EGFR, thus holding promise for the development of a novel class of EGFR allosteric inhibitors.

[0005] The first aspect of this invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, tautomers, solvates, isotope-substituted products, polymorphs, prodrugs, or metabolites: (I), in, R1 is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, nitro, -CF3, -OCF3, C 1-3 Alkoxy, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-7 cycloalkyl, C 6-10 The aryl or heteroaryl group may consist of one or two 5-7 membered rings and 1-4 heteroatoms from N, O, and S, wherein the above groups are independently and optionally further surrounded by one or more atoms selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, nitro, -CF3, -OCF3, -O(CH2). 1-3 C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-7 cycloalkyl, C 6-10 Aryl, heteroaryl, or substituted by one or two 5-7 membered rings and 1-4 heteroatoms from N, O, and S; R2 is independently selected from hydrogen, deuterium, and C. 1-3 alkyl; R3 is independently selected from hydrogen, deuterium, and C. 1-3 alkyl; Ring A is C 5-10 The aryl group may contain one, two, or three five-membered, six-membered, or seven-membered rings and 1-5 heteroaryl groups selected from O, N, and S atoms, wherein the heteroaryl group and the aryl group may be independently substituted by one or more R0 groups. R4 is independently selected from hydrogen, deuterium, and C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-7 cycloalkyl, C 5-10 Aryl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The aryl group comprises a haloalkoxy group and one, two, or three five-membered, six-membered, or seven-membered rings, and 1-5 heteroaryl groups selected from O, N, and S atoms, wherein each heteroaryl group and aryl group is independently separated by one or more R groups. 41 Substitution, q represents the substituent R on R4 41 The number of; R 41Independently selected from hydrogen, deuterium, hydroxyl, cyano, nitro, optionally with 1, 2 or 3 selected from halogen, deuterium and -NR. c R d Substituents of -NR a R b (e.g., amino), halogen, thio group, -CF3, -OCF3, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-7 cycloalkyl, C 5-10 Aryl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The alkyl halogroup and a heteroaryl group comprising one, two, or three five-membered, six-membered, or seven-membered rings and 1-5 heteroaryl groups selected from O, N, and S atoms; wherein, R a R b R c and R d Each is independently selected from H and C 1-6 alkyl; Q is selected from O, S, NR5, CR5R6. R5 is selected from hydrogen, deuterium, and C. 1-8 Alkyl, C 2-8 alkenyl or ynyl, C 3-8 cycloalkyl or heterocyclic groups, C 5-10 heteroaryl, the C 1-8 Alkyl, C 2-8 alkenyl or alkyne, C 3-8 cycloalkyl or heterocyclic groups, C 5-10 The heteroaryl group may be further converted by one or more hydroxyl, cyano, nitro, amino, halogen, thio, C group, etc. 1-8 Alkyl, C 2-8 alkenyl or ynyl, C 3-8 cycloalkyl or heterocyclic groups, C 5-10 Substituents of heteroaryl groups; R6 is selected from hydrogen, deuterium, hydroxyl, cyano, nitro, amino, halogen, thio, and C. 1-8 Alkyl, C 2-8 alkenyl or ynyl, C 3-8 cycloalkyl or heterocyclic groups, C 5-10 Metaaryl aromatics; wherein the C 1-8 Alkyl, C 2-8 alkenyl or ynyl, C 3-8 cycloalkyl or heterocyclic groups, C 5-10 The heteroaryl group may be further converted by one or more hydroxyl, cyano, nitro, amino, halogen, thio, C group, etc. 1-8 Alkyl, C 2-8 alkenyl or ynyl, C 3-8cycloalkyl or heterocyclic groups, C 5-10 Substituents of heteroaryl groups; m and n are independent 0s or 1s; p and q are independent values ​​of 0, 1, or 2. R0 is H, C 1-3 Alkyl, C 1-3 Alkoxy, amino, F, Br, Cl or -OH, preferably, R0 is C 1-3 Alkyl, C 1-3 Alkoxy, amino, F or Cl.

[0006] In one or more embodiments, R1 is independently H, halogen, unsubstituted or 1-3 halogenated C. 1-3 Alkyl, unsubstituted or 1-3 halogenated C 1-3 Alkoxy, unsubstituted or R0-substituted phenyl, unsubstituted or R0-substituted pyridyl, unsubstituted or R0-substituted amino, p is 0, 1 or 2.

[0007] In one or more embodiments, R1 is independently H, halogen, -CF3, -OCF3, C 1-3 Alkyl, phenyl, pyridyl, C 1-3 Alkoxy or amino, p is 0, 1 or 2.

[0008] In one or more implementations, R1 is H, or R1 is Cl or F, and p is 2, or R1 is C 1-3 Alkyl or amino, and p is 1 or 2, or R1 is -CF3, -OCF3, methyl, phenyl, or pyridyl, and p is 1.

[0009] In one or more embodiments, R2 is selected from hydrogen or C. 1-3 alkyl.

[0010] In one or more embodiments, m is 0; or m is 1 and R3 is selected from hydrogen or C. 1-3 alkyl.

[0011] In one or more embodiments, p, m, and n are 0, q is 1 or 2, and R2 is H or C. 1-3 alkyl.

[0012] In one or more embodiments, m and n are 0, p is 1 or 2, q is 1 or 2, and R2 is H or C. 1-3 Alkyl group, R1 independently is halogen, -CF3, -OCF3, C 1-3 Alkyl, phenyl, pyridyl, C 1-3 Alkyl groups and amino groups.

[0013] In one or more embodiments, m is 1, n is 0 or 1, p is 0, 1, or 2, q is 1 or 2, and R2 is H or C. 1-3 Alkyl group, R3 is H or C 1-3 alkyl.

[0014] In one or more embodiments, m is 0 or 1, n is 1, p is 0, 1, or 2, q is 1 or 2, and R2 is H or C. 1-3 Alkyl group, R3 is H or C 1-3 alkyl.

[0015] In one or more embodiments, ring A is a phenyl or a heteroaryl group comprising a five-membered or six-membered ring and 1-3 heteroaryl groups selected from O, N, and S atoms, wherein the heteroaryl group and the phenyl group are optionally each independently substituted by one or more R0 groups; preferably, ring A is a five-membered heteroaryl group comprising 1-2 N atoms, wherein the heteroaryl group is optionally substituted by one or more R0 groups.

[0016] In one or more embodiments, ring A includes, but is not limited to: .

[0017] In one or more embodiments, ring A is a five-membered heteroaryl group comprising 1-3 atoms selected from N and S atoms.

[0018] In one or more embodiments, ring A is optionally replaced by R0. (Thiazole).

[0019] In one or more embodiments, Q is NR5, and R5 is H, F, Br, Cl, or -OH. In one or more embodiments, R4 is independently selected from an unsubstituted or R7-substituted phenyl group, an unsubstituted or R0-substituted six-membered heteroaryl group containing 1-3 N atoms, or an unsubstituted or R0-substituted fused-ring heteroaryl group containing a six-membered ring and 1-3 N atoms, wherein R7 is C 1-3 Alkyl, C 1-3 Alkoxy, amino, F, Br, Cl, hydroxy, cyano, NCH3(CH2)2N(CH3)2, preferably R7 is F, Br, Cl, hydroxy, cyano, NCH3(CH2)2N(CH3)2.

[0020] In one or more embodiments, R4 is independently selected from: an unsubstituted or R7-substituted phenyl group, an unsubstituted six-membered heteroaryl group containing 1-3 N atoms, an unsubstituted or R8-substituted fused-ring heteroaryl group containing one five-membered ring and one six-membered ring and 1-3 N atoms, an unsubstituted or R8-substituted fused-ring heteroaryl group containing two six-membered rings and 1-3 N atoms, R7 being F, Br, Cl, hydroxyl, cyano, or NCH3(CH2)2N(CH3)2, and R8 being selected from C. 1-3 Alkyl, C 1-3 Alkyl groups and amino groups.

[0021] In one or more embodiments, R4 is independently selected from: unsubstituted or R7-substituted phenyl groups, C 1-3 Alkyl-substituted benzopyrrole, pyridine, pyrimidine, unsubstituted or R8-substituted benzopyrimidine, pyridopyrimidine.

[0022] In one or more implementations, q is 1.

[0023] In one or more implementations, R4 is independently selected from: , , , , , , , , , , .

[0024] In one or more implementations, p, m, and n are 0, q is 1 or 2, and R2 is H or C. 1-3 alkyl, Ring A is a phenyl group or a ring comprising a five- or six-membered ring and 1-3 heteroaryl groups selected from O, N, and S atoms, wherein the heteroaryl groups and the phenyl group are optionally each independently substituted by one or more R0 groups. Q is selected from O, S, NR5, CR5R6. R4 is independently selected from unsubstituted or R7-substituted phenyl groups, unsubstituted or R0-substituted six-membered heteroaryl groups containing 1-3 N atoms, and unsubstituted or R0-substituted fused-ring heteroaryl groups containing a six-membered ring and 1-3 N atoms. R7 is C10. 1-3 Alkyl, C 1-3 Alkoxy, amino, F, Br, Cl, hydroxy, cyano, NCH3(CH2)2N(CH3)2, preferably R7 is F, Br, Cl, hydroxy, cyano, NCH3(CH2)2N(CH3)2.

[0025] In one or more embodiments, p, m, and n are 0, q is 1 or 2, and R2 is H or C. 1-3 alkyl, Ring A is a five-membered heteroaryl group containing 1-2 N atoms, wherein the heteroaryl group is optionally substituted by one or more R0 atoms. Q is selected from O, S, NR5, CR5R6. R4 is independently selected from: unsubstituted or R7-substituted phenyl, unsubstituted six-membered heteroaryl containing 1-3 N atoms, unsubstituted or R8-substituted fused-ring heteroaryl containing one five-membered ring and one six-membered ring and 1-3 N atoms, unsubstituted or R8-substituted fused-ring heteroaryl containing two six-membered rings and 1-3 N atoms, R7 is F, Br, Cl, hydroxyl, cyano, NCH3(CH2)2N(CH3)2, and R8 is selected from C. 1-3 Alkyl, C 1-3 Alkyl groups and amino groups.

[0026] In one or more embodiments, p, m, and n are 0, q is 1, and R2 is H or C. 1-3 alkyl, Ring A is a five-membered heteroaryl group containing 1-2 nitrogen atoms. Q is selected from O, S, NR5, CR5R6. R4 is independently selected from: unsubstituted or R7-substituted phenyl groups, C 1-3 Alkyl-substituted benzopyrrole, pyridine, pyrimidine, unsubstituted or R8-substituted benzopyrimidine, pyridopyrimidine.

[0027] In one or more implementations, p, m, and n are 0, R2 is H, and q is 1 or 2. Ring A is (Thiazole), Q is NH, R4 is selected independently from: , , , , , , , , , , .

[0028] In one or more embodiments, m and n are 0, p is 1 or 2, q is 1 or 2, and R2 is H or C. 1-3 alkyl, R1 is independently halogen, -CF3, -OCF3, C 1-3 Alkyl, phenyl, pyridyl, C 1-3 Alkoxy, amino Ring A is a phenyl group or a ring comprising a five- or six-membered ring and 1-3 heteroaryl groups selected from O, N, and S atoms, wherein the heteroaryl groups and the phenyl group are optionally each independently substituted by one or more R0 groups. Q is selected from O, S, NR5, CR5R6. R4 is independently selected from unsubstituted or R7-substituted phenyl groups, unsubstituted or R0-substituted six-membered heteroaryl groups containing 1-3 N atoms, and unsubstituted or R0-substituted fused-ring heteroaryl groups containing a six-membered ring and 1-3 N atoms. R7 is C10. 1-3 Alkyl, C 1-3 Alkoxy, amino, F, Br, Cl, hydroxy, cyano, NCH3(CH2)2N(CH3)2, preferably R7 is F, Br, Cl, hydroxy, cyano, NCH3(CH2)2N(CH3)2.

[0029] In one or more embodiments, m and n are 0, p is 1 or 2, q is 1 or 2, and R2 is H or C. 1-3 alkyl, R1 is independently halogen, -CF3, -OCF3, C 1-3 Alkyl, phenyl, pyridyl, C 1-3 Alkoxy, amino Ring A is a five-membered heteroaryl group containing 1-2 N atoms, wherein the heteroaryl group is optionally substituted by one or more R0 atoms. Q is selected from O, S, NR5, CR5R6. R4 is independently selected from: unsubstituted or R7-substituted phenyl, unsubstituted six-membered heteroaryl containing 1-3 N atoms, unsubstituted or R8-substituted fused-ring heteroaryl containing one five-membered ring and one six-membered ring and 1-3 N atoms, unsubstituted or R8-substituted fused-ring heteroaryl containing two six-membered rings and 1-3 N atoms, R7 is F, Br, Cl, hydroxyl, cyano, NCH3(CH2)2N(CH3)2, and R8 is selected from C. 1-3 Alkyl, C 1-3 Alkyl groups and amino groups.

[0030] In one or more embodiments, m and n are 0, p is 1 or 2, q is 1 or 2, and R2 is H or C. 1-3 alkyl, R1 is independently halogen, -CF3, -OCF3, C 1-3 Alkyl, phenyl, pyridyl, C 1-3 Alkoxy, amino Ring A is a five-membered heteroaryl group containing 1-2 nitrogen atoms. Q is selected from O, S, NR5, CR5R6. R4 is independently selected from: unsubstituted or R7-substituted phenyl groups, C 1-3 Alkyl-substituted benzopyrrole, pyridine, pyrimidine, unsubstituted or R8-substituted benzopyrimidine, pyridopyrimidine.

[0031] In one or more implementations, m and n are 0, p is 1 or 2, q is 1 or 2, and R2 is H. R1 is independently halogen, -CF3, -OCF3, C 1-3 Alkyl, phenyl, pyridyl, C 1-3 Alkoxy, amino Ring A is (Thiazole) Q is NH. R4 is selected independently from: , , , , , , , , , , Preferably, q is 1 and R4 is: or .

[0032] In one or more embodiments, m and n are 0, p is 0, 1, or 2, q is 1, and R2 is H or C. 1-3 alkyl, Q is selected from O, S, NR5, CR5R6. Ring A is a five-membered heteroaryl group containing 1-2 N atoms, wherein the heteroaryl group is optionally substituted by one or more R0 atoms. R4 is independently selected from: unsubstituted or substituted with one or more R8s, a fused-ring heteroaryl group comprising one five-membered ring and one six-membered ring and 1-3 N atoms; or unsubstituted or substituted with one or more R8s, a fused-ring heteroaryl group comprising two six-membered rings and 1-3 N atoms, wherein R8 is selected from C. 1-3 Alkyl, C 1-3 Alkoxy or amino; preferably, R4 is: or , R1 is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, nitro, -CF3, -OCF3, C1-C3 alkoxy, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-7 cycloalkyl, C 6-10The aryl or heteroaryl group may consist of one or two 5-7 membered rings and 1-4 heteroatoms from N, O, and S, wherein the above groups are independently and optionally further surrounded by one or more atoms selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, nitro, -CF3, -OCF3, -O(CH2). 1-3 C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-7 cycloalkyl, C 6-10 Aryl, heteroaryl, or substituted by one or two 5-7 membered rings and 1-4 heteroatoms from N, O, and S.

[0033] In one or more embodiments, m and n are 0, p is 0, 1, or 2, q is 1, and R2 is H or C. 1-3 alkyl, Q is selected from O, S, NR5, CR5R6. Ring A is a five-membered heteroaryl group containing 1-2 N atoms, wherein the heteroaryl group is optionally substituted by one or more R0 atoms. R4 is independently selected from: unsubstituted or substituted with one or more R8s, a fused-ring heteroaryl group comprising one five-membered ring and one six-membered ring and 1-3 N atoms; or unsubstituted or substituted with one or more R8s, a fused-ring heteroaryl group comprising two six-membered rings and 1-3 N atoms, wherein R8 is selected from C. 1-3 Alkyl, C 1-3 Alkoxy or amino; preferably, R4 is: or , R1 is independently a C that is H, halogen, unsubstituted, or substituted with 1-3 halogens. 1-3 Alkyl, unsubstituted or 1-3 halogenated C 1-3 Alkoxy, unsubstituted or R0-substituted phenyl, unsubstituted or R0-substituted pyridyl, unsubstituted or R0-substituted amino.

[0034] In one or more embodiments, m and n are 0, p is 0, 1, or 2, q is 1, and R2 is H or C. 1-3 alkyl, Ring A is (Thiazole) Q is NH. R4 is independently selected from: unsubstituted or substituted with one or more R8s, a fused-ring heteroaryl group comprising one five-membered ring and one six-membered ring and 1-3 N atoms; or unsubstituted or substituted with one or more R8s, a fused-ring heteroaryl group comprising two six-membered rings and 1-3 N atoms, wherein R8 is selected from C. 1-3 Alkyl, C 1-3 Alkoxy or amino; preferably, R4 is: or , R1 is independent of H, halogen, -CF3, -OCF3, C 1-3 Alkyl, phenyl, pyridyl, C 1-3 Alkyl groups and amino groups.

[0035] In one or more embodiments, the compound of formula (I) has the structure shown in formula (IA):

[0036] (IA)

[0037] The definitions of R1, p, R2, A, Q, R4, and q are as described in any of the embodiments herein.

[0038] In one or more embodiments, the compound of formula (I) has the structure shown in formula (IB):

[0039] (IB)

[0040] Wherein, R1, p, R2, A and Q are defined as described in any of the embodiments herein; Ring B is an optional substitution of C 6-14 Aryl or optionally substituted 5-14 heteroaryl groups.

[0041] In one or more embodiments of formula (IB), ring B is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of: hydroxyl, deuterium, nitro, halogenated C. 1-10 Alkyl, Halogenated C 1-10 Alkoxy, C 1-10 Alkyl, C 1-10 Alkyl, cyano, halogen, and optionally one, two, or three selected from halogen, deuterium, and -NR c R d Substituents of -NR a R b Preferably, ring B is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of: C 1-10 Alkyl, C 1-10 Alkyl, cyano, halogen, and optionally one, two, or three selected from halogen, deuterium, and -NR c R d Substituents of -NR a R b Preferably, C 6-14 The aryl group is optionally substituted by 1, 2, or 3 substituents selected from the group consisting of cyano, halogen, and optionally substituted by 1, 2, or 3 substituents selected from halogen, deuterium, and -NR. c R d Substituents of -NR a Rb Preferably, the 5-14 membered heteroaryl group is optionally substituted by 1, 2, or 3 substituents selected from the group consisting of: hydroxyl, amino, halogenated C. 1-10 Alkyl, Halogenated C 1-10 Alkoxy, C 1-10 Alkyl, C 1-10 Alkyl group.

[0042] In one or more embodiments of formula (IB), ring B is optionally replaced by C. 6-14 Aryl, optionally substituted 5-7 membered monocyclic heteroaryl, or optionally substituted 8-11 membered bicyclic heteroaryl. Preferably, C 6-14 The aryl group is optionally substituted by 1, 2, or 3 substituents selected from the group consisting of cyano, halogen, and optionally substituted by 1, 2, or 3 substituents selected from halogen, deuterium, and -NR. c R d Substituents of -NR a R b Preferably, the 8-11 membered bicyclic heteroaryl group is optionally substituted by 1, 2, or 3 substituents selected from the group consisting of hydroxyl, amino, or halogenated C. 1-10 Alkyl, Halogenated C 1-10 Alkoxy, C 1-10 Alkyl, C 1-10 Alkyl group.

[0043] In one or more embodiments of formula (IB), ring B is surrounded by one or more R 41 Replace, R 41 The definition is as described in any of the embodiments herein.

[0044] In one or more embodiments, the compound of formula (I) has the structure shown in formula (IC):

[0045] (IC)

[0046] The definitions of R1, p, R2, Q, and B are as described in any of the embodiments herein.

[0047] In one or more embodiments of formula (IC), p is 0.

[0048] In one or more embodiments of formula (IC), R2 is hydrogen, deuterium, C 1-3 Alkyl group; preferably hydrogen.

[0049] In one or more embodiments of formula (IC), Q is NR5, and R5 is defined as described in any embodiment herein; Q is preferably NH.

[0050] In one or more embodiments of formula (IC), ring B is an optionally substituted 5-14 membered heteroaryl, preferably an optionally substituted 8-11 membered bicyclic heteroaryl.

[0051] In one or more embodiments of formula (IC), ring B is optionally surrounded by 1, 2, or 3 groups selected from hydroxyl, amino, or halogenated C. 1-10 Alkyl, Halogenated C 1-10 Alkoxy, C 1-10 Alkyl and C 1-10 The alkoxy group is substituted, preferably with one, two, or three alkyl groups selected from amino, C, and D groups. 1-6 Alkyl and C 1-6 Substitution of alkoxy groups.

[0052] In one or more embodiments of formula (IC), ring B is optionally substituted benzopyrrole or optionally substituted benzopyrimidine. Preferably, ring B is optionally substituted with C. 1-6 Alkyl-substituted benzopyrroles, or optionally substituted with 1, 2, or 3 alkyl groups selected from amino, C 1-6 Alkyl and C 1-6 Benzopyrimidine with alkyl substituents.

[0053] In one or more embodiments of formula (IC), ring B is or The wavy line indicates the position where ring B and Q are connected.

[0054] In one or more embodiments, the compound of formula (I) is selected from: .

[0055] In one or more embodiments, the compound of formula (I) is of formula I-1 or formula I-6: , .

[0056] The present invention also provides a pharmaceutical composition comprising a compound of formula (I) as described in any embodiment herein, or a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a tautomer, a solvate, an isotope substitute, a polymorph, a prodrug, or a metabolite thereof, and a pharmaceutically acceptable carrier or excipient.

[0057] This invention relates to the use of compounds of formula (I) or pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotope substitutes, polymorphs, prodrugs or metabolites thereof, as described in any embodiment herein, in the preparation of medicaments for the prevention and / or treatment of diseases or conditions, said diseases or conditions being tumors, cancers or proliferative metastatic diseases.

[0058] In one or more embodiments, the disease or condition includes tumors, cancers, or proliferative metastatic diseases caused by malignant proliferation and induced cell death disorders.

[0059] In one or more embodiments, the disease or condition includes tumors, cancers, or proliferative metastatic diseases associated with EGFR protein mutations.

[0060] In one or more embodiments, the disease or condition includes EGFR protein mutation-related lung cancer, non-small cell lung cancer, rectal cancer, non-melanoma skin cancer, breast cancer, ovarian cancer, prostate cancer, gastric cancer, kidney cancer, liver cancer, cervical cancer, thyroid cancer, leukemia, esophageal cancer, pancreatic cancer, bladder cancer, lymphoma, adenoid cystic carcinoma, bile duct cancer, anal canal cancer, malignant mesothelioma, testicular cancer, malignant embryonal tumor, chordoma, gastrointestinal pancreatic neuroendocrine tumor, adrenocortical carcinoma, and glioblastoma.

[0061] In one or more embodiments, the EGFR protein mutation includes the C797S point mutation.

[0062] The present invention also relates to a method for preventing and / or treating a disease or condition, comprising administering to a patient a therapeutically effective dose of a compound of formula (I) as described in any embodiment herein, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substitute, polymorph, prodrug, or metabolite thereof, wherein the disease or condition is a tumor, cancer, or a proliferative metastatic disease.

[0063] In one or more embodiments, the disease or condition includes tumors, cancers, or proliferative metastatic diseases caused by malignant proliferation and induced cell death disorders.

[0064] In one or more embodiments, the disease or condition includes tumors, cancers, or proliferative metastatic diseases associated with EGFR protein mutations.

[0065] In one or more embodiments, the disease or condition includes EGFR protein mutation-related lung cancer, non-small cell lung cancer, rectal cancer, non-melanoma skin cancer, breast cancer, ovarian cancer, prostate cancer, gastric cancer, kidney cancer, liver cancer, cervical cancer, thyroid cancer, leukemia, esophageal cancer, pancreatic cancer, bladder cancer, lymphoma, adenoid cystic carcinoma, bile duct cancer, anal canal cancer, malignant mesothelioma, testicular cancer, malignant embryonal tumor, chordoma, gastrointestinal pancreatic neuroendocrine tumor, adrenocortical carcinoma, and glioblastoma.

[0066] In one or more embodiments, the EGFR protein mutation includes the C797S point mutation. Attached Figure Description

[0067] Figure 1 The target plasmids for stable expression of NIH3T3 were Compound A, B, and C, 1 μM (4h), and the cell lysate was collected for Western blot verification.

[0068] Figure 2 yes Figure 2 The structure-activity relationship prediction of the compound prepared in Example 1 (using protein number PDB:7JXM).

[0069] Figure 3 The image shows the 1H NMR spectrum of the compound prepared in Example 1. Detailed Implementation

[0070] Through in-depth research, the inventors of this application have, for the first time, developed an EGFR allosteric agent having the structure of formula (I). This series of compounds is intended for use as a drug in the prevention and / or treatment of tumors, cancers, or metastatic diseases associated with EGFR protein C797S point mutations or other mutations, as well as drugs for tumors, cancers, or metastatic diseases caused by malignant proliferation and induced cell death disorders. Based on this, the present invention was completed.

[0071] The compound of formula (I) of this invention is a fourth-generation allosteric inhibitor, which is effective against drug resistance mutations such as the C797S mutation that occur after third-generation EGFR-TKI treatment. Compared with the first three generations of inhibitors that compete with ATP for binding sites to inhibit tumor cells, the fourth-generation allosteric inhibitor exerts its efficacy based on a different mechanism of action, which helps to overcome acquired drug resistance generated during treatment and makes it more selective, reduces off-target toxicity, and has good drug activity. At the same time, this type of compound has good blood-brain barrier penetration and can effectively treat brain metastases.

[0072] Detailed Explanation: The following examples are merely illustrative of the implementation process, including but not limited to the conditions therein. The compounds of the present invention can be prepared using suitable substances as raw materials according to the general scheme described below, and are specifically illustrated by the following examples. Of course, various known reasonable variations of the conditions and methods of the preparation steps of the illustrative compounds in the examples can also be used to prepare these compounds.

[0073] I. Terminology

[0074] Unless otherwise defined, all technical terms herein have the same meanings as commonly understood by one of ordinary skill in the art. Unless otherwise stated, all references or portions thereof cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are incorporated herein by reference in their entirety. Section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter.

[0075] It should be understood that the above brief description and the following detailed description are exemplary and for illustrative purposes only, and do not limit the subject matter of the invention in any way. In this application, unless specifically stated otherwise, the singular is used to include the plural. It must be noted that unless clearly stated otherwise, the singular form used in this specification and claims includes the plural form of the referred to. It should also be noted that unless otherwise stated, “or” or “or” means “and / or”. Furthermore, the term “comprising” and other forms such as “including,” “containing,” and “containing” are not limiting and can be open-ended, semi-closed, or closed. In other words, the term also includes the meaning of “substantially constituted by” or “composed of.”

[0076] Definitions of standard chemical terms can be found in the references (including Carey and Sundberg, "Advanced Organic Chemistry 4th Edition." Vols. A(2000) and B(2001), Plenum Press, New York). Unless otherwise stated, conventional methods within the scope of the art, such as mass spectrometry, NMR, IR, and UV / VIS spectroscopy, and pharmacological methods, are used. Unless specifically defined, the terminology used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry is known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and in the treatment of patients. For example, reactions and purifications can be carried out using the manufacturer's instructions for use of kits, or in accordance with methods known in the art or the description of this invention. The techniques and methods described above can generally be carried out according to conventional methods well known in the art, based on the descriptions in the various summary and more specific references cited and discussed in this specification. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0077] When a substituent is described using a conventional chemical formula written from left to right, it also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0078] Certain chemical groups defined herein are preceded by simplified symbols to indicate the total number of carbon atoms present in the group. For example, C1-C6 alkyl refers to alkyl groups having a total of 1 to 6 carbon atoms as defined below. The total number of carbon atoms in the simplified symbols does not include carbons that may be present in substituents of the group.

[0079] Except as otherwise specified, when used in the specification and claims of this application, the following terms shall have the following meanings.

[0080] In this application, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0081] "Hydroxy group" refers to the -OH group.

[0082] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxyl group (-OH) as defined below.

[0083] "Carbonyl" refers to the -C(=O)- group.

[0084] "Nitro" refers to -NO2.

[0085] "Cyano" refers to -CN.

[0086] "Amino" refers to -NH2.

[0087] "Substituted amino" refers to an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, aryl, heteroaryl, heterocyclic, or heteroaryl groups as defined below, such as monoalkylamino, dialkylamino, alkylamide, aralkylamino, heteroarylalkylamino, heteroarylamino, and arylamino. In some embodiments herein, "substituted amino" is represented as -NR'R'', where R' and R'' are each independently selected from H, an amino group, and a substituted or unsubstituted alkyl group.

[0088] The "carboxyl group" refers to -COOH.

[0089] In this application, as a group or part of other groups (e.g., in alkyl groups substituted with halogens such as fluorine, chlorine, bromine, or iodine), the term "alkyl" refers to a fully saturated straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6, or 1 to 3) carbon atoms, and connected to the rest of the molecule by single bonds, such as including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, etc. The alkyl group comprises, but isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2-ethylpentyl, 3-ethylpentyl, octyl, nonyl, and decyl, or various isomers thereof. In various embodiments of the present invention, each alkyl group is preferably a C1-C4 alkyl group. In some embodiments, the carbon chain length of the alkyl group may be 8-22 carbon atoms, preferably an aliphatic chain. 1-10 Refers to straight-chain or branched alkyl groups containing 1 to 10 carbon atoms; C 1-8 Refers to straight-chain or branched alkyl groups containing 1 to 8 carbon atoms; C 1-3 This refers to methyl, ethyl, n-propyl, and isopropyl. The alkyl group can be substituted or unsubstituted.

[0090] In this application, as part of a group or other group, the term "alkenyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one double bond, having, for example, 2 to 20 (preferably 2 to 10, 2 to 8, more preferably 2 to 6) carbon atoms connected to the rest of the molecule by single bonds, such as, but not limited to, vinyl, 1- or 2-propenyl, allyl, but-1-enyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl, etc. The alkenyl group may be substituted or unsubstituted.

[0091] In this application, as part of a group or other group, the term "alkynyl" refers to a hydrocarbon group containing at least one carbon-carbon triple bond, selectively including alkynyl groups containing 2 to 10 carbon atoms or 2 to 8 carbon atoms, whether branched or straight-chain. Common alkynyl categories include, but are not limited to, ethynyl, 1- or 2-propynyl, etc. The alkynyl group may be substituted or unsubstituted.

[0092] In this application, as part of a group or other group, the term "alkoxy" refers to -O-alkyl, wherein the alkyl group is defined as described above, and is selected from alkyloxy groups containing 1 to 3 carbon atoms or 1 to 4 carbon atoms. This includes, but is not limited to, common methoxy, ethoxy, propoxy, butoxy, etc. The alkyloxy group may be substituted or unsubstituted.

[0093] In this application, as part of a group or other group, the term "cycloalkyl group" or "carbocyclic group" means a stable non-aromatic monocyclic or polycyclic alkyl group (e.g., alkyl, alkenyl, or alkynyl) consisting only of carbon and hydrogen atoms. It may include fused ring (ring) systems, bridged ring systems, or spirocyclic systems, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, such as 3, 4, 5, 6, 7, or 8 carbon atoms, and may be saturated or unsaturated and may be connected to the rest of the molecule via a single bond through any suitable carbon atom. Unsaturated monocyclic or polycyclic substituents contain one or more double bonds (all rings do not possess a fully conjugated π-electron system). The cycloalkyl group or carbocyclic group may be substituted or unsubstituted. Unless otherwise specifically indicated in this specification, the carbon atoms in the cycloalkyl group may optionally be oxidized. In preferred embodiments, the cycloalkyl group is a cycloalkyl group, preferably C3-C8 cycloalkyl, as well as a bridged ring group and a spirocyclic group. The number of ring atoms in both bridged and spirocyclic groups can be 5-10. Examples of cyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indenyl, 2,3-dihydroindenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl, fluorene. Bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl, adamantyl, octahydro-4,7-methylene-1H-indenyl and octahydro-2,5-methylene-cyclopentadienyl, spiro[3.3]heptyl, etc.

[0094] In this application, as part of a group or other group, the term "heterocyclic group" means a stable 3- to 20-membered non-aromatic cyclic group consisting of 2 to 14 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen, and sulfur. Heterocyclic refers to a saturated or partially unsaturated monocyclic or polycyclic substituent, wherein the unsaturated monocyclic or polycyclic substituent contains one or more double bonds, and all rings do not possess a complete conjugated π-electron system. Unless otherwise specifically indicated in this specification, a heterocyclic group can be a monocyclic, bicyclic, tricyclic, or more cyclic system, which may include fused ring systems (also called fused ring systems), bridged ring systems, or spirocyclic systems; the nitrogen, carbon, or sulfur atoms in the heterocyclic group may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclic group may be partially or fully saturated. Heterocyclic groups can be connected to the remainder of the molecule via carbon atoms or heteroatoms and through single bonds. In heterocyclic groups containing fused rings, one or more rings can be aryl or heteroaryl as defined below, provided that the connection point with the remainder of the molecule is a non-aromatic ring atom. For the purposes of this invention, the heterocyclic group is preferably a stable 4- to 12-membered, 5- to 12-membered, or 4- to 9-membered non-aromatic monocyclic or fused heterocyclic (e.g., bicyclic), 6-12-membered bridged heterocyclic, or 6-12-membered spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, more preferably a stable 5- to 9-membered non-aromatic monocyclic, bicyclic, bridged heterocyclic, or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the fused heterocyclic group of this invention has 6-12 ring atoms.

[0095] Examples of heterocyclic groups described in the various embodiments herein include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]nonane-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2-oxa-6-aza-spiro[3.4]octane-7-yl, 8-oxa-2-aza-spiro[4.5]decane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptane-2-yl, azacyclic butyl, oxygen Heterocyclic butyl, thiocyclic butyl, thiocyclic pentyl, pyranyl, tetrahydropyranyl, thiaranyl, tetrahydrofuranyl, oxazinyl, dioxocyclopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, quinazinyl, thiazoalkyl, isothiazyl, isoxazylalkyl, dihydroindolyl, octahydroindolyl, octahydroisoindolyl, pyrazolyl, phthalimide, dioxothiomorpholine, dioxothiocyclic pentyl, dioxothiocyclic butyl, thiocyclic hexyl, dioxothiocyclic hexyl, etc.

[0096] In this application, as part of a group or other group, the term "aryl" or "aromatic ring" refers to a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms (preferably 6 to 14 carbon atoms, more preferably 6 to 10 carbon atoms, such as 6, 7, 8, 9, or 10 carbon atoms), for example, an all-carbon aryl group comprising 6-10 carbon atoms or 5-10 carbon atoms. For the purposes of this invention, the aryl group can be a monocyclic, bicyclic, tricyclic, or more cyclic system, and can be fused with a cycloalkyl or heterocyclic group as defined above or a heteroaryl group as defined below, provided that the aryl group is connected to the rest of the molecule via a single bond through an atom on the aromatic ring. The aryl group is a polycyclic group with a fully conjugated π-electron system. The aryl group may be substituted or unsubstituted. Examples of aryl groups described in the embodiments herein include, but are not limited to, phenyl, naphthyl, anthracene, phenanthrene, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1,4-benzoxazine-3(4H)-one-7-yl, etc.

[0097] In this application, the term "arylalkyl" refers to an alkyl group as defined above that has been replaced by an aryl group as defined above.

[0098] In this application, as part of a group or other group, the term "heteroaryl" or "aromatic heterocycle" means a 5- to 16-membered conjugated cyclic group having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur, such as a heteroaromatic system comprising 6-10 carbon atoms or 5-10 carbon atoms. Unless otherwise specifically indicated in this specification, a heteroaryl group may be a monocyclic, bicyclic, tricyclic, or more cyclic system, and may be fused with a cycloalkyl or heterocyclic group as defined above, provided that the heteroaryl group is connected to the remainder of the molecule via a single bond through an atom on the aromatic ring. The nitrogen, carbon, or sulfur atom in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. For the purposes of this invention, the heteroaryl group is preferably a stable 5- to 12-membered aromatic group comprising 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur; more preferably, a stable 5- to 10-membered aromatic group comprising 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur; or a 5- to 6-membered aromatic group comprising 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. The heteroaryl group may be substituted or unsubstituted. Examples of heteroaryl groups described in the various embodiments herein include, but are not limited to, thiopheneyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyrazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolithyl, triazolyl, tetrazolyl, triazinyl, inazinyl, isoindolyl, inzolyl, isoinzolyl, purinyl, quinolinyl, isoquinolinyl, diazonyl, naphthidyl, quinoxolinyl, pteridyl, carbazolyl, carolinyl, phenanthridine, phenanthroxolinyl, acridineyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothiopheneyl. Oxatriazolyl, oxazolinyl, cyclolinyl, quinazolinyl, phenylthioyl, indene, o-diazaphenyl, isoxazolyl, phenoxazinyl, phenthiazinyl, 4,5,6,7-tetrahydrobenzo[b]thiophenyl, naphthopyridyl, [1,2,4]triazolo[4,3-b]pyrazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1,2,4]triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,2-b]pyrazine, imidazo[1,2-a]pyrazine, etc.

[0099] In this application, the term "heteroarylalkyl" refers to an alkyl group as defined above that has been replaced by a heteroaryl group as defined above.

[0100] In this application, "optional" or "optionally" means that the event or condition described below may or may not occur, and the description includes both the occurrence and non-occurrence of the event or condition. For example, "optionally substituted aryl" means that the aryl group is substituted or not substituted, and the description includes both substituted and unsubstituted aryl groups. When substituted, the substituent may be selected from one or more of the alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, cyano, hydroxyl, amino, monoalkylamino, dialkylamino, nitro, aryl, heteroaryl, cycloalkyl, and heterocyclic groups described herein; these substituents include alkyl, alkenyl, alkynyl, alkyl of haloalkyl, alkenyl of haloalkenyl, alkynyl of haloalkynyl, alkoxy, alkyl of monoalkylamino, alkyl of dialkylamino, aryl, heteroaryl, cycloalkyl, and heterocyclic groups, and may optionally be substituted by one or more groups selected from alkyl, halogen, haloalkyl, alkoxy, hydroxyl, amino, monoalkylamino, dialkylamino, nitro, aryl, heteroaryl, cycloalkyl, and heterocyclic groups. In this document, the number of substituents may be one or more, i.e., 1, 2, 3, 4, 5, or 6 or more, depending on the substituted group and the nature of the substituent. For example, when the substituent is halogen, depending on the structure of the substituted group, the group can be replaced by 1 to 6 substituents, such as trifluoromethyl, pentafluoroethyl, etc.; when the substituent is aryl, heteroaryl, heterocyclic, cycloalkyl, cyano, sulfone, etc., the number of substituents is usually 1.

[0101] The terms “part,” “structural part,” “chemical part,” “group,” and “chemical group” used in this article refer to specific segments or functional groups within a molecule. A chemical part is generally considered to be a chemical entity embedded in or attached to a molecule.

[0102] Those skilled in the art will also understand that, in the methods described below, the functional groups of the intermediate compounds may require protection by appropriate protecting groups. Such functional groups include hydroxyl, amino, mercapto, and carboxylic acids. Suitable hydroxyl protecting groups include trialkylsilyl or diarylalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, etc. Suitable amino, amidine, and guanidine protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, etc. Suitable mercapto protecting groups include -C(O)-R (where R is alkyl, aryl, or aralkyl), p-methoxybenzyl, triphenylmethyl, etc. Suitable carboxyl protecting groups include alkyl, aryl, or aralkyl esters.

[0103] Protective elements can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protective elements is detailed in Greene, TW and PGM Wuts, Protective Groups in OrganiSynthesis, (1999), 4th Ed., Wiley.

[0104] II. compound

[0105] This article also includes pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotope-substituted products, polymorphs, prodrugs, or metabolites of the aforementioned compounds.

[0106] In this article, "stereoisomer" refers to a compound composed of identical atoms bonded by the same bonds, but with different three-dimensional structures. This invention will cover various stereoisomers and mixtures thereof.

[0107] When the compounds of the present invention contain alkene double bonds, unless otherwise stated, the compounds of the present invention are intended to contain E- and Z-geometric isomers.

[0108] "Tautomer" refers to an isomer formed when a proton is transferred from one atom of a molecule to another atom of the same molecule. All tautomer forms of the compounds of this invention are also included within the scope of this invention.

[0109] The compounds of the present invention, or pharmaceutically acceptable salts thereof, may contain one or more chiral carbon atoms, and thus may produce enantiomers, diastereomers, and other stereoisomers. Each chiral carbon atom may be defined as (R)- or (S)- based on stereochemistry. The present invention aims to include all possible isomers, as well as their racemic and optically pure forms. The preparation of the compounds of the present invention may select racemic, diastereomer, or enantiomer as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

[0110] Conventional techniques for preparing / separating individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography, see GeR. a ldGübitz and Martin G. Schmid(Eds.), ChiR a l SepaR ations, Methods and Protocols,Methods in Molecular Biology, Vol. 243, 2004; AM Stalcup, ChiR a l SepaR a tions, Annu. Rev. Anal. Chem. 3: 341-63, 2010; Fumiss et al. (eds.), VOGEL'SENCYCLOPEDIA OF PR a CTICAL ORGANIC CHEMISTRY.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc. Chem. Res. 1990, 23,128.

[0111] This invention also includes all suitable isotopic variants of the compounds of the invention or pharmaceutically acceptable salts thereof. An isotopic variant of the compounds of the invention or pharmaceutically acceptable salts thereof is defined as one in which at least one atom is replaced by an atom having the same number of atoms but a different atomic mass than those commonly found in nature. Isotopes that can be incorporated into the compounds of the invention and pharmaceutically acceptable salts thereof include, but are not limited to, isotopes of H, C, N, and O, for example... 2 H, 3 H, 11 C 13 C 14 C 15 N、 17 O、 18 O、 35 S, 18 F, 36 Cl and 125 I. Isotopic variants of the compounds described in this invention or of their pharmaceutically acceptable salts can be prepared using conventional techniques and appropriate isotopic variants with suitable reagents.

[0112] In this application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts, which can be prepared by methods known in the art. Pharmaceutically acceptable salts include, but are not limited to, organic acid salts such as acetates, citrates, fumarates, maleates, oxalates, malates, citrates, succinates, tartrates, lactates, camphor sulfonates, benzene sulfonates, p-toluene sulfonates, methanesulfonates, trifluoroacetates, trifluoromethanesulfonates, etc.; and inorganic acid salts such as hydrohalic acid salts (hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid), sulfates, phosphates, nitrates, etc. Furthermore, drug molecules can also form specific salts with amino acids (such as glutamic acid or aspartic acid), such as glutamate or aspartate.

[0113] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the bioavailability of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobroms, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formates, acetates, 2,2-dichloroacetate, trifluoroacetate, propionates, hexanoates, octanoates, decanoates, undecenoates, glycolates, gluconates, lactates, sebates, adipates, glutarate, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamates, pyroglutamates, aspartate, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginates, ascorbic acid salts, salicylates, 4-aminosalicylic acid salts, and naphthalene disulfonates. These salts can be prepared using methods known in this field.

[0114] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary amines, secondary amines, and tertiary amines; substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.

[0115] Examples of prodrugs of the compounds of the present invention may include simple esters of compounds containing carboxylic acids (e.g., esters obtained by condensation with C1-C4 alcohols according to methods known in the art); esters of compounds containing hydroxyl groups (e.g., esters obtained by condensation with C1-C4 carboxylic acids, C3-C6 diacids, or their anhydrides, such as succinic anhydride and fumaric anhydride, according to methods known in the art); imines of compounds containing amino groups (e.g., imines obtained by condensation with C1-C4 aldehydes or ketones according to methods known in the art); carbamates of compounds containing amino groups, such as those esters described by Leu et al. (J. Med. Chem., 42: 3623-3628 (1999)) and Greenwald et al. (J. Med. Chem., 42: 3657-3667 (1999)); and aldol acetals or ketal acetals of compounds containing alcohols (e.g., those acetals obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether according to methods known in the art).

[0116] Compound preparation

[0117] In this paper, the compound of formula I can be obtained by first preparing intermediate E or K and then by conventional substitution experiments: Intermediate E can be obtained by the following general synthetic route:

[0118] Intermediate K can be obtained by the following general synthetic route:

[0119] The preparation flow chart of an exemplary compound of the present invention is shown below:

[0120] Other compounds of the present invention can be prepared by referring to the above reaction flowchart.

[0121] The structures of all compounds involved in this invention were characterized using NMR and / or LC-MS. The NMR instrument used was from Oxford University, and the compounds were dissolved in deuterated methanol, deuterated chloroform, or deuterated dimethyl sulfoxide. The LC-MS instrument used was from Waters, and the compounds were dissolved in methanol or other solvents. The HPLC instrument used was from Waters, and the compounds were dissolved in HPLC-grade methanol or acetonitrile.

[0122] The brand of silica gel plates used in TLC thin-layer chromatography is Nortech, and the TLC specification is 2. 5 cm. The silica gel used in the column chromatography for product separation and purification is from the brand Nortech, and the silica gel size is 300-500 mesh.

[0123] Pharmaceutical compositions, methods and applications

[0124] The compounds of Formula I of this invention, their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotope-substituted derivatives, polymorphs, prodrugs, and metabolites exhibit specific selectivity for the inhibition of EGFR containing one or more mutations, with better inhibitory effects compared to wild-type EGFR. In some specific embodiments, the compounds disclosed herein exhibit at least 2, 5, 10, 25, 20, 50, 100, 1000, and greater inhibitory effects compared to wild-type EGFR on EGFR containing one or more mutations as described herein. In this study, EGFR mutations included T790M, L718Q, L844V, V948R, L858R, I941R, C797S, Del (deletion in exon 19), Insertion (insertion in exon 20), Del / L718Q, Del / L844V, Del / T790M, Del / T790M / L718Q, and Del / T790M / L844V, L858R / L718Q, L858R / L844V, L858R / T790M, L858R / T790M / I941R, Del / T790M, Del / T790M / C797S , L858R / T790M / C797S, L858R / T790M / L718Q, G719X, E709A, S768I, L861X, V843I, R776H, P848L, V834L.

[0125] Therefore, the Formula I compounds of the present invention, their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotope substitutes, polymorphs, prodrugs and metabolites may be used to treat or prevent tumors, cancers or proliferative metastatic diseases, especially tumors, cancers or proliferative metastatic diseases associated with EGFR protein mutations.

[0126] In this article, "EGFR protein mutation-related diseases" refers to diseases in which EGFR protein mutations are involved in the occurrence and / or development of the disease, and diseases for which euthanasia, treatment, and / or prevention can be achieved by inhibiting EGFR expression and / or activity. In this invention, EGFR protein mutation-related diseases include tumors, cancers, or proliferative metastatic diseases, including solid tumors or hematologic malignancies. The tumors or cancers mentioned are not limited to mesotheliomas (including pleural mesothelioma, malignant pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma, and tunica vaginalis mesothelioma), cervical squamous cell carcinoma, endometrial cancer, esophageal squamous cell carcinoma, esophageal adenocarcinoma, bladder urothelial carcinoma, skin squamous cell carcinoma, poroma (benign poroma), porocarcinoma (including malignant porocarcinoma), supratentorial ependymoma (including pediatric supratentorial ependymoma), epithelioid hemangioendothelioma (EHE), ependymoma, breast cancer (including triple-negative breast cancer), and lung cancer (including...). This includes non-small cell lung cancer, ovarian cancer, colorectal cancer, melanoma, pancreatic cancer, prostate cancer, gastric cancer, esophageal cancer, liver cancer (including hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma), neuroblastoma, schwannoma, renal cancer, sarcomas (including rhabdomyosarcoma, embryonal rhabdomyosarcoma (ERMS), osteosarcoma, undifferentiated pleomorphic sarcoma (UPS), Kaposi's sarcoma, soft tissue sarcoma, and rare soft tissue sarcoma), bone cancer, brain cancer, medulloblastoma, glioma, meningioma, and head and neck cancer (including head and neck squamous cell carcinoma). In some embodiments, the cancers include lung cancer (such as non-small cell lung cancer), breast cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, prostate cancer, mesothelioma, pancreatic cancer, melanoma, colon cancer, thyroid cancer, and skin cancer, etc. Preferably, the diseases associated with EGFR protein mutations are lung cancer, non-small cell lung cancer, rectal cancer, non-melanoma skin cancer, breast cancer, ovarian cancer, prostate cancer, gastric cancer, kidney cancer, liver cancer, cervical cancer, thyroid cancer, leukemia, esophageal cancer, pancreatic cancer, bladder cancer, lymphoma, adenoid cystic carcinoma, bile duct cancer, anal canal cancer, malignant mesothelioma, testicular cancer, malignant embryonal tumor, chordoma, gastrointestinal pancreatic neuroendocrine tumors, adrenocortical carcinoma, and glioblastoma associated with EGFR protein C797S mutations.

[0127] Therefore, the present invention provides a method for treating or preventing diseases associated with EGFR protein mutations as described herein, the method comprising administering to a desired subject a therapeutically effective amount of a compound of Formula I of the present invention, a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a tautomer, a solvate, an isotope substitute, a polymorph, a prodrug or a metabolite thereof, or a pharmaceutical composition thereof.

[0128] The “object” or “individual” referred to in this article refers to mammals, especially primates, and more specifically, humans.

[0129] As used herein, the terms “prevention” and “avoidance” include reducing the likelihood of a patient developing or worsening a disease or condition; the term also includes preventing the occurrence of a disease or condition in mammals, particularly when such mammals are susceptible to the disease or condition but have not yet been diagnosed with it. “Treatment” and other similar synonyms include the following meanings: (i) suppressing a disease or condition, i.e., curbing its development; (ii) alleviating a disease or condition, i.e., bringing the state of the disease or condition to an end; or (iii) reducing the symptoms caused by the disease or condition.

[0130] As used herein, the terms “effective amount,” “therapeutic effective amount,” “dosage,” and “pharmaceutical effective amount” refer to the amount of at least one drug or compound that, when taken, is sufficient to alleviate, to some extent, one or more symptoms of the disease or condition being treated. The result may be a reduction and / or relief of signs, symptoms, or causes, or any other desired change in a biological system. For example, an “effective amount” for treatment is the amount of a composition comprising a compound of formula I disclosed herein, a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a tautomer, a solvate, an isotope substitute, a polymorph, a prodrug, or a metabolite required to provide significant symptom relief clinically. Dosage may be determined based on factors such as the subject’s age, sex, the nature and severity of the disease. Effective amounts suitable for any individual case may be determined using techniques such as dose escalation testing.

[0131] As used herein, the terms “administration,” “application,” “dosage,” etc., refer to methods that deliver a compound or composition to the desired site for biological action. Methods of administration known in the art are applicable to this invention. These methods include, but are not limited to, oral administration, duodenal administration, parenteral administration (including intrapulmonary, intranasal, intrathecal, intravenous, subcutaneous, intraperitoneal, intramuscular, and intra-arterial injection or infusion), local administration, and rectal administration. Those skilled in the art are familiar with administration techniques applicable to the compounds and methods described herein, such as those discussed in Goodman and Gilman, *The Pharmacological Basis of Therapeutics*, current ed.; Pergamon; and Remington's, *Pharmaceutical Sciences* (current edition), Mack Publishing Co., Easton, Pa. In a preferred embodiment, the compound of formula I of this invention, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug, or metabolite, or pharmaceutical composition thereof, are administered orally.

[0132] The compound of formula I of the present invention, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug, or metabolite, or pharmaceutical composition thereof, can be used in combination with other pharmacologically active compounds, particularly for the treatment of cancer. For example, the compound of formula I of the present invention, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug, or metabolite, or pharmaceutical composition thereof, can be administered simultaneously, sequentially, or separately with one or more drugs selected from the following: chemotherapeutic agents, such as mitotic inhibitors, such as taxane, vinblastine, paclitaxel, docetaxel, vinblastine, vinblastine, vinorelbine, or vinflunine; other anticancer agents such as cisplatin, 5-fluorouracil or 5-fluoro-2-4(1H,3H)-pyrimidinidone (5FU), flutamide, or gemcitabine, etc. In some embodiments, the compound of formula I of the present invention, its pharmaceutically acceptable salts and isomers, or pharmaceutical compositions containing the compound of formula I of the present invention, its pharmaceutically acceptable salts and isomers, may also be used in combination with tumor immunotherapy drugs known in the art, such as anti-PD1 antibodies, for the treatment of cancer. Alternatively, the compound of formula I of the present invention, its pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotope-substituted products, polymorphs, prodrugs or metabolites, or pharmaceutical compositions thereof, may also be used in combination with conventional radiotherapy.

[0133] In this article, terms such as "combination therapy," "drug combination therapy," "combined medication," or "combination treatment" refer to drug therapy achieved by mixing or combining more than one active ingredient. This includes fixed and non-fixed combinations of active ingredients, or combinations of two or more different treatment modalities. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or single dosage form. The term "non-fixed combination" refers to the simultaneous, combined, or sequential administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity at variable intervals. These also apply to cocktail therapies, such as the administration of three or more active ingredients.

[0134] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I of the present invention, a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a tautomer, a solvate, an isotope substitute, a polymorph, a prodrug or metabolite, and a pharmaceutically acceptable carrier or excipient.

[0135] In this application, "pharmaceutical composition" refers to a formulation containing a compound of formula I, a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a tautomer, a solvate, an isotope-substituted product, a polymorph, a prodrug, or a metabolite, and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). This medium includes pharmaceutically acceptable carriers. The purpose of a pharmaceutical composition is to facilitate administration to an organism, thereby facilitating the absorption of the active ingredient and the exertion of its biological activity. As used herein, the term "pharmaceutically acceptable" means a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound of formula I of the present invention, its pharmaceutically acceptable salt, an enantiomer, a diastereomer, a tautomer, a solvate, an isotope-substituted product, a polymorph, a prodrug, or a metabolite, and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological response or interacting adversely with any component contained in the composition. "Pharmaceutically acceptable carriers or excipients" include, but are not limited to, any adjuvants, carriers, excipients, flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that are permitted by the relevant government regulatory authorities to be acceptable for human or livestock use.

[0136] In some embodiments, the active ingredient of the pharmaceutical composition of the present invention may contain, in addition to the compound of Formula I of the present invention, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substitute, polymorph, prodrug or metabolite, other known anticancer agents, including but not limited to taxane, vinblastine alkaloids, paclitaxel, docetaxel, vinblastine, vinblastine, vinorelbine, vinflunine, cisplatin, 5-fluorouracil, 5-fluoro-2-4(1H,3H)-pyrimidinidone (5FU), flutamide and gemcitabine, etc.

[0137] This invention relates to the use of the Formula I compounds of this invention, pharmaceutically acceptable salts thereof, enantiomers, diastereomers, tautomers, solvates, isotope-substituted products, polymorphs, prodrugs, or metabolites thereof, or pharmaceutical compositions thereof, in the treatment or prevention of EGFR protein mutation-related diseases described herein, or in the preparation of medicaments for the treatment or prevention of EGFR protein mutation-related diseases described herein. This invention also provides for the treatment or prevention of EGFR protein mutation-related diseases described herein, including the Formula I compounds of this invention, pharmaceutically acceptable salts thereof, enantiomers, diastereomers, tautomers, solvates, isotope-substituted products, polymorphs, prodrugs, or metabolites thereof, or pharmaceutical compositions thereof.

[0138] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0139] The starting materials used in all embodiments of this invention are commercially available and known materials, or synthesized according to known synthetic methods in the art. Unless otherwise specified, the reaction temperature is room temperature, and the unit of reaction temperature is degrees Celsius (°C). All reactions of this invention are carried out under continuous magnetic stirring in an anhydrous and oxygen-free reaction environment, and the solvents are all anhydrous solvents.

[0140] Preparation of Specific Embodiments

[0141] Example 1. Preparation of (R)-N-(4-((6-amino-7-methoxyquinazoline-4-yl)amino)thiazoline-2-yl)-2-(5-fluoro-2-hydroxyphenyl)-2-(1-oxoisoindoline-2-yl)acetamide (I-6)

[0142] Step 1. 2-Amino-2-(5-fluoro-2-hydroxyphenyl)acetic acid

[0143] Take a four-necked flask and add substrate A (10-16g) to each flask. Purge the reaction system with ammonia gas and add 80ml of methanol solution to dissolve substrate A. Add trimethylcyanosilane dropwise at a uniform rate and react at 40-60℃ for 4-6 hours. After the reaction is complete, concentrate the reaction solution. Add 80-120ml of 2N hydrochloric acid solution to the reaction system to dissolve the product and filter out insoluble impurities. Adjust the pH to 7-8, extract and concentrate the reaction solution with ethyl acetate, and heat under reflux for 5 hours with concentrated hydrochloric acid. Concentrate the reaction solution and evaporate to dryness to obtain 16.2g of amino acid hydrochloride D.

[0144] Step 3. (S)-2-amino-2-(5-fluoro-2-hydroxyphenyl)acetic acid

[0145] Product D was separated by a chiral preparative column to obtain product E.

[0146] Step 4. (S)-2-(5-fluoro-2-hydroxyphenyl)-2-(1-oxoisoindoline-2-yl)acetic acid

[0147] Take a four-necked flask, add an appropriate amount of toluene, and add 18.5 g of product E and 23 g of benzylbromobenzoic acid F (obtained by hydrolysis of commercially available benzylbromobenzoate) to the flask. Add an appropriate amount of potassium carbonate to the reaction system. Heat the reaction mixture to separate the water, and after the reaction is complete, cool to room temperature. Quench the reaction with an appropriate amount of hydrochloric acid, extract the reaction solution, and dry and concentrate to obtain 28.4 g of product G.

[0148] Step 5. (S)-2-(2-acetoxy-5-fluorophenyl)-2-(1-oxoisoindol-2-yl)acetic acid

[0149] Take a manila flask and add 30.1 g of intermediate G from the previous step, 40-60 ml of triethylamine, and an appropriate amount of acetic anhydride. Dichloromethane is preferred as the solvent. Stir the mixture at room temperature for 6 hours, monitoring the reaction until completion. Extract the reaction solution with ethyl acetate or dichloromethane, with ethyl acetate being preferred. Wash the organic phase successively with citric acid and sodium chloride solution, and after drying and concentration, obtain 33 g of product H.

[0150] Step 6. Methyl (S)-2-(2-(2-acetoxy-5-fluorophenyl)-2-(1-oxoisoindol-2-yl)acetamido)thiazole-4-carboxylate

[0151] Take a flask and add 33g of intermediate H from the previous step, 35-45g of 2-(1H-benzotriazo-L-1-yl)-1,1,3,3-tetramethylurea tetrafluoroborate, the amount of N,N-diisopropylethylamine catalyst, and 20-30g of methyl 2-aminothiazo-4-carboxylate. Dichloromethane is preferred as the solvent. Stir the reaction mixture at room temperature for 5-6 hours. Monitor the reaction for completion. Extract the reaction solution with ethyl acetate or dichloromethane (ethyl acetate is preferred). Wash the organic phase successively with citric acid and sodium chloride solution, and after drying and concentration, obtain 46.2g of product I.

[0152] Step 7. (R)-2-(2-((4-carbamoylthiazolyl-2-yl)amino)-2-oxo-1-(1-oxoisoindoline-2-yl)ethyl)-4-fluorophenylacetate

[0153] Take a flask and add 24g of intermediate I from the previous step and saturated methanol-ammonia to the flask. Stir the reaction mixture overnight at room temperature. Concentrate the reaction solution and evaporate to dryness to obtain 23g of product J.

[0154] Step 8. (R)-2-(2-((4-aminothiazol-2-yl)amino)-2-oxo-1-(1-oxoisoindol-2-yl)ethyl)-4-fluorophenylacetate

[0155] Take a flask and add 18g of intermediate J from the previous step, followed by 30-40g of iodophenyldiacetic acid. Use a mixed solvent, adding appropriate amounts of ethyl acetate, acetonitrile, and water. React at 15-25°C for half an hour, then raise the temperature to room temperature and continue the reaction for 3-5 hours. Monitor the reaction until completion, add an appropriate amount of water, and extract with ethyl acetate. Concentrate and dry the organic phase to obtain 12.5g of product K.

[0156] Step Nine. 4-Chloro-7-methoxy-6-nitroquinazolino

[0157] Take a flask and add 15-20g of raw material L to it, along with an appropriate amount of thionyl chloride solution. Heat the reaction mixture under reflux, slowly adding an appropriate amount of dimethylformamide solution. Continue heating under reflux until the mixture is completely dissolved. After the reaction is complete, add dichloromethane to concentrate and dry to obtain 22g of product M.

[0158] Step 10. (R)-4-fluoro-2-(2-((4-((7-methoxy-6-nitroquinazolin-4-yl)amino)thiazo-2-yl)amino)-2-oxo-1-(1-oxoisoindoline-2-yl)ethyl)phenyl acetate

[0159] Take a flask and add approximately 40g of compound K and approximately 25g of compound M, the intermediates from the previous steps, to the flask. React at 50-60°C for 4-6 hours. In another reaction flask, add DMF solvent, then add 44g of compound K and 24g of compound M, and heat to 60°C for 4-6 hours. DMF is preferred as the solvent. Once the reaction is complete, pour the reaction mixture into an ice-water mixture and adjust the pH to 7-8. Extract with ethyl acetate to obtain the organic phase, concentrate and dry to obtain 65g of product N.

[0160] Step 11. (R)-2-(2-((4-((6-amino-7-methoxyquinazoline-4-yl)amino)thiazoline-2-yl)amino)-2-oxo-1-(1-oxoisoindoline-2-yl)ethyl)-4-fluorophenylacetate

[0161] Take a four-necked flask and add 30g of the intermediate N product from the previous step, along with the catalyst amount of palladium on carbon. Fill the reaction system with hydrogen gas and react at 30-35℃ for 4-6 hours. After the reaction is complete, filter off the palladium on carbon, concentrate and dry the filtrate to obtain 28g of compound O.

[0162] Step 12. (R)-N-(4-((6-amino-7-methoxyquinazoline-4-yl)amino)thiazolyl-2-yl)-2-(5-fluoro-2-hydroxyphenyl)-2-(1-oxoisoindoline-2-yl)acetamide

[0163] Take a flask and add 15g of compound O (the intermediate from the previous step). Dissolve a small amount of lithium hydroxide in methanol and stir at room temperature. Once the reaction is complete, pour the reaction mixture into a saturated ammonium chloride aqueous solution and extract with ethyl acetate. Wash the organic phase with sodium chloride solution, dry, and concentrate to obtain the final product P. 1 H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 10.03 (s, 1H), 8.63 (d, J = 2.9 Hz, 1H), 7.96 (s, 2H), 7.73 (d, J = 7.5 Hz, 1H), 7.60 (dt, J = 12.7, 7.3 Hz, 2H), 7.50 (t, J = 7.3Hz, 1H), 7.44 (d, J = 2.9 Hz, 1H), 7.11 (d, J = 9.9 Hz, 2H), 6.89 (ddd, J =12.2, 9.2, 4.0 Hz, 2H), 6.31 (s, 1H), 5.68 (s, 2H), 4.60 (d, J = 17.6 Hz,1H), 4.03 - 3.93 (m, 4H).

[0164] Example 2. Synthesis of intermediate E

[0165] Intermediate E can be obtained by the following general synthetic route:

[0166] Repeat the synthesis steps of intermediate E in Example 1. 1 H NMR (500 MHz, Chloroform-d) δ7.60 (s, 1H), 7.05 - 6.95 (m, 2H), 6.89 (dd, J = 8.4, 5.1 Hz, 1H), 5.03 (td, J = 5.3, 1.1 Hz, 1H), 4.58 (dd, J = 7.3, 5.3 Hz, 1H), 4.46 (dd, J = 7.1, 5.3Hz, 1H).

[0167] Example 3. Synthesis of intermediate K

[0168] Intermediate K can be obtained by the following general synthetic route:

[0169] Intermediate K was prepared by repeating the synthesis steps of Example 1. 1 H NMR (500 MHz, Chloroform-d) δ7.87 (dd, J = 7.7, 1.7 Hz, 1H), 7.55 (td, J = 7.5, 1.6 Hz, 1H), 7.48 (td, J =7.5, 2.7 Hz, 1H), 7.42 (ddt, J = 7.7, 2.7, 1.0 Hz, 1H), 7.24 (ddd, J = 8.1,2.1, 1.0 Hz, 1H), 7.11 - 7.00 (m, 2H), 6.19 (s, 1H), 5.77 - 5.69 (m, 2H),5.60 (d, J = 6.2 Hz, 1H), 4.37 (t, J = 1.0 Hz, 2H), 2.62 (dq, J = 15.6, 7.8Hz, 1H), 2.52 (dq, J = 15.7, 7.9 Hz, 1H), 1.23 (t, J = 7.9 Hz, 3H).

[0170] Example 4. Synthesis of target compound I-1

[0171] The synthesis steps of Example 1 were repeated, but compound M was replaced with commercially available 7-bromo-1-methyl-1H-indole to obtain the target product. 1 H NMR (500 MHz, Chloroform-d) δ 8.52 (s, 1H), 7.98 (s, 1H), 7.90(dd, J = 7.7, 1.7 Hz, 1H), 7.58 - 7.52 (m, 1H), 7.48 (td, J = 7.5, 2.7, Hz,1H), 7.43 (ddt, J = 7.8, 2.8, 1.0 Hz, 1H), 7.33 (dt, 7.7, 1.3 Hz, 1H), 7.17 -7.09 (m, 3H), 7.05 (t, J= 7.9 Hz, 1H), 7.00 - 6.89 (m, 2H), 6.73 - 6.68 (m,1H), 6.16 (s, 1H), 5.71 (d, J = 0.9 Hz, 2H), 3.88 (s, 3H).

[0172] Example 5. Synthesis of target compound I-2

[0173] The synthesis steps of Example 1 were repeated, but compound M was replaced with commercially available 4-bromopyrimidine to obtain the target product. 1 HNMR (500 MHz, Chloroform-d) δ 8.81 (d, J = 1.5 Hz, 1H), 8.65 (s, 1H), 8.60(d, J = 5.7 Hz, 1H), 8.22 (s, 1H), 8.05 (dd, J = 5.7, 1.4 Hz, 1H), 7.89 (dd, J = 7.7, 1.7 Hz, 1H), 7.55 (td, J = 7.5, 1.6 Hz, 1H), 7.48 (td, J = 7.5, 2.7Hz, 1H), 7.43 (ddt, J = 7.8, 2.8, 1.0 Hz, 1H), 7.03 (ddd, J = 7.9, 1.7, 1.0Hz, 1H), 6.99 - 6.89 (m, 3H), 5.78 (d, J = 1.0 Hz, 1H), 4.37 (dd, J = 13.5, 1.0 Hz, 1H), 4.31 (dd, J = 13.6, 1.1 Hz, 1H).

[0174] Example 6. Synthesis of target compound I-3

[0175] The synthesis steps of Example 1 were repeated, but compound M was replaced with commercially available 4-chloropyridine hydrochloride to obtain the target product. 1H NMR (500 MHz, Chloroform-d) δ 8.38 (s, 1H), 8.29 - 8.24 (m, 2H), 7.89(dd, J = 7.7, 1.7 Hz, 1H), 7.59 - 7.51 (m, 2H), 7.48 (td, J = 7.5, 2.7 Hz, 1H), 7.43 (ddt, J = 7.9, 2.9, 1.0 Hz, 1H), 7.26 (ddd, J = 7.8, 1.8, 1.0 Hz,1H), 6.99 - 6.88 (m, 2H), 6.51 - 6.45 (m, 2H), 6.16 (s, 1H), 5.78 (d, J = 1.1Hz, 1H), 4.37 (d, J = 1.1 Hz, 2H).

[0176] Example 7. Synthesis of target compound I-4

[0177] The synthesis steps of Example 1 were repeated, but compound M was replaced with commercially available 2-bromopyridine to obtain the target product. 1 HNMR (500 MHz, Chloroform-d) δ 8.99 (s, 1H), 8.12 (dd, J = 3.5, 1.6 Hz, 1H), 7.89 (dd, J = 7.7, 1.7 Hz, 1H), 7.64 (td, J = 7.7, 1.6 Hz, 1H), 7.55 (td, J =7.5, 1.6 Hz, 1H), 7.48 (td, J = 7.5, 2.7 Hz, 1H), 7.43 (ddt, J = 7.8, 2.8,1.0 Hz, 1H), 7.34 (ddd, J = 8.0, 1.9, 0.9 Hz, 1H), 7.18 (s, 1H), 6.99 - 6.88(m, 3H), 6.88 - 6.78 (m, 2H), 5.78 (d, J = 1.1 Hz, 1H), 4.37 (d,J = 1.1 Hz, 2H).

[0178] Example 8. Synthesis of target compound I-5

[0179] The synthesis steps of Example 1 were repeated, but compound M was replaced with commercially available 4-bromoquinazoline to obtain the target product. 1 H NMR (500 MHz, Chloroform-d) δ 8.86 (s, 1H), 8.56 (s, 1H), 8.08 (ddd, J =14.5, 8.1, 1.5 Hz, 2H), 7.90 (dd, J = 7.7, 1.7 Hz, 1H), 7.84 (ddd, J = 8.0,6.8, 1.2 Hz, 1H), 7.76 (s, 1H), 7.58 - 7.39 (m, 4H), 7.03 - 6.97 (m, 2H),6.95 - 6.84 (m, 2H), 5.78 (d, J = 1.1 Hz, 1H), 4.31 (d, J = 1.1 Hz, 2H).

[0180] Example 9. Synthesis of target compound I-7

[0181] The synthesis steps of Example 1 were repeated, but compound M was replaced with commercially available 4-bromopyrido[2,3-d]pyrimidine to obtain the target product. 1 H NMR (500 MHz, Chloroform-d) δ 8.97 (d, J = 4.8 Hz, 2H), 8.89 (dd, J = 3.5, 2.2 Hz, 1H), 8.71 (dd, J = 7.9, 2.2 Hz, 1H), 7.99 (s, 1H), 7.90(dd, J = 7.7, 1.7 Hz, 1H), 7.58 - 7.52 (m, 1H), 7.48 (td, J = 7.5, 2.7 Hz, 1H), 7.43 (ddt, J= 7.5, 2.6, 0.9 Hz, 1H), 7.30 (ddd, J = 8.0, 1.9, 1.0 Hz,1H), 7.22 (dd, J = 7.9, 3.5 Hz, 1H), 6.99 (s, 1H), 6.94 - 6.83 (m, 2H), 5.82(d, J = 1.0 Hz, 1H), 4.37 (d, J = 1.0 Hz, 2H).

[0182] Example 10. Synthesis of target compound I-8

[0183] The synthesis steps of Example 1 were repeated, but compound M was replaced with commercially available 4-bromobenzonitrile to obtain the target product. 1 HNMR (500 MHz, Chloroform-d) δ 8.42 (s, 1H), 7.90 (dd, J = 7.7, 1.7 Hz, 1H),7.67 - 7.61 (m, 2H), 7.55 (td, J = 7.4, 1.7 Hz, 1H), 7.52 - 7.39 (m, 4H),7.32 (ddd, J = 7.8, 1.9, 1.0 Hz, 1H), 7.18 (s, 1H), 6.99 - 6.87 (m, 2H), 6.16(s, 1H), 5.83 (d, J = 1.0 Hz, 1H), 4.37 (d, J = 1.1 Hz, 2H).

[0184] Example 11. Synthesis of target compound I-9

[0185] The synthesis steps of Example 1 were repeated, but compound M was replaced with commercially available 3-chloro-4-bromofluorobenzene to obtain the target product. 1 H NMR (500 MHz, Chloroform-d) δ 8.14 (s, 1H), 7.94 - 7.87 (m, 2H), 7.59 -7.52 (m, 2H), 7.48 (td, J = 7.5, 2.7 Hz, 1H), 7.43 (ddt,J = 7.8, 2.8, 1.1Hz, 1H), 7.30 (ddd, J = 8.0, 1.9, 1.0 Hz, 1H), 7.16 - 7.08 (m, 2H), 6.98 -6.87 (m, 2H), 6.16 (s, 1H), 5.82 (d, J = 1.0 Hz, 1H), 4.37 (d, J = 1.1 Hz, 2H).

[0186] Example 12. Synthesis of target compound I-10

[0187] The synthesis steps of Example 1 were repeated, but compound M was replaced with commercially available 3-chloro-2-fluorobromobenzene to obtain the target product. 1 H NMR (500 MHz, Chloroform-d) δ 8.24 (s, 1H), 7.90 (dd, J = 7.7, 1.7 Hz, 1H), 7.55 (td, J = 7.4, 1.7 Hz, 1H), 7.52 - 7.39 (m, 3H), 7.22 (ddt, J = 7.9,3.8, 1.3 Hz, 2H), 7.15 - 7.08 (m, 2H), 7.00 - 6.87 (m, 2H), 6.16 (s, 1H),5.75 (d, J = 1.1 Hz, 1H), 4.37 (dd, J = 13.5, 1.0 Hz, 1H), 4.31 (dd, J =13.6, 1.1 Hz, 1H).

[0188] Example 13. Synthesis of target compound I-11

[0189] The synthesis steps of Example 1 were repeated, but compound M was replaced with commercially available p-bromofluorobenzene to obtain the target product. 1 HNMR (500 MHz, Chloroform-d) δ 8.43 (s, 1H), 7.89 (dd, J = 7.7, 1.7 Hz, 1H), 7.55 (td, J= 7.4, 1.7 Hz, 1H), 7.48 (td, J = 7.5, 2.7 Hz, 1H), 7.43 (ddt, J = 7.8, 2.9, 1.0 Hz, 1H), 7.35 (ddd, J = 8.0, 1.9, 0.9 Hz, 1H), 7.29 - 7.22(m, 2H), 7.20 - 7.11 (m, 3H), 6.99 - 6.87 (m, 2H), 6.16 (s, 1H), 5.79 (d, J =1.1 Hz, 1H), 4.37 (d, J = 1.1 Hz, 2H).

[0190] Example 14. Synthesis of target compound I-12

[0191] The synthesis steps of Example 1 were repeated, and 4-bromo-N,N-dimethylaniline and N,N-dimethyl-β-alanine were used in a condensation reaction to generate an intermediate to replace compound M, thereby obtaining the target product. 1 H NMR (500 MHz, Chloroform-d) δ 8.64 (s, 1H), 7.90 (dd, J = 7.8, 1.8 Hz, 1H), 7.63 - 7.57 (m,2H), 7.54 (td, J = 7.5, 1.7 Hz, 1H), 7.48 (td, J = 7.5, 2.7 Hz, 1H), 7.42(ddt, J = 7.7, 2.9, 1.0 Hz, 1H), 7.11 (ddd, J = 8.0, 1.8, 1.0 Hz, 1H), 6.98 -6.88 (m, 3H), 6.84 - 6.78 (m, 2H), 6.16 (s, 1H), 5.86 (d, J = 1.1 Hz, 1H), 4.37 (dd, J = 13.6, 0.9 Hz, 1H), 4.31 (dd, J = 13.6, 1.1 Hz, 1H), 3.74 (dt, J= 11.8, 5.9 Hz, 1H), 3.53 (dt, J = 11.8, 5.7 Hz, 1H), 2.90 (s, 3H), 2.88 -2.80 (m, 1H), 2.56 - 2.47 (m, 1H), 2.36 (s, 6H).

[0192] Example 15. Synthesis of target compound I-13

[0193] The synthesis steps of Example 4 were repeated, but 2-(bromomethyl)-5-methylbenzoate was hydrolyzed to obtain 2-(bromomethyl)-5-methylbenzoic acid instead of compound F to give the target product. ¹H NMR (500MHz, Chloroform-d) δ 8.19 (s, ¹H), 7.98 (s, ¹H), 7.76 (d, ¹H). J = 1.9 Hz, 1H),7.36 - 7.30 (m, 2H), 7.26 (t, J = 7.7 Hz, 1H), 7.19 - 7.11 (m, 2H), 7.10 (d, J = 4.2 Hz, 1H), 7.02 (ddd, J = 7.8, 1.6, 1.0 Hz, 1H), 6.98 - 6.89 (m, 2H), 6.70 (dd, J = 4.5, 1.3 Hz, 1H), 6.16 (s, 1H), 5.81 (d, J = 1.1 Hz, 1H), 4.38(dd, J = 13.6, 1.1 Hz, 1H), 4.32 (dd, J = 13.6, 1.1 Hz, 1H), 3.85 (s, 3H), 2.39 (d, J = 0.7 Hz, 3H).

[0194] Example 16. Synthesis of target compound I-14

[0195] The synthesis steps of Example 4 were repeated, but 6-bromomethyl-3-chloro-2-fluorobenzoic acid was obtained by hydrolyzing a commercially available 6-bromomethyl-3-chloro-2-fluorobenzoic acid compound to give 6-bromomethyl-3-chloro-2-fluorobenzoic acid, thus replacing compound F, to yield the target product. ¹H NMR (500MHz, Chloroform-d) δ 8.04 (s, ¹H), 7.98 (s, ¹H), 7.47 (dd, δ ... J = 8.4, 5.1 Hz, 1H), 7.41 (dt, J = 7.7, 1.4 Hz, 1H), 7.33 - 7.27 (m, 1H), 7.21 - 7.15 (m,1H), 7.15 - 7.07 (m, 3H), 6.99 - 6.89 (m, 2H), 6.72 (dd, J = 4.2, 1.2 Hz,1H), 6.16 (s, 1H), 5.83 (d, J = 0.9 Hz, 1H), 4.37 (dd, J = 13.5, 1.0 Hz, 1H), 4.30 (dd, J = 13.6, 0.9 Hz, 1H), 3.80 (s, 3H).

[0196] Example 17. Synthesis of target compound I-15

[0197] The synthesis steps of Example 4 were repeated, but 2-(bromomethyl)-5-(trifluoromethyl)benzoate was hydrolyzed to obtain 2-(bromomethyl)-5-(trifluoromethyl)benzoic acid, replacing compound F, to give the target product. ¹H NMR (500 MHz, Chloroform-d) δ 8.24 (d, J = 1.9 Hz, 1H), 7.98 (s, 1H), 7.94(s, 1H), 7.77 (dd, J = 8.4, 1.8 Hz, 1H), 7.41 (dt, J = 8.4, 1.0 Hz, 1H), 7.33(dt, J = 7.6, 1.4 Hz, 1H), 7.17 - 7.07 (m, 4H), 6.98 - 6.88 (m, 2H), 6.70(dd, J= 4.3, 1.2 Hz, 1H), 6.16 (s, 1H), 5.83 (d, J = 1.1 Hz, 1H), 4.38 (d, J = 1.2 Hz, 2H), 3.84 (s, 3H).

[0198] Example 18. Synthesis of target compound I-16

[0199] The synthesis steps of Example 4 were repeated, but compound F was replaced with commercially available 2-bromomethyl-5-(trifluoromethoxy)benzoic acid to obtain the target product. ¹H NMR (500 MHz, Chloroform-d) δ 7.89 (s, ¹H), 7.57 (d, ¹H). J = 1.9 Hz, 1H), 7.33 (dddd, J = 7.5, 6.5, 4.8, 1.2 Hz, 3H), 7.31 - 7.21(m, 2H), 7.17 - 7.08 (m, 3H), 6.99 - 6.87 (m, 2H), 6.72 - 6.67 (m, 1H), 6.16(s, 1H), 5.81 (d, J = 0.9 Hz, 1H), 4.37 (d, J = 1.0 Hz, 2H), 3.88 (s, 3H).

[0200] Example 19. Synthesis of target compound I-17

[0201] The synthetic steps of Example 4 were repeated, but compound F was replaced with the compound obtained by bromination of commercially available 2-methyl-5-(4-pyridyl)benzoic acid to obtain the target product. ¹H NMR (500 MHz, Chloroform-d) δ 8.71–8.66 (m, 2H), 8.21 (d, J = 1.9 Hz, 1H), 8.04 (s, 1H), 7.89 (s, 1H), 7.70(dd, J = 8.4, 1.8 Hz, 1H), 7.64 - 7.55 (m, 3H), 7.42 (dt, J = 7.8, 1.4 Hz, 1H), 7.14 (dd, J= 7.8, 1.2 Hz, 1H), 7.11 - 7.03 (m, 2H), 7.03 - 6.98 (m,1H), 6.98 - 6.88 (m, 2H), 6.75 - 6.70 (m, 1H), 6.16 (s, 1H), 6.02 (d, J = 1.1Hz, 1H), 4.38 (t, J = 0.8 Hz, 2H), 3.72 (s, 3H).

[0202] Example 20. Synthesis of target compound I-18

[0203] The synthetic steps of Example 4 were repeated, but compound F was replaced with the compound obtained by bromination of commercially available 4-methyl-[1,1'-biphenyl]-3-carboxylic acid to obtain the target product. ¹H NMR (500 MHz, Chloroform-d) δ 8.21 (d, J = 1.9 Hz, 1H), 8.14 (s, 1H), 7.89 (s, 1H), 7.68 (dd, J = 8.4, 2.0 Hz,1H), 7.63 - 7.57 (m, 2H), 7.54 (dt, J = 8.4, 1.0 Hz, 1H), 7.47 - 7.39 (m,3H), 7.39 - 7.32 (m, 1H), 7.17 - 7.08 (m, 2H), 7.08 - 7.00 (m, 2H), 6.99 -6.89 (m, 2H), 6.74 - 6.69 (m, 1H), 6.16 (s, 1H), 5.82 (d, J = 0.9 Hz, 1H), 4.39 (d, J = 1.0 Hz, 2H), 3.80 (s, 3H).

[0204] Example 21. Synthesis of target compound I-19

[0205] The synthesis steps of Example 1 were repeated, using commercially available methyl 2-(bromomethyl)-5-methoxy-4-nitrobenzene, which underwent reduction and hydrolysis reactions sequentially to obtain 2-(bromomethyl)-5-methoxy-4-aminobenzoic acid in place of compound F, yielding the target product. ¹H NMR (500 MHz, Chloroform-d) δ 9.04 (s, ¹H), 8.57 (s, ¹H), 7.75 (d, ¹H). J = 14.1 Hz, 2H), 7.13 (dt, J = 7.9, 1.3 Hz, 1H), 7.07 (s, 1H), 6.99 (s, 1H), 6.94 - 6.85 (m, 3H), 6.74 (t, J = 1.0 Hz, 1H), 5.86 (d, J = 1.1Hz, 1H), 4.93 (d, J = 7.0 Hz, 1H), 4.71 (d, J = 7.0 Hz, 1H), 4.32 (dd, J =13.5, 1.1 Hz, 1H), 4.20 (dd, J = 13.6, 1.1 Hz, 1H), 4.10 (d, J = 7.0 Hz, 1H), 4.01 (d, J = 7.0 Hz, 1H), 3.84 (d, J = 2.0 Hz, 6H).

[0206] Example 22. Synthesis of target compound I-20

[0207] The synthesis steps of Example 1 were repeated, but 2-bromomethyl-5-methoxybenzoic acid was obtained by hydrolyzing commercially available methyl 2-bromomethyl-5-methoxybenzoic acid instead of compound F to give the target product. ¹H NMR (500MHz, Chloroform-d) δ 9.04 (s, 1H), 8.57 (s, 1H), 7.76 (s, 1H), 7.50 - 7.43 (m, 2H), 7.30 (dt, J = 8.4, 1.0 Hz, 1H), 7.18 - 7.12 (m, 1H), 6.99 (s, 1H), 6.97 - 6.85 (m, 4H), 5.76 (d,J = 0.9 Hz, 1H), 4.93 (d, J = 7.0 Hz, 1H), 4.71(d, J = 7.0 Hz, 1H), 4.42 - 4.30 (m, 2H), 3.82 (d, J = 18.7 Hz, 6H).

[0208] Bioactivity

[0209] To verify the efficacy of the compound described in the patent, we measured relevant values ​​4 hours after drug administration, demonstrating the epidermal growth factor receptor phosphorylation level (pEGFR) in NIH3T3 cells carrying the C797S point mutation after treatment with DMSO or with a specified concentration of the positive control or the target test substance. Figure 1 As shown, the target test substance (Compound B is compound I-6 of this invention) has a better inhibitory effect than the two positive control drugs (Compound A is BDTX-1535, and Compound C is osimertinib).

[0210] Figure 2 To predict and evaluate potential drug candidates, software simulation was used to model the interaction between the target drug small molecule (compound I-6) and the biomacromolecule (7JXM).

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a tautomer, a solvate, an isotope-substituted product, a polymorph, a prodrug, or a metabolite thereof: (I)， in, R1 is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, nitro, -CF3, -OCF3, C 1-3 Alkoxy, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-7 cycloalkyl, C 6-10 The aryl or heteroaryl group may consist of one or two 5-7 membered rings and 1-4 heteroatoms from N, O, and S, wherein the above groups are independently and optionally further surrounded by one or more atoms selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, nitro, -CF3, -OCF3, -O(CH2). 1-3 C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-7 cycloalkyl, C 6-10 Aryl, heteroaryl, or substituted by one or two 5-7 membered rings and 1-4 heteroatoms from N, O, and S; R2 is independently selected from hydrogen, deuterium, and C. 1-3 alkyl; R3 is independently selected from hydrogen, deuterium, and C. 1-3 alkyl; Ring A is C 5-10 The aryl group may contain one, two, or three five-membered, six-membered, or seven-membered rings and 1-5 heteroaryl groups selected from O, N, and S atoms, wherein the heteroaryl group and the aryl group may be independently substituted by one or more R0 groups. R4 is independently selected from hydrogen, deuterium, and C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-7 cycloalkyl, C 5-10 Aryl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The aryl group comprises a haloalkoxy group and one, two, or three five-membered, six-membered, or seven-membered rings, and 1-5 heteroaryl groups selected from O, N, and S atoms, wherein each heteroaryl group and aryl group is independently separated by one or more R groups. 41 Substitution, q represents the substituent R on R4 41 The number of; R 41 Independently selected from hydrogen, deuterium, hydroxyl, cyano, nitro, optionally with 1, 2 or 3 selected from halogen, deuterium and -NR. c R d Substituents of -NR a R b Halogen, sulfur group, -CF3, -OCF3, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-7 cycloalkyl, C 5-10 Aryl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The alkyl halogroup and a heteroaryl group comprising one, two, or three five-membered, six-membered, or seven-membered rings and 1-5 heteroaryl groups selected from O, N, and S atoms; wherein, R a R b R c and R d Each is independently selected from H and C 1-6 alkyl; Q is selected from O, S, NR5, CR5R6. R5 is selected from hydrogen, deuterium, and C. 1-8 Alkyl, C 2-8 alkenyl or ynyl, C 3-8 cycloalkyl or heterocyclic groups, C 5-10 heteroaryl, the C 1-8 Alkyl, C 2-8 alkenyl or alkyne, C 3-8 cycloalkyl or heterocyclic groups, C 5-10 The heteroaryl group may be further converted by one or more hydroxyl, cyano, nitro, amino, halogen, thio, C group, etc. 1-8 Alkyl, C 2-8 alkenyl or ynyl, C 3-8 cycloalkyl or heterocyclic groups, C 5-10 Substituents of heteroaryl groups; R6 is selected from hydrogen, deuterium, hydroxyl, cyano, nitro, amino, halogen, thio, and C. 1-8 Alkyl, C 2-8 alkenyl or ynyl, C 3-8 cycloalkyl or heterocyclic groups, C 5-10 Metaaryl aromatics; wherein the C 1-8 Alkyl, C 2-8 alkenyl or ynyl, C 3-8 cycloalkyl or heterocyclic groups, C 5-10 The heteroaryl group may be further converted by one or more hydroxyl, cyano, nitro, amino, halogen, thio, C group, etc. 1-8 Alkyl, C 2-8 alkenyl or ynyl, C 3-8 cycloalkyl or heterocyclic groups, C 5-10 Substituents of heteroaryl groups; m and n are independent 0s or 1s; p and q are independent values ​​of 0, 1, or 2. R0 is H, C 1-3 Alkyl, C 1-3 Alkoxy, amino, F, Br, Cl or -OH, preferably, R0 is C 1-3 Alkyl, C 1-3 Alkoxy, amino, F or Cl, Preferably, m is 1, n is 0 or 1, p is 0, 1, or 2, and q is 1 or 2. m is 0, n is 0 or 1, p is 0, 1 or 2, q is 1 or 2. More preferably, p, m, and n are 0, q is 1 or 2, or m and n are 0, p is 1 or 2, and q is 1 or 2.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug, or metabolite, characterized in that, p, m, and n are 0, q is 1 or 2, and R2 is H or C. 1-3 alkyl, m and n are 0, p is 1 or 2, q is 1 or 2, R2 is H or C. 1-3 Alkyl group, R1 independently is halogen, -CF3, -OCF3, C 1-3 Alkyl, phenyl, pyridyl, C 1-3 Alkoxy, amino m is 1, n is 0 or 1, p is 0, 1, or 2, q is 1 or 2, R2 is H or C. 1-3 Alkyl group, R3 is H or C 1-3 alkyl, or m is 0 or 1, n is 1, p is 0, 1, or 2, q is 1 or 2, and R2 is H or C. 1-3 Alkyl group, R3 is H or C 1-3 alkyl.

3. The compound as described in claim 1 or 2, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug, or metabolite thereof, characterized in that, R4 is independently selected from unsubstituted or R7-substituted phenyl groups, unsubstituted or R0-substituted six-membered heteroaryl groups containing 1-3 N atoms, and unsubstituted or R0-substituted fused-ring heteroaryl groups containing a six-membered ring and 1-3 N atoms. R7 is C10. 1-3 Alkyl, C 1-3 Alkyl, amino, F, Br, Cl, hydroxyl, cyano, NCH3(CH2)2N(CH3)2, preferably R7 is F, Br, Cl, hydroxyl, cyano, NCH3(CH2)2N(CH3)2, q is 1 or 2. Preferably, R4 is independently selected from: unsubstituted or R7-substituted phenyl, unsubstituted six-membered heteroaryl containing 1-3 N atoms, unsubstituted or R8-substituted fused-ring heteroaryl containing one five-membered ring and one six-membered ring and 1-3 N atoms, unsubstituted or R8-substituted fused-ring heteroaryl containing two six-membered rings and 1-3 N atoms, R7 is F, Br, Cl, hydroxyl, cyano, NCH3(CH2)2N(CH3)2, and R8 is selected from C. 1-3 Alkyl, C 1-3 alkoxy, amino, q is 1 or 2, More preferably, R4 is independently selected from: unsubstituted or R7-substituted phenyl groups, C 1-3 Alkyl-substituted benzopyrrole, pyridine, pyrimidine, unsubstituted or R8-substituted benzopyrimidine, pyridopyrimidine, where q is 1 or 2.

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug, or metabolite, characterized in that, Ring A is a phenyl group or a ring comprising a five-membered or six-membered ring and 1-3 heteroaryl groups selected from O, N, and S atoms, wherein the heteroaryl group and the phenyl group are optionally each independently substituted by one or more R0 atoms; preferably, ring A is a five-membered heteroaryl group comprising 1-2 N atoms, wherein the heteroaryl group is optionally substituted by one or more R0 atoms. Preferably, ring A is a five-membered heteroaryl group containing 1-3 N or S atoms. More preferably, ring A is optionally replaced by R0. (Thiazole).

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug, or metabolite, characterized in that, R1 is independently a C that is H, halogen, unsubstituted, or substituted with 1-3 halogens. 1-3 Alkyl, unsubstituted or 1-3 halogenated C 1-3 Alkoxy, unsubstituted or R0-substituted phenyl, unsubstituted or R0-substituted pyridyl, unsubstituted or R0-substituted amino, p is 0, 1 or 2. R2 is hydrogen or C. 1-3 alkyl, m is 0; or m is 1 and R3 is selected from hydrogen or C. 1-3 alkyl, n is 0 or 1, Ring A is a phenyl group or a ring comprising a five-membered or six-membered ring and 1-3 heteroaryl groups selected from O, N, and S atoms, wherein the heteroaryl group and the phenyl group are optionally each independently substituted by one or more R0 atoms; preferably, ring A is a five-membered heteroaryl group comprising 1-2 N atoms, wherein the heteroaryl group is optionally substituted by one or more R0 atoms. Q is NR5, and R5 is H, F, Br, Cl, or -OH. R4 is independently selected from unsubstituted or R7-substituted phenyl groups, unsubstituted or R0-substituted six-membered heteroaryl groups containing 1-3 N atoms, and unsubstituted or R0-substituted fused-ring heteroaryl groups containing a six-membered ring and 1-3 N atoms. R7 is C10. 1-3 Alkyl, C 1-3 Alkoxy, amino, F, Br, Cl, hydroxy, cyano, NCH3(CH2)2N(CH3)2, preferably R7 is F, Br, Cl, hydroxy, cyano, NCH3(CH2)2N(CH3)2, and q is 1 or 2.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug, or metabolite, characterized in that, R1 is independent of H, halogen, -CF3, -OCF3, C 1-3 Alkyl, phenyl, pyridyl, C 1-3 Alkoxy or amino, p is 0, 1 or 2. R2 is hydrogen or C. 1-3 alkyl, m is 0; n is 0 or 1, Ring A includes, but is not limited to: ， Q is NR5, and R5 is H, F, Br, Cl, or -OH. R4 is independently selected from: unsubstituted or R7-substituted phenyl, unsubstituted six-membered heteroaryl containing 1-3 N atoms, unsubstituted or R8-substituted fused-ring heteroaryl containing one five-membered ring and one six-membered ring and 1-3 N atoms, unsubstituted or R8-substituted fused-ring heteroaryl containing two six-membered rings and 1-3 N atoms, R7 is F, Br, Cl, hydroxyl, cyano, NCH3(CH2)2N(CH3)2, and R8 is selected from C. 1-3 Alkyl, C 1-3 Alkoxy or amino, q is 1 or 2.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug, or metabolite, characterized in that, R1 is independent of H, halogen, -CF3, -OCF3, C 1-3 Alkyl, phenyl, pyridyl, C 1-3 Alkoxy or amino, p is 0, 1 or 2. R2 is hydrogen or C. 1-3 alkyl, m is 0; n is 0 or 1, Ring A is a five-membered heteroaryl group containing 1-3 N or S atoms; preferably, ring A is optionally substituted with R0. (Thiazole) Q is NR5, and R5 is H, F, Br, Cl, or -OH. R4 is independently selected from: unsubstituted or R7-substituted phenyl groups, C 1-3 Alkyl-substituted benzopyrrole, pyridine, pyrimidine, unsubstituted or R8-substituted benzopyrimidine, pyridopyrimidine, where q is 1 or 2.

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug, or metabolite, characterized in that, R4 is selected independently from: ， ， ， ， ， ， ， ， ， ， 。 9. The compound of claim 7 or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug, or metabolite, characterized in that, p, m, and n are 0, q is 1 or 2, and R2 is H or C. 1-3 Alkyl group, ring A is phenyl or contains a five- or six-membered ring and 1-3 heteroaryl groups selected from O, N, and S atoms, wherein the heteroaryl group and phenyl group are optionally each independently substituted by one or more R0 atoms, Q is NH, R4 is independently selected from unsubstituted or R7-substituted phenyl groups, unsubstituted or R0-substituted six-membered heteroaryl groups containing 1-3 N atoms, unsubstituted or R0-substituted fused-ring heteroaryl groups containing a six-membered ring and 1-3 N atoms, and R7 is C 1-3 Alkyl, C 1-3 Alkyl, amino, F, Br, Cl, hydroxyl, cyano, NCH3(CH2)2N(CH3)2, preferably R7 is F, Br, Cl, hydroxyl, cyano, NCH3(CH2)2N(CH3)2. Preferably, p, m, and n are 0, q is 1 or 2, and R2 is H or C. 1-3 Alkyl group, ring A is a five-membered heteroaryl group containing 1-2 nitrogen atoms, said heteroaryl group optionally substituted by one or more R0 groups, Q is NH, R4 is independently selected from: unsubstituted or R7-substituted phenyl group, unsubstituted six-membered heteroaryl group containing 1-3 nitrogen atoms, unsubstituted or R8-substituted fused-ring heteroaryl group containing one five-membered ring and one six-membered ring and 1-3 nitrogen atoms, unsubstituted or R8-substituted fused-ring heteroaryl group containing two six-membered rings and 1-3 nitrogen atoms, R7 is F, Br, Cl, hydroxyl, cyano, NCH3(CH2)2N(CH3)2, R8 is selected from C 1-3 Alkyl, C 1-3 Alkoxy, amino More preferably, p, m, and n are 0, q is 1, and R2 is H or C. 1-3 Alkyl group, ring A is a five-membered heteroaryl group containing 1-2 nitrogen atoms, Q is NH, and R4 is independently selected from: unsubstituted or R7-substituted phenyl groups, C 1-3 Alkyl-substituted benzopyrroles, pyridines, pyrimidines, unsubstituted or R8-substituted benzopyrimidines, and pyridopyrimidines; More preferably, p, m, and n are 0, R2 is H, q is 1 or 2, and ring A is... (Thiazole), Q is NH, R4 is independently selected from: , , , , , , , , , , .

10. The compound of claim 7 or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug, or metabolite, characterized in that, m and n are 0, p is 1 or 2, q is 1 or 2, R2 is H or C. 1-3 Alkyl group, R1 independently is halogen, -CF3, -OCF3, C 1-3 Alkyl, phenyl, pyridyl, C 1-3 The alkoxy or amino group, ring A being a phenyl group or a group comprising a five- or six-membered ring and 1-3 heteroaryl groups selected from O, N, and S atoms, wherein the heteroaryl group and the phenyl group are optionally each independently substituted by one or more R0 groups, R4 is independently selected from unsubstituted or R7-substituted phenyl groups, unsubstituted or R0-substituted six-membered heteroaryl groups comprising 1-3 N atoms, unsubstituted or R0-substituted fused-ring heteroaryl groups comprising a six-membered ring and 1-3 N atoms, and R7 is C 1-3 Alkyl, C 1-3 Alkyl, amino, F, Br, Cl, hydroxyl, cyano, NCH3(CH2)2N(CH3)2, preferably R7 is F, Br, Cl, hydroxyl, cyano, NCH3(CH2)2N(CH3)2. Preferably, m and n are 0, p is 1 or 2, q is 1 or 2, and R2 is H or C. 1-3 Alkyl group, R1 independently is halogen, -CF3, -OCF3, C 1-3 Alkyl, phenyl, pyridyl, C 1-3 The alkoxy or amino group, ring A being a five-membered heteroaryl group containing 1-2 nitrogen atoms, wherein the heteroaryl group is optionally substituted by one or more R0 groups, and R4 is independently selected from: unsubstituted or R7-substituted phenyl groups, unsubstituted six-membered heteroaryl groups containing 1-3 nitrogen atoms, unsubstituted or R8-substituted fused-ring heteroaryl groups containing one five-membered ring and one six-membered ring and 1-3 nitrogen atoms, and unsubstituted or R8-substituted fused-ring heteroaryl groups containing two six-membered rings and 1-3 nitrogen atoms, wherein R7 is F, Br, Cl, hydroxyl, cyano, or NCH3(CH2)2N(CH3)2, and R8 is selected from C. 1-3 Alkyl, C 1-3 Alkoxy, amino; More preferably, m and n are 0, p is 1 or 2, q is 1 or 2, and R2 is H or C. 1-3 Alkyl group, R1 independently is halogen, -CF3, -OCF3, C 1-3 Alkyl, phenyl, pyridyl, C 1-3 Alkoxy or amino, ring A is a five-membered heteroaryl group containing 1-2 nitrogen atoms, and R4 is independently selected from: unsubstituted or R7-substituted phenyl, C 1-3 Alkyl-substituted benzopyrroles, pyridines, pyrimidines, unsubstituted or R8-substituted benzopyrimidines, and pyridopyrimidines; More preferably, m and n are 0, p is 1 or 2, q is 1 or 2, R2 is H, and R1 is independently a halogen, -CF3, -OCF3, or C. 1-3 Alkyl, phenyl, pyridyl, C 1-3 Alkoxy, amino, and ring A are (Thiazole), R4 is independently selected from: , , , , , , , , , , Preferably, q is 1 and R4 is: or .

11. The compound of claim 1 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug, or metabolite thereof, characterized in that, The compounds of formula (I) are selected from: 。 12. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1-11 or a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a tautomer, a solvate, an isotope substitute, a polymorph, a prodrug or a metabolite, and a pharmaceutically acceptable carrier or excipient.

13. Use of any compound of formula (I) according to any one of claims 1-11, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug, or metabolite thereof, in the preparation of a medicament for the prevention and / or treatment of a disease or condition, said disease or condition being a tumor, cancer, or a proliferative metastatic disease. Preferably, the disease or condition includes tumors, cancers, or metastatic diseases caused by malignant proliferation and induced cell death disorders. More preferably, the disease or condition includes tumors, cancers, or proliferative metastatic diseases associated with EGFR protein mutations. More preferably, the disease or condition includes EGFR protein mutation-related lung cancer, non-small cell lung cancer, rectal cancer, non-melanoma skin cancer, breast cancer, ovarian cancer, prostate cancer, gastric cancer, kidney cancer, liver cancer, cervical cancer, thyroid cancer, leukemia, esophageal cancer, pancreatic cancer, bladder cancer, lymphoma, adenoid cystic carcinoma, bile duct cancer, anal canal cancer, malignant mesothelioma, testicular cancer, malignant embryonal tumor, chordoma, gastrointestinal pancreatic neuroendocrine tumor, adrenocortical carcinoma, and glioblastoma.

14. The use as described in claim 13, characterized in that, EGFR protein mutations include the C797S point mutation.

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