Nitrogen-containing heterocyclic ring compound, preparation method and application

Abstract

The invention discloses a nitrogen-containing heterocyclic ring compound as well as a preparation method and application thereof, and particularly relates to a nitrogen-containing heterocyclic ring compound as shown in a general formula (I), or pharmaceutically acceptable salts thereof, or enantiomers, diastereoisomers, tautomers, torsion isomers, solvates, polymorphic substances or prodrugs thereof, and a preparation method and pharmaceutical application thereof. Wherein the definition of each group is described in the specification.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and in particular, to a class of nitrogen-containing heterocyclic compounds, compounds with inhibitory activity against Ras mutant proteins, methods of preparation and uses. BACKGROUND

[0002] KRAS is a molecular switch. Under normal physiological conditions, the protein is bound to guanosine diphosphate (GDP) and is in the "off state". Upon signaling through epidermal growth factor receptor tyrosine kinases (RTKs) such as the epidermal growth factor receptor, the GDP is exchanged for guanosine triphosphate (GTP), a process facilitated by guanine nucleotide exchange factors (GEFs) such as SOS. KRAS bound to GTP is in the "on state" and interacts with proteins such as RAF and PBK, promoting downstream signaling, leading to cell proliferation and survival. KRAS can slowly hydrolyze GTP back to GDP through GAP (GTPase-activating Proteins), returning to the off state.

[0003] KRAS mutations are found in about 30% of all human cancers and are most prevalent in three of the most deadly cancers: pancreatic (95%), colorectal (45%), and lung (35%). In the United States alone, more than 200,000 people are afflicted with these cancers each year. One particular mutation, the substitution of glycine to cysteine at position 12 (G12C), occurs in more than 40,000 patients each year. The KRAS G12C mutation affects the hydrolysis of GTP to GDP, leaving KRAS in the on state, promoting cancer cell proliferation. The cysteine residue at G12C offers an opportunity to develop targeted covalent drugs against this mutant KRAS. Early clinical trial results with KRAS G12C inhibitors AMG 510 and MRTX849 in non-small cell lung cancer (NSCLC) are encouraging, but these data are not as compelling. Moreover, there are indications that the duration of response can be limited and drug resistance can develop rapidly, even in patients who have responded to initial therapy.

[0004] Most KRAS mutant inhibitors preferentially bind to the protein in the GDP-bound conformation. For example, the KRAS inhibitor AMG 510 from Amgen and the KRAS inhibitor MRTX849 from Mirati react at least 1000-fold faster with the GDP-bound form of KRAS G12C protein than with the GTP-bound form of the protein. One form of resistance that has been observed is that cancer cells increase signaling through RTKs, increasing the amount of GTP-bound KRAS, which is less inhibited by current inhibitors.

[0005] Therefore, it would be of great use to create an inhibitor that binds to and inhibits KRAS that binds to both GDP and GTP. What is needed are compounds that can be used to treat cancer, for example, cancers characterized by KRAS G12C. What is also needed are compounds that can be used to treat cancers characterized by KRAS G12C that act on both inactive GDP-bound and activated GTP-bound KRAS and inhibit both forms. What is also needed are compounds that can be used to treat cancers characterized by KRAS G12C where the compounds have improved inhibition of KRAS G12C in the GTP-bound form. SUMMARY

[0006] One of the technical problems to be solved by the present application is to provide a new G12C inhibitor for preparing a cancer treatment drug. Through long-term and in-depth research, the inventors prepared a new class of nitrogen-containing fused ring compounds with the structure shown in Formula I, and found that they have inhibitory effects on both inactive GDP-bound and activated GTP-bound KRAS G12C, and have improved inhibition of KRAS G12C in the GTP-bound form, and can be used as inhibitors of KRAS G12C in both inactive and activated states. Based on the above findings, the inventors completed the present application.

[0007] The present application solves the above technical problems through the following technical solutions.

[0008] The present application provides a nitrogen-containing heterocyclic compound having the structure shown in general formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereoisomer, tautomer, rotamer, solvate, polymorph or prodrug thereof,

[0009]

[0010] wherein R is selected from hydrogen, deuterium, halogen;

[0011] R 1 selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, amino, hydroxyl, -SH, C 6-10 aryl, 5-10 membered heteroaryl, and the "substituted" means substituted with one or more (preferably 1, 2 or 3) R 11 substituents, R 11 are independently selected from deuterium, halogen, cyano, amino, C 1-4 alkyl, C 1-4 alkoxy, =O, =S, -C 0-4substituted with one or more groups independently selected from deuterium or halogen; 11 optionally further substituted with one or more groups independently selected from deuterium or halogen;

[0012] R 2 is

[0013] wherein n is independently selected from 0, 1, 2, 3, or 4; R a1 are independently selected from H, halogen (preferably F), substituted or unsubstituted -OH, C1-C4alkyl, C1-C4alkoxy, -C1-C4alkyl-OH, amino, or multiple R a1 and the atoms to which they are attached form a 3-6 membered cycloalkyl or heterocycloalkyl; "substituted" means substituted with one, two, or three R a11 substituted, R a11 are independently selected from halogen, -OH, C1-C4alkyl, C1-C4alkoxy, (C 1-3 alkyl)2-N-(CO)-, (C 1-3 alkyl)-NH-(CO)-;

[0014] R 4 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-SF5, C 3-18 cycloalkyl-C 1-6 alkyl-, 3-18 membered heterocyclyl-C 1-6 alkyl-, -C 1-8 alkyl-OH, -C 1-8 alkyl-NH2, -C 0-6 alkyl-(CO)-NH2, -C 0-6 alkyl-(CO)-C 1-6 alkyl, -C 0-6 alkyl-(CO)-O-C 1-6 alkyl, -C 0-6 alkyl-P(O)(C 1-6 alkyl)2, amino, hydroxyl, -SH; "substituted" means substituted with one or more (1, 2, 3, or 4) R 41 substituted, R 41 are independently selected from deuterium, halogen, cyano, amino, 3-6 membered cycloalkyl, 4-8 membered heterocycloalkyl, C 6-10Aryl, 5-10 membered heteroaryl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-CO-, C 1-4 Alkyl-S(O) r -、NH2-S(O) r -; r is independently selected from 0, 1 or 2; said R 41 Optionally further represented by one or more (preferably 1, 2 or 3) R 411 Substituted, the R 411 independently selected from deuterium or halogen;

[0015] Or, R 4 With R 5c and the atoms to which they are connected form a substituted or unsubstituted 5-12 membered heterocyclic ring, wherein the "substituted" refers to being substituted by one or more (1, 2 or 3) groups independently selected from the following: deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 alkyl halide;

[0016] R 5a 、R 5b 、R 5c and R 5d Each is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted amino, hydroxyl, -SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; the "substituted" refers to one or more (1, 2, 3 or 4) R 51 Replacement, R 51 independently selected from deuterium, halogen, cyano, amino, 3-6 membered cycloalkyl, 4-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-CO-, C 1-4 Alkyl-S(O) r -、NH2-S(O) r -; r is independently selected from 0, 1 or 2; said R 51 Optionally further represented by one or more (preferably 1, 2 or 3) R 511 Substituted, the R 511 independently selected from deuterium or halogen;

[0017] R6a R 6b each independently is selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted: 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-12 cycloalkyl-C 1-6 alkyl-, 3-12 membered heterocyclyl-C 1-6 alkyl-, C 1-8 alkoxy, -C 1-8 alkyl-OH, -C 1-8 alkyl-NH2, -C 0-6 alkyl-(CO)-NH2, -C 0-6 alkyl-(CO)-C 0-6 alkyl, -C 0-6 alkyl-(CO)-O-C 0-6 alkyl, -C 0-6 alkyl-P(O)(C 0-6 alkyl)2, amino, hydroxyl, -SH, C 0-4 alkyl-S(O) r -; said "substituted" means substituted with one or more (1, 2, 3, or 4) R 61 substituents, R 61 are independently selected from the group consisting of deuterium, halogen, cyano, amino, 3-6 membered cycloalkyl, 4-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl-CO-, C 1-4 alkyl-S(O) r -, NH2-S(O) r -; r is independently selected from 0, 1, or 2; said R 61 are optionally further substituted with one or more (preferably 1, 2, or 3) R 611 substituents, R 611 are independently selected from deuterium or halogen;

[0018] Y is independently selected from N or CR Y , R Y is selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted: 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl; "substituted" means substituted with one or more (1, 2, 3, or 4) R Y1 substituted, R Y1 is independently selected from the group consisting of deuterium, halogen, cyano, amino, 3-6 membered cycloalkyl, 4-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl-CO-, C 1-4 alkyl-S(O) r -, NH2-S(O) r -; r is independently selected from 0, 1, or 2; R Y1 is optionally further substituted with one or more (preferably 1, 2, or 3) R Y11 substituted, R Y11 is independently selected from the group consisting of deuterium or halogen;;

[0019] Z, M are each independently selected from N, CR Z1 ; each R Z1 is each independently selected from the group consisting of hydrogen, halogen, cyano, deuterium, substituted or unsubstituted C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, "substituted" means substituted with one or more (1, 2, or 3) R Z11 substituted, R Z11 is independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, amino, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 0-4 alkyl-CO-, C 0-4 alkyl-CO-NH-, C 1-4 alkyl-C(O)O-, C 0-4 alkyl-S(O) r -, NH2-S(O) r -, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl;

[0020] Ar is selected from substituted or unsubstituted 5-12 membered aromatic or heteroaromatic ring, "substituted" means Ar is substituted with one or more (preferably 1, 2, 3, 4, or 5) R 3 substituted;

[0021] each R 3 each independently selected from cyano, amino, halogen, deuterium, substituted or unsubstituted: amino, hydroxyl, -SH, C 1-8 alkyl (e.g., methyl), C 1-8 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl (e.g., ethynyl), C 3-12 cycloalkyl (e.g., cyclopropyl), 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-SF5, C 3-12 cycloalkyl-C 1-6 alkyl-, 3-12 membered heterocyclyl-C 1-6 alkyl-, C 1-8 alkoxy, -C 1-8 alkyl-OH, -C 1-8 alkyl-NH2, -C 0-6 alkyl-(CO)-NH2, -C 0-6 alkyl-(CO)-C 1-6 alkyl, -C 0-6 alkyl-(CO)-O-C 1-6 alkyl, -C 0-6 alkyl-P(O)(C 1-6 alkyl)2; "substituted" means substituted with one or more (1, 2, 3, or 4) R 31 substituents, R 31 independently selected from deuterium, halogen, cyano, amino, 3-6 membered cycloalkyl, 4-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl-CO-, C 1-4 alkyl-S(O) r -, NH2-S(O) r -; each r is independently selected from 0, 1, or 2; the R 31 are optionally further substituted with one or more (preferably 1, 2, or 3) R 311 substituents, the R 311 independently selected from deuterium, halogen, or C 1-3 alkyl;

[0022] wherein the heteroatoms in the above heterocycloalkyl (heterocyclyl), heteroaryl (heteroaromatic) are independently selected from N, O, P, S, Se, Si, and different oxidation states thereof, and the number of heteroatoms is independently 1, 2, or 3.

[0023] In some preferred embodiments of the present application, certain groups in the nitrogen-containing fused ring compounds of Formula I, or pharmaceutically acceptable salts or enantiomers, diastereomers, tautomers, rotamers, solvates, polymorphs, or prodrugs thereof, are defined as follows, and the groups not mentioned are as described in any of the aspects of the present application (simply "in some preferred embodiments"),

[0024] In some preferred embodiments, R is independently hydrogen, deuterium, halogen (preferably F).

[0025] In some preferred embodiments, R 1 is selected from the group consisting of hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, amino, hydroxyl, -SH, C 6-8 aryl, 5-8 membered heteroaryl, said "substituted" means substituted with one or more (preferably 1, 2, or 3) R 11 substituents.

[0026] In some preferred embodiments, R 1 is selected from the group consisting of hydrogen, deuterium, F, Cl, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetanyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, methylthio, and ethylthio, said "substituted" means substituted with one or more (preferably 1, 2, or 3) R 11 substituents.

[0027] In some preferred embodiments, R 11 is independently selected from the group consisting of deuterium, halogen (preferably F, Cl).

[0028] In some preferred embodiments, R a1 is independently selected from the group consisting of H, halogen (preferably F), substituted or unsubstituted:

[0029] -OH, C1-C4 alkyl, C1-C4 alkoxy; said "substituted" means substituted with 1, 2, or 3 R a11 substituents.

[0030] In some preferred embodiments, R a11 is independently selected from the group consisting of halogen, -OH, C1-C3 alkyl, C1-C3 alkoxy, (C 1-3 alkyl)2-N-(CO)-, (C 1-3 alkyl)-NH-(CO)-;

[0031] In some preferred embodiments, R a11 Independently selected from F, Cl, -OH, methyl, methoxy, methoxymethyl, (methyl)2-N-(CO)-, (methyl)-NH-(CO)-.

[0032] In some preferred embodiments, R 2 Selected from the following structures:

[0033]

[0034] In some preferred embodiments, R 2 Selected from

[0035] In some preferred embodiments, R 4 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-9 Aryl, 5-9 membered heteroaryl, -C 0-4 Alkyl-SF5, C 3-6 Cycloalkyl-C 1-4 Alkyl-, 3-6 membered heterocyclic-C 1-4 Alkyl-, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-NH2, -C 0-3 Alkyl-(CO)-NH2, -C 0-3 Alkyl-(CO)-C 1-3 Alkyl, -C 0-3 Alkyl-(CO)-OC 1-3 Alkyl, -C 0-3 Alkyl-P(O)(C 1-3 alkyl) 2, amino, hydroxy, -SH; the "substituted" refers to one or more (1, 2, 3 or 4) R 41 replace.

[0036] In some preferred embodiments, R 4 Selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted groups: amino, hydroxyl, -SH, C 1-4 Alkyl, C 1-4 Alkoxy, (C 1-4 Alkyl)NH-, (C 1-4 Alkyl) 2NH-, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6cycloalkyl, 3-6 membered heterocyclyl; said "substituted" means substituted with one or more (1, 2, 3, or 4) R 41 substituted.

[0037] In some preferred embodiments, R 4 is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C 1-4 alkyl, C 1-4 alkoxy; said "substituted" means substituted with one or more (1, 2, 3, or 4) R 41 substituted.

[0038] In some preferred embodiments, R 4 is selected from hydrogen, deuterium, F, Cl, cyano, substituted or unsubstituted methoxy, ethoxy, methyl, ethyl; said "substituted" means substituted with one or more (1, 2, 3, or 4) R 41 substituted.

[0039] In some preferred embodiments, R 41 is independently selected from deuterium, halogen, cyano, amino, 3-4 membered cycloalkyl, 4-6 membered heterocycloalkyl, C 6-9 aryl, 5-9 membered heteroaryl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkyl-CO-, C 1-3 alkyl-S(O) r -, NH2-S(O) r -; r is independently selected from 0, 1, or 2; said R 41 is optionally further substituted with one or more (preferably 1, 2, or 3) R 411 substituted.

[0040] In some preferred embodiments, R 411 is independently selected from deuterium or halogen.

[0041] In some preferred embodiments, R 41 is independently selected from deuterium, halogen, C 1-3 alkyl, C 1-3 alkoxy, said R 41 is optionally further substituted with one or more (preferably 1, 2, or 3) R 411 substituted.

[0042] In some preferred embodiments, R 4 forms, together with R 5c and the atom to which they are attached, a substituted or unsubstituted 6-9 membered heterocyclic ring.

[0043] In some preferred embodiments, when R 4 forms, together with R5c and the atom to which they are attached form a substituted or unsubstituted heterocycle, "substituted" meaning substituted with one or more (1, 2, or 3) groups independently selected from deuterium, halogen, cyano, hydroxyl, C 1-3 alkyl, C 1-3 haloalkyl.

[0044] In some preferred embodiments,

[0045] In some preferred embodiments, R 4 is selected from hydrogen, F, Cl, methyl, ethyl, methoxy, ethoxy, deutero-methoxy, deutero-ethoxy.

[0046] In some preferred embodiments, R 5a , R 5b , R 5c , and R 5d are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted: amino, hydroxyl, -SH, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-9 aryl, 5-9 membered heteroaryl; "substituted" meaning substituted with one or more (1, 2, 3, or 4) R 51 substituents.

[0047] In some preferred embodiments, R 5a , R 5b , R 5c , and R 5d are each independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted: amino, hydroxyl, -SH, C 1-4 alkyl, C 1-4 alkoxy; "substituted" meaning substituted with one or more (1, 2, 3, or 4) R 51 substituents.

[0048] In some preferred embodiments, R 51 is independently selected from deuterium, halogen, cyano, amino, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, C 6-9 aryl, 5-9 membered heteroaryl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkyl-CO-, C 1-3 alkyl-S(O) r -, NH2-S(O) r; r is independently selected from 0, 1 or 2; said R 51 optionally further substituted by one or more (preferably 1, 2 or 3) R 511 substituents.

[0049] In some preferred embodiments, R 511 is independently selected from deuterium or halogen (preferably F, CI).

[0050] In some preferred embodiments, R 51 is independently selected from deuterium, halogen, C 1-3 alkyl, C 1-3 alkoxy.

[0051] In some preferred embodiments, R 5a , R 5b , R 5c and R 5d are each independently selected from hydrogen, F, CI, cyano, methyl, methoxy.

[0052] In some preferred embodiments, R 6a , R 6b are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-9 aryl, 5-9 membered heteroaryl, C 3-6 cycloalkyl-C 1-3 alkyl-, 3-6 membered heterocyclyl-C 1-3 alkyl-, C 1-6 alkoxy, -C 1-6 alkyl-OH, -C 1-6 alkyl-NH2, -C 0-4 alkyl-(CO)-NH2, -C 0-4 alkyl-(CO)-C 0-3 alkyl, -C 0-4 alkyl-(CO)-O-C 0-3 alkyl, -C 0-4 alkyl-P(O)(C 0-3 alkyl)2, amino, hydroxyl, -SH, C 0-4 alkyl-S(O) r ; said "substituted" means substituted with one or more (1, 2, 3 or 4) R 61 substituents.

[0053] In some preferred embodiments, R 6a , R 6beach independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, substituted or unsubstituted: hydroxy, amino, C 1-6 alkyl; "substituted" means substituted with one or more (1, 2, 3, or 4) R 61 substituents.

[0054] In some preferred embodiments, R 6a , R 6b are independently selected from the group consisting of hydrogen, deuterium, halogen, substituted or unsubstituted: methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, oxetanyl, azetanyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy and cyclobutoxy, oxetanyl-CH2-, cyclopropyl-CH2-, pyrrolyl-CH2-, -(CO)-O-CH3, CH3-O-CH2-, CH3-SO2-CH2-, -CH2-NH2, -(CO)-CH3, -CO-NH2, -CH2-SH; "substituted" means substituted with one or more (1, 2, 3, or 4) R 61 substituents.

[0055] In some preferred embodiments, R 61 are independently selected from the group consisting of deuterium, halogen, cyano, amino, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, C 6-9 aryl, 5-9 membered heteroaryl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl-CO-, C 1-4 alkyl-S(O) r -, NH2-S(O) r -; r is independently selected from 0, 1, or 2; said R 61 are optionally further substituted with one or more (preferably 1, 2, or 3) R 611 substituents.

[0056] In some preferred embodiments, R 61 are independently selected from the group consisting of deuterium, halogen, cyano, amino, methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, oxetanyl, azetanyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy and cyclobutoxy; said R 61 are optionally further substituted with one or more (preferably 1, 2, or 3) R 611 substituents.

[0057] In some preferred embodiments, said R 611 are independently selected from the group consisting of deuterium or halogen (preferably F, Cl).

[0058] In some preferred embodiments, R 61 Independently selected from deuterium, F, Cl, cyano.

[0059] In some preferred embodiments, R 6a 、R 6b Each is independently selected from hydrogen, methyl, ethyl, cyanomethyl, and cyanoethyl.

[0060] In some preferred embodiments, Y is independently selected from N or CR Y , R Y is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted groups: C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-5 Cycloalkyl, 3-6 membered heterocyclic group, C 6-9 Aryl, 5-9 membered heteroaryl.

[0061] In some preferred embodiments, R Y1 are independently selected from deuterium, halogen, cyano, amino, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, C 6-9 Aryl, 5-9 membered heteroaryl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkyl-CO-, C 1-3 Alkyl-S(O) r -、NH2-S(O) r -; r is independently selected from 0, 1 or 2; said R Y1 Optionally further represented by one or more (preferably 1, 2 or 3) R Y11 Substituted, the R Y11 are independently selected from deuterium or halogen.

[0062] In some preferred embodiments, Y is independently selected from N or CR Y , R Y Selected from hydrogen, deuterium, halogen (preferably F, Cl).

[0063] In some preferred embodiments, Z is N, M is N; Z is CR Z1 , M is N; Z is N, M is CR Z1 ; or Z is CR Z1 , M is CR Z1 ;

[0064] In some preferred embodiments, each R Z1 are each independently selected from hydrogen, halogen, cyano, deuterium, substituted or unsubstituted groups: C 1-3alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-9 aryl, 5-9 membered heteroaryl; said "substituted" means substituted with one or more (1, 2, or 3) R Z11 substituents.

[0065] In some preferred embodiments, R Z11 is independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, amino, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, C 0-3 alkyl-CO-, C 0-3 alkyl-CO-NH-, C 1-3 alkyl-C(O)O-, C 0-3 alkyl-S(O) r -, NH2-S(O) r -, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-9 aryl, 5-9 membered heteroaryl.

[0066] In some preferred embodiments, each R Z1 is each independently selected from the group consisting of hydrogen, F, Cl, cyano, deuterium, substituted or unsubstituted C 1-4 alkyl, C 1-4 alkoxy.

[0067] In some preferred embodiments, Z, M are each independently selected from the group consisting of N, -C-Cl, -C-F, -C-CN.

[0068] In some preferred embodiments, Ar is selected from the group consisting of substituted or unsubstituted 6-10 membered aromatic or aromatic heterocyclic ring, more preferably substituted or unsubstituted phenyl, pyridyl, naphthyl, benzopyridyl, benzothiazolyl, benzothienyl, benzimidazolyl; said "substituted" means Ar is substituted with one or more (preferably 1, 2, 3, 4, or 5) R 3 substituents.

[0069] In some preferred embodiments, Ar is selected from the group consisting of the following structures:

[0070]

[0071] wherein t is independently selected from 0, 1, 2, 3, 4, or 5; R3is as defined elsewhere herein.

[0072] In some preferred embodiments, each R 3each independently selected from the group consisting of cyano, amino, halogen, deuterium, substituted or unsubstituted: amino, hydroxy, -SH, C 1-6 alkyl(methyl), C 1-6 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl(ethynyl), C 3-6 cycloalkyl(cyclopropyl), 3-6 membered heterocyclyl, C 6-9 aryl, 5-9 membered heteroaryl, -C 0-4 alkyl-SF5, C 3-6 cycloalkyl-C 1-3 alkyl-, 3-6 membered heterocyclyl-C 1-3 alkyl-, C 1-6 alkoxy, -C 1-6 alkyl-OH, -C 1-6 alkyl-NH2, -C 0-4 alkyl-(CO)-NH2, -C 0-4 alkyl-(CO)-C 1-3 alkyl, -C 0-4 alkyl-(CO)-O-C 1-3 alkyl, -C 0-4 alkyl-P(O)(C 1-3 alkyl)2; "substituted" means substituted with one or more (1, 2, 3, or 4) R 31 substituents.

[0073] In some preferred embodiments, R 31 are independently selected from the group consisting of deuterium, halogen, cyano, amino, 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl, C 6-9 aryl, 5-9 membered heteroaryl, -C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkyl-CO-, C 1-3 alkyl-S(O) r -, NH2-S(O) r -; each r is independently selected from 0, 1, or 2; said R 31 are optionally further substituted with one or more (preferably 1, 2, or 3) R 311 substituents, said R 311 are independently selected from the group consisting of deuterium, halogen, or C 1-3 alkyl.

[0074] In some preferred embodiments, R 31 are independently selected from the group consisting of halogen, amino, cyano, hydroxy, ethynyl, cyclopropyl, methyl, trifluoromethyl.

[0075] In some preferred embodiments, Ar is selected from the group consisting of the following structures:

[0076]

[0077] In some preferred embodiments, Ar is selected from:

[0078] In some preferred embodiments, R, R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 5c , R 5d , R 6a , R 6b , Y, Z, M, Ar are each independently as the corresponding group in the compounds of the respective embodiments.

[0079] In some preferred embodiments, the compound of formula (I) has the structure,

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087] Throughout this specification, the skilled person can select the groups and substituents thereof described in the nitrogen-containing heterocyclic compounds of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph or prodrug thereof, to provide a stable nitrogen-containing heterocyclic compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph or prodrug thereof, including but not limited to the compounds described in the embodiments of the application.

[0088] The nitrogen-containing heterocyclic compound of Formula I, or a pharmaceutically acceptable salt, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph or prodrug thereof, can be synthesized by methods comprising similar methods known in the art, and the steps and conditions can refer to the steps and conditions of similar reactions in the art, and in particular, according to the description herein. The starting materials are generally obtained from commercial sources, such as Aldrich, or can be readily prepared by methods known to those skilled in the art (available through SciFinder, Reaxys online databases).

[0089] In the present application, the nitrogen-containing heterocyclic compound of Formula I, or a pharmaceutically acceptable salt, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph or prodrug thereof, can also be obtained by further modifying the nitrogen-containing heterocyclic compound of Formula I, or a pharmaceutically acceptable salt, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph or prodrug thereof, which has been prepared, using conventional methods in the art.

[0090] Generally, the compounds of the present application can be prepared by the methods described herein, unless otherwise indicated, wherein the substituents are as defined in Formula I. The following reaction schemes and examples are intended to further illustrate the present application.

[0091] The present application also provides a preparation method of the nitrogen-containing heterocyclic compound of Formula I, which comprises steps a-d:

[0092] a) substituting the compound of general formula (A) with a bridged compound under basic conditions to form a compound of general formula (B);

[0093] b) substituting the compound of general formula (B) with R 2 -L-H under basic conditions or metal-catalyzed coupling reaction to form a compound of general formula (C);

[0094] c) coupling the compound of general formula (C) with aryl boronic acid or aryl boronic acid ester or aryl metal reagent (R3-Ar-M) by transition metal-catalyzed coupling reaction to form a compound of general formula (D).

[0095] d) reacting the compound of general formula (D) with acyl chloride or carboxylic acid under the catalysis of base or (and) the action of condensing agent to form a compound of general formula (I).

[0096]

[0097] X is halogen, LG, LG1is a leaving group, Pg is a protecting group on the amino group, such as t-butyl carbonate, benzyl carbonate, benzyl and the like. The definitions of the other groups are as described above;

[0098] Preferably, each of the steps a), b), c), d) is carried out in a solvent, and the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, butanol, ethylene glycol, ethylene glycol methyl ether, N-methyl pyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or combinations thereof.

[0099] Preferably, the inorganic base is selected from the group consisting of sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, or combinations thereof; the organic base is selected from the group consisting of pyridine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), lithium hexamethyldisilyl, sodium hexamethyldisilyl, dimethylpyridine, or combinations thereof.

[0100] Preferably, the transition metal catalyst is selected from the group consisting of tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), palladium acetate, palladium chloride, dichlorobis(triphenylphosphine)palladium, palladium trifluoroacetate, palladium acetate triphenylphosphine, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, bis(trio-tolylphosphine)dichloropalladium, 1,2-bis(diphenylphosphino)ethanedichloropalladium, or combinations thereof; the catalyst ligand is selected from the group consisting of tri-tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate, tri-n-butylphosphine, triphenylphosphine, tri-p-tolylphosphine, tricyclohexylphosphine, tri-o-tolylphosphine, or combinations thereof.

[0101] The necessary starting materials or reagents for preparing the compounds of Formula I can be commercially available or prepared by synthetic methods known in the art. The compounds of the present application can be prepared as free bases or as acid addition salts thereof by the methods described in the Experimental Section below. The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt as defined herein and has all the pharmaceutical activities of the parent compound. The pharmaceutically acceptable salts can be prepared by treating the free base with the appropriate organic or inorganic acid in a suitable organic solvent according to conventional methods. Examples of salt formation include: salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; and salts with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid or trifluoromethylacetic acid.

[0102] The nitrogen-containing heterocyclic compounds of Formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph or prodrug thereof, can have one or more chiral carbon atoms and thus can be isolated as optically pure isomers, such as pure enantiomers, or as racemates, or as mixtures of isomers. Pure single isomers can be obtained by separation methods known in the art, such as chiral crystallization or chiral preparative column separation.

[0103] The chemicals used in the synthetic routes described in the present patent, including solvents, reagents, catalysts and protecting groups, deprotecting groups. The above methods can further include additional steps before or after the steps specifically described herein, and appropriate protecting groups can be added or removed to obtain the target compounds. In addition, various synthetic steps can be interchanged or sequential to obtain the final target product.

[0104] Another object of the present application is to provide a medicament for treating or preventing tumors and a composition thereof. The technical solutions for achieving the above object are as follows:

[0105] The present application provides a pharmaceutical composition Z comprising an effective amount of the nitrogen-containing heterocyclic compound of Formula I, or a pharmaceutically acceptable salt, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph or prodrug thereof, and a pharmaceutically acceptable carrier (pharmaceutical excipient). For example, the pharmaceutical composition can comprise one or more additional nitrogen-containing heterocyclic compounds of Formula I, or a pharmaceutically acceptable salt, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph or prodrug thereof. In the pharmaceutical composition, the nitrogen-containing heterocyclic compound of Formula I, or a pharmaceutically acceptable salt, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph or prodrug thereof, can be present in a therapeutically effective amount.

[0106] The present application provides a pharmaceutical composition Z for treating tumors, which comprises the nitrogen-containing heterocyclic compound of Formula I, or a pharmaceutically acceptable salt, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph or prodrug thereof, and a pharmaceutically acceptable carrier.

[0107] Another object of the present application is to provide a use of the compound of Formula I or the pharmaceutical composition Z. The technical solution to achieve the above object is as follows:

[0108] The present application also provides a use of the nitrogen-containing heterocyclic compound of Formula I, or a pharmaceutically acceptable salt, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph or prodrug thereof, or the pharmaceutical composition Z in the preparation of a Ras mutant protein inhibitor. In the use, the Ras mutant protein can be KRAS G12c ; the Ras mutant protein inhibitor can be used in vivo in a mammalian organism; it can also be used in vitro, mainly as an experimental use, for example, as a standard or control sample to provide a comparison, or prepared into a kit according to the conventional method in the art, to provide a rapid detection of the inhibitory effect of the Ras mutant protein.

[0109] The present application also provides a use of the nitrogen-containing heterocyclic compound of Formula I, or a pharmaceutically acceptable salt, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph or prodrug thereof, or the pharmaceutical composition Z in the preparation of a drug. The drug can be a drug for treating a disease related to the activity or expression amount of a Ras mutant protein; or the drug can be a drug for treating tumors. The Ras mutant protein can be KRAS G12cThe tumor can be independently selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, stomach cancer, intestinal cancer, bile duct cancer, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, kidney cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer, pancreatic cancer, etc.

[0110] Another aspect of the present application relates to a method for preventing and / or treating a disease related to Ras mutant protein activity or expression amount, which comprises administering to a patient a therapeutically effective dose of the nitrogen-containing heterocyclic compound of Formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph or prodrug thereof, or a pharmaceutical composition Z.

[0111] Another aspect of the present application relates to a method for preventing and / or treating a tumor, which comprises administering to a patient a therapeutically effective dose of the nitrogen-containing heterocyclic compound of Formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph or prodrug thereof, or a pharmaceutical composition Z.

[0112] Another aspect of the present application relates to a medicament for preventing and / or treating a disease related to Ras mutant protein activity or expression amount, or a tumor, which comprises the nitrogen-containing heterocyclic compound of Formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph or prodrug thereof, or a pharmaceutical composition Z.

[0113] The pharmaceutical excipient can be those widely used in the field of pharmaceutical production. The excipient is mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide a method for allowing the active ingredient to be dissolved at a desired rate after administration to a subject, or to facilitate effective absorption of the active ingredient after administration of the composition to a subject. The pharmaceutical excipient can be an inert filler, or provide a certain function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredient of the composition. The pharmaceutical excipient can include one or more of the following excipients: binders, suspending agents, emulsifying agents, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavorings and sweeteners.

[0114] Substances which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylate, waxes, polyethylene-polyoxypropylene- block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, phosphate buffer solutions, and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions, according to the judgment of the formulator.

[0115] The pharmaceutical compositions of the present application can be manufactured in any manner known to one of skill in the art according to the disclosure. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.

[0116] The pharmaceutical dosage forms of the present application can be provided in the form of immediate release, controlled release, sustained release or targeted drug release systems. For example, common dosage forms include solutions and suspensions, (micro)emulsions, ointments, gels and patches, liposomes, tablets, dragees, soft or hard shell capsules, suppositories, ovules, implants, amorphous or crystalline powders, aerosols and lyophilized formulations. Depending on the route of administration used, special devices can be required to apply or administer the drug, such as syringes and needles, inhalers, pumps, injection pens, applicators or special flasks. Pharmaceutical dosage forms often consist of the drug, excipients and a container / sealing system. One or more excipients (also known as inactive ingredients) can be added to the compounds of the present application to improve or facilitate the manufacture, stability, administration and safety of the drug, and can provide a means to obtain the desired drug release profile. Thus, the type of excipients added to the drug can depend on various factors, such as the physical and chemical properties of the drug, the route of administration and the preparation steps.

[0117] Pharmaceutical dosage forms of the compounds of the present application can be manufactured by any of the methods well-known in the art, e.g., by conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tabletting, suspending, extruding, spray-drying, sifting, emulsifying, (nano / micro)encapsulating, pan-coating, or lyophilizing processes. As described above, the compositions of the present application can include one or more physiologically acceptable non-active ingredients that facilitate processing of the active molecules into preparations for medical use.

[0118] The pharmaceutical compositions of the present application can be administered topically or systemically, e.g., for enteral administration, such as rectal or oral administration, or for parenteral administration to mammals, especially humans, and include a therapeutically effective amount of a compound according to the present application, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as an active ingredient, together with a pharmaceutically acceptable excipient, such as a pharmaceutically acceptable carrier. The therapeutically effective amount of the active ingredient is as defined above and below and depends on the species, body weight, age, individual condition, individual pharmacokinetic parameters of the mammal, the disease to be treated, and the mode of administration. For enteral administration, such as oral administration, the compounds of the present application can be formulated into a wide variety of dosage forms.

[0119] The pharmaceutical compositions and dosage forms can contain one or more compounds of the present application, stereoisomers thereof, or one or more pharmaceutically acceptable salts thereof as active ingredients. The pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, caplets, cachets, suppositories, and dispersible granules. A solid carrier can also be one or more substances which can also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally includes fine division solids, which are used in combinations with the active compound. In tablets, the active ingredient is generally mixed with the carrier materials and, if necessary, with any of the following: binders, lubricants, diluents, disintegrating agents, or wetting agents. Examples of binders include, but are not limited to, corn starch, wet corn starch, gelatine, methylcellulose, hydroxypropylmethylcellulose, magnesium aluminium silicate, and polyvinylpyrrolidone. Examples of diluents include, but are not limited to, lactose, sucrose, dextrose, mannitol, sorbitol, cellulose, acacia, kaolin, calcium carbonate, sodium chloride, and dry starch. Examples of lubricants include, but are not limited to, magnesium stearate, stearic acid, sodium stearyl fumarate, and talc. Examples of disintegrating agents include, but are not limited to, starch, methylcellulose, guar gum, and sodium starch glycolate. Examples of wetting agents include, but are not limited to, propylene glycol monostearate, talc, and sodium dodecyl sulphate. Examples of encapsulating materials include, but are not limited to, gelatine, hydroxpropylmethylcellulose, and starch.

[0120] Other forms adapted for oral administration include liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations. Emulsions can be prepared in solutions, for example, in aqueous propylene glycol solutions or can contain emulsifying agents, such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with a surfactant to aid suspension. Solid form preparations include solutions, suspensions, and emulsions, for example, for reconstitution before use. They can contain colorants, flavors, stabilizing, buffering, artificial and natural

[0121] Exemplary compositions for rectal administration include suppositories, which can be prepared from a mixture of the active ingredient and a non-irritating excipient such as a cocoa butter, synthetic glyceride, or a polyethylene glycol which is solid at ordinary temperatures but liquid at rectal temperatures and will therefore melt in the rectum to release the drug.

[0122] The compounds of the present application can also be administered parenterally, e.g., by inhalation, injection, or infusion, such as intravenous, intraarterial, intraosseous, intramuscular, intracerebral, intracerebroventricular, intrasynovial, intrasternal, intrathecal, intralesional, intracranial, intratumoral, intradermal, and subcutaneous injection or infusion.

[0123] Thus, for parenteral administration, the pharmaceutical composition of the present application can be in the form of a sterile injectable or infusible solution or suspension in a non-toxic parenterally acceptable diluent or solvent. For example, the pharmaceutical composition can be in the form of a solution in 1,3-butanediol. Other examples of acceptable vehicles and solvents that can be used in the pharmaceutical compositions of the present application include, but are not limited to, mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant. Solutions for parenteral use can also include suitable stabilizing agents, and if desired, buffer substances. Suitable stabilizing agents include antioxidants such as, singly or in combination, sodium sulfite, sodium bisulfite or ascorbic acid, citric acid and its salts, and EDTA sodium salt. Parenteral solutions can also contain preservatives such as benzalkonium chloride, methyl or propyl p-hydroxybenzoate, and chlorobutanol.

[0124] For inhalation or nasal administration, the suitable pharmaceutical formulations are in the form of a room particle, aerosol, powder, mist or droplet, for example, having an average size of about 10 microns or less in diameter. For example, compositions for inhalation can be prepared in the form of a solution in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubility or dispersibility enhancers known in the art.

[0125] The pharmaceutical composition of the present application can also be administered topically to the skin or mucosa. For topical application, the pharmaceutical composition can be, for example, in the form of a lotion, gel, paste, tincture, transdermal patch, gel for transmucosal delivery.

[0126] The pharmaceutical composition can be in the form of a suitable ointment containing the active ingredient suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this application include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated in a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical composition of the present application can also be administered rectally via a suppository formulation or suitable enema formulation to be applied locally in the lower intestinal tract.

[0127] It should be understood that, in the scope of the present application, the above technical features of the present application and the technical features specifically described hereinafter (e.g. in the examples) can be combined with each other to form new or preferred technical solutions. Due to the limited space, they are not listed one by one here.

[0128] The term

[0129] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of the application belongs. All patents, patent applications, published materials referred to throughout the entire disclosure herein, unless otherwise indicated, are incorporated by reference herein in their entirety.

[0130] It should be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that as used herein and in the appended claims, the singular forms "a", "an" and "the" include plural reference unless the context clearly dictates otherwise. It should also be noted that the term "or" as used herein is equivalent to the term "and / or", unless the context clearly indicates otherwise. In addition, the use of the term "including" as well as other forms such as "contain", "comprise", and "comprises" is not limiting.

[0131] Definitions of standard chemical terminology can be found in reference works, including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods used in the field of synthetic organic chemistry, medicinal chemistry, and related chemical arts were employed in the examples. Unless specifically defined, the terms used in the description of analytical chemistry, organic synthetic chemistry, and related descriptions of drugs and medicinal chemistry are known in the art. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. For example, reactions and purification can be performed utilizing the instructions provided by manufacturers of reagents, or according to methods well known in the art or as described herein. The foregoing techniques and procedures can be readily implemented by the skilled artisan in light of the teachings of the present specification and the numerous exemplary embodiments described herein. In the specification, groups and substituents thereof can be chosen by one of ordinary skill in the art to provide a stable structure and compound.

[0132] When a substituent is described as being "optionally substituted" or "substituted" it can be unsubstituted or substituted with one or more of the same or different substituents. When a substituent is described as being "optionally substituted" or "substituted" it can be unsubstituted or substituted with one or more of the same or different substituents. When a substituent is described as being "optionally substituted" or "substituted" it can be unsubstituted or substituted with one or more of the same or different substituents. When a substituent is described as being "optionally substituted" or "substituted" it can be unsubstituted or substituted with one or more of the same or different substituents. When a substituent is described as being "optionally substituted" or "substituted" it can be unsubstituted or substituted with one or more of the same or different substituents. When a substituent is described as being "optionally substituted" or "substituted" it can be unsubstituted or substituted with one or more of the same or different substituents. When a substituent is described as being "optionally substituted" or "substituted" it can be unsubstituted or substituted with one or more of the same or different substituents. When a substituent is described as being "optionally substituted" or "substituted" it can be unsubstituted or substituted with one or more of the same or different substituents. When a substituent is described as being "optionally substituted" or "substituted" it can be unsubstituted or substituted with one or more of the same or different substituents. When a substituent is described as being "optionally substituted" or "substituted" it can be unsubstituted or substituted with one or more of the same or different substituents. When a substituent is described as being "optionally substituted" or "substituted" it can be unsubstituted or substituted with one or more of the same or different substituents. When a substituent is described as being "optionally substituted" or "substituted" it can be unsubstituted or substituted with one or more of the same or different substituents. When a substituent is described as being "optionally substituted" or "substituted" it can be unsubstituted or substituted with one or more of the same or different substituents. When a substituent is described as being "optionally substituted" or "substituted" it can be unsubstituted or substituted with one or more of the same or different substituents. When a substituent is described as being "optionally substituted" or "substituted" it can be unsubstituted or substituted with one or more of the same or different substituents. When a substituent is described as being "optionally substituted" or "substituted" it can be unsubstituted or substituted with one or more of the same or different substituents. When a substituent is described as being "optionally substituted" or "substituted" it can be unsubstituted or substituted with one or more of the same or different substituents.

[0133] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents or other similar documents cited in this application, including but not limited to patents, patent applications, articles, books, treatises, and webpages, are hereby incorporated by reference in their entirety.

[0134] Certain chemical groups defined herein are preceded by a simplifying symbol to indicate the total number of carbon atoms present in the group. For example, C1-6alkyl, C 1-6 alkyl or C 1- C6alkyl means an alkyl group as defined below having a total of 1 to 6 (1, 2, 3, 4, 5, or 6) carbon atoms. The total number of carbon atoms in the simplifying symbol does not include carbon that can be present in substituents of the group.

[0135] In this text, numerical ranges defined in substituents, such as 0 to 4, 1-4, 1 to 3, etc., mean the integers within the range, such as 1-6 is 1, 2, 3, 4, 5, 6.

[0136] In parts of the application, connecting substituents are described. When the structure clearly requires a connecting group, the Markush variable listed for that group is to be understood as the connecting group. For example, if the structure requires a connecting group and the Markush group definition listed for that variable lists "alkyl" or "aryl", then it is to be understood that the "alkyl" or "aryl" respectively stands for a connected alkylene group or arylene group.

[0137] In some specific structures, when an alkyl group is clearly indicated as a connecting group, then the alkyl group stands for a connected alkylene group, for example, C1-C6alkyl in the group "halo-C1-C6alkyl" is to be understood as C1-C6alkylene (e.g. methylene, ethylene, propylene, butylene, pentylene, isopropylene, isobutylene, sec-butylene, t-butylene, iso-pentylene, 2-methylbutylene, 1-methylbutylene, 1-ethylpropylene, 1,2-dimethylpropylene, neopentylene, or 1,1-dimethylpropylene, etc.).

[0138] In addition to the foregoing, the following terms have the following meanings as indicated below, when used in the specification and claims of this application, unless specifically indicated otherwise.

[0139] The term "comprising" is a open-ended term, i.e. it includes what the invention specifically mentions, but not excluding other aspects.

[0140] The term "substituted" means that any one or more hydrogen atoms on the particular atom is replaced with a substituent group, including deuterium and variants of hydrogen, as long as the valency of the particular atom is not normally and the substituted compound is stable.

[0141] In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Further, when a group is substituted with more than one of such substituents, the substituents are independent of each other, i.e., the substituents can be the same or different. Unless otherwise indicated, a substituent group can be substituted at any available substitutable position. When more than one position in a given structure can be substituted with one or more substituents selected from a particular group, the substituents can be the same or different at each position.

[0142] Throughout the specification, substituents of compounds disclosed herein are disclosed by reference to a group or substructure. It is specifically intended that the invention include each and every independent combination of members of the groups and substructures disclosed herein. For example, the term "C1-C6alkyl" or "C1-C6alkyl" specifically includes methyl, ethyl, C3alkyl, C4alkyl, C5alkyl, and C6alkyl, independently disclosed. Similarly, the term "C1-C6alkyl" specifically includes methyl, ethyl, C3alkyl (i.e., propyl, including n-propyl and isopropyl), C4alkyl (i.e., butyl, including n-butyl, isobutyl, sec-butyl, and t-butyl), independently disclosed. 1-6 The term "alkyl" specifically includes methyl, ethyl, C3alkyl (i.e., propyl, including n-propyl and isopropyl), C4alkyl (i.e., butyl, including n-butyl, isobutyl, sec-butyl, and t-butyl), independently disclosed. 1-4 The term "alkyl" specifically includes methyl, ethyl, C3alkyl (i.e., propyl, including n-propyl and isopropyl), C4alkyl (i.e., butyl, including n-butyl, isobutyl, sec-butyl, and t-butyl), independently disclosed.

[0143] In this application, the term "halogen" designates fluorine, chlorine, bromine, or iodine; "hydroxy" designates the -OH group; "hydroxyalkyl" designates an alkyl group as defined below, substituted with a hydroxy (-OH) group; "carbonyl" designates the -C(=O)- group; "nitro" designates -NO2; "cyano" designates -CN; "amino" designates -NH2; "substituted amino" designates an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, e.g., monoalkylamino, dialkylamino, alkylamido, aralkylamino, heteroaralkylamino; "carboxy" designates -COOH; "acyl" designates the -C(=O)H group; "sulfone" designates the -S(=O)2- group; "sulfoxide" designates the -S(=O)- group; "sulfonyl" designates the -S(=O)2H group; "urea" designates -NH-C(=O)-NH2; "sulfonylurea" designates the -S(=O)2-NH-C(=O)-NH2 group; "alkoxy" designates an alkyl-O- group as defined below.

[0144] In the present application, the term "alkyl" as a group or part of a group (for example in groups such as halo-substituted alkyl etc.) means a straight or branched chain hydrocarbon group having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, consisting solely of carbon and hydrogen atoms, having no unsaturation, and being attached to the rest of the molecule by a single bond. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, decyl, and the like.

[0145] The term "alkylene" as used herein means a saturated, branched or straight chain or cyclic hydrocarbon group of the number of carbon atoms indicated (typically 1-6 carbon atoms) and having two monovalent radical centres derived from removal of two hydrogen atoms from the same or two different carbon atoms of the parent alkane. Typical alkylene groups include, but are not limited to, methylene (-CH2-), ethylene {including 1,2-ethylene (-CH2CH2-), 2,2-dimethylene (-CH(CH3)-)}, propylene {including 2-methylpropylene (-CH(CH3)CH2-), isopropylene (-C(CH3)2-), 1,3-propylene (-CH2CH2CH2-)}, butylene {including 1,4-butylene (-CH2CH2CH2CH2-)}.

[0146] In the present application, the term "alkenyl" as a group or part of a group means a straight or branched chain hydrocarbon group having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms, containing at least one double bond, consisting solely of carbon and hydrogen atoms, and being attached to the rest of the molecule by a single bond, for example, but not limited to, ethenyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl, and the like.

[0147] In the present application, the term "alkynyl" as a group or part of a group means a straight or branched chain hydrocarbon group having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms, containing at least one triple bond and optionally one or more double bonds, consisting solely of carbon and hydrogen atoms, and being attached to the rest of the molecule by a single bond, for example, but not limited to, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1- en-4-ynyl, and the like.

[0148] In the present application, the term "cycloalkyl" as a group or part of a group refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting solely of carbon and hydrogen atoms, which can include fused ring systems, bridged ring systems or spirocyclic ring systems, having from 3 to 15 carbon atoms, preferably having from 3 to 10 carbon atoms, more preferably having from 3 to 8 carbon atoms, and which is saturated or unsaturated and can be attached through a single bond via any suitable carbon atom to the rest of the molecule. Unless otherwise specifically noted in the specification, the carbon atoms in a cycloalkyl group can optionally be oxidized. Examples of cycloalkyl 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, fluorenyl, 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-methano-1H-indenyl, and octahydro-2,5-methano-indenyl, and the like.

[0149] In the present application, the term "heterocyclyl" as a group or as part of a group refers to a stable 3- to 20-membered non-aromatic ring radical consisting of two to fourteen carbon atoms and one to six heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl group can be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which can include fused, bridged, or spiro ring systems; the nitrogen, carbon, or sulfur atoms in the heterocyclyl radical thereof can be optionally oxidized; the nitrogen atom(s) can be optionally quaternized; and the heterocyclyl radical can be partially or fully saturated. The heterocyclyl radical can be attached to the remainder of the molecule via a carbon atom or a heteroatom and by a single bond. In a heterocyclyl radical comprising fused rings, one or more of the rings can be an aryl or heteroaryl group as defined below, provided the point of attachment to the remainder of the molecule is a non-aromatic ring atom. For the purposes of this application, the heterocyclyl radical is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged, or spiro radical comprising one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged, or spiro radical comprising one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Examples of heterocyclyl radicals include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]non-7-yl, 2-oxa-6-aza-spiro[3.3]heptan-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxolanyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolinyl, octahydroindolinyl, octahydroisoindolinyl, pyrrolidinyl, pyrazolidinyl, phthalimido, and the like.

[0150] In the present application, the term "heterocycloalkyl" as a group or part of a group refers to a stable 3- to 20-membered saturated cyclic group consisting of 2-14 carbon atoms and 1-6 heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen, silicon, boron, selenium and sulfur. Unless stated otherwise in the present description, the heterocycloalkyl group can be monocyclic ("monocyclic heterocycloalkyl") or a bicyclic, tricyclic or more ring ring system, which can include fused, bridged or spiro ring systems (e.g. a bicyclic system ("bicyclic heterocycloalkyl"). The heterocycloalkyl bicyclic ring system can include one or more heteroatoms in one or both rings; and is saturated. For the purposes of the present application, the heterocycloalkyl group is preferably a stable 4- to 12-membered saturated monocyclic, bicyclic, bridged or spiro group comprising 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, selenium, boron, phosphorus, silicon and sulfur, more preferably a stable 4- to 7-membered saturated monocyclic, bicyclic, bridged or spiro group comprising 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In particular, the 4- to 7-membered heterocycloalkyl group can contain 3, 4, 5 or 6 carbon atoms and one or two of the above-mentioned heteroatoms or heteroatom-containing groups, provided that the total number of ring atoms is not greater than 7; more particularly, the heterocycloalkyl group can contain 3, 4 or 5 carbon atoms and one or two of the above-mentioned heteroatoms or heteroatom-containing groups, provided that the total number of ring atoms is not greater than 6 ("4- to 6-membered heterocycloalkyl").

[0151] In the present application, the term "aryl" as a group or part of a group refers to a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms. For the purposes of the present application, the aryl group can be a monocyclic, bicyclic, tricyclic or more ring ring system, which can also be fused with a cycloalkyl or heterocyclyl group as defined above, provided that the aryl group is connected to the rest of the molecule via a single bond through an atom on the aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, fluorenyl, 2,3-dihydro-1 H-isoindolyl, 2-benzoxazolinonyl, 2H-1,4-benzoxazin-3(4H)-on-7-yl and the like.

[0152] In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above.

[0153] In the present application, the term "heteroaryl" as a group or part of another group means a 5- to 16-membered, conjugated ring system having 1 to 15 carbon atoms, preferably having 1 to 10 carbon atoms, and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Unless specifically indicated otherwise in the present specification, the heteroaryl group can be a monocyclic, bicyclic, tricyclic or more ring system, and can also be fused with a cycloalkyl or heterocyclyl group as defined above, provided that the heteroaryl group is connected to the rest of the molecule via a single bond through an atom of the aromatic ring. The nitrogen, carbon or sulfur atom in the heteroaryl group can optionally be oxidized; the nitrogen atom can optionally be quaternized. For the purposes of the present application, the heteroaryl group is preferably a stable 5- to 12-membered aromatic group comprising 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, more preferably a stable 5- to 10-membered aromatic group comprising 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur or a 5- to 6-membered aromatic group comprising 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolyl, isoquinolyl, naphthylidinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxatriazolyl, cinnolinyl, quinazolinyl, thiophenyl, indolizinyl, phenanthrolinyl, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthpyridinyl, [1,2,4]triazolo[4,3-b]pyridazine, [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]pyridazine, imidazo[1,2-a]pyrazine and the like.

[0154] In the present application, the term "heteroarylalkyl" means an alkyl group as defined above which is substituted by a heteroaryl group as defined above.

[0155] It should be understood that, in the present application, the singular forms "a", "an", "the", include plural references unless otherwise stated. Furthermore, the term "comprising" is to be construed as an open-ended term not excluding other elements or steps, that is, including the elements specifically mentioned as well as other elements.

[0156] Unless otherwise indicated, the present application employs the conventional methods of mass spectroscopy, elemental analysis, and the conventional procedures of the art for each of the steps and conditions.

[0157] Unless otherwise indicated, the present application employs standard nomenclature used in analytical chemistry, organic synthesis chemistry, and optics. In certain instances, standard techniques are used for chemical synthesis, chemical analysis, and testing of luminescent device performance.

[0158] Also, it should be noted that the description manner "… independently are" used in the present application should be interpreted broadly, unless explicitly indicated otherwise, that is, each individual described is independent of each other, and can be independently the same or different specific group. In more detail, the description manner "… independently are" can mean that the specific options expressed by the same symbols in different groups do not affect each other; or it can mean that the specific options expressed by the same symbols in the same group do not affect each other.

[0159] As understood by those skilled in the art, according to the convention used in the art, the means that the corresponding group is connected to other fragments, groups in the compound through the site.

[0160] In the present application, "optional" or "optionally" means that the subsequent described event or condition can or can not occur, and the description includes both the occurrence and non-occurrence of the event or condition. For example, "optionally substituted aryl" means aryl is substituted or unsubstituted, and the description includes both substituted aryl and unsubstituted aryl.

[0161] The term "moiety", "structural moiety", "chemical moiety", "group", "chemical group" as used herein refers to a specific fragment or functional group in a molecule. A chemical moiety is generally considered to be a chemical entity that is embedded or appended to a molecule.

[0162] "Stereoisomer" refers to a compound composed of the same atoms, bonded by the same sequence of bonds, but having a different three-dimensional structure. The present application will encompass all stereo isomers and mixtures thereof.

[0163] When the compounds of the present application contain alkenyl double bonds, the compounds of the present application are intended to include both E- and Z- geometric isomers, unless otherwise indicated.

[0164] "Tautomer" refers to isomers that exist in equilibrium with each other, involving the proton shift between a donor atom and an acceptor atom. All tautomeric forms of the compounds of the present application are also intended to be included within the scope of the present application.

[0165] The compounds of the present application, or their pharmaceutically acceptable salts, can contain one or more chiral carbon atoms and thus can give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral carbon atom can be defined, based on its stereochemistry, as either the (R)- or (S)-enantiomeric form. The present application is intended to include all possible isomers, as well as their racemic and optically pure forms. The preparation of the compounds of the present application can select either the racemate, diastereomer, or enantiomer as starting material or intermediate. The optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as, for example, crystallization and chromatography on chiral supports.

[0166] Conventional techniques for preparing / isolating the individual isomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or salt or derivative of the racemate) using, for example, chiral high pressure liquid chromatography.

[0167] In the present application, the term "pharmaceutically acceptable salt" includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0168] A "pharmaceutically acceptable acid addition salt" means a salt with an inorganic or organic acid that retains the biological effectiveness of the free base and does not impart undesired toxicological effects to the recipient. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, and the like; organic acid salts include, but are not limited to, formates, acetates, 2,2-dichloroacetates, trifluoroacetates, propionates, hexanoates, octanoates, decanoates, undecylenates, glycolates, gluconates, lactates, sebacates, adipates, glutarates, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamates, pyroglutamates, aspartates, benzoates, mesylates, besylates, tosylates, alginates, ascorbates, salicylates, 4-aminosalicylates, naphthalene-2-disulfonates, and the like. These salts can be prepared by methods known in the art.

[0169] "Pharmaceutically acceptable base addition salt" refers to those salts which retain the biological effectiveness and non-toxicity of the free acids and are formed with inorganic or organic bases. Salts derived from inorganic bases include but are not limited to sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include but are not limited to salts of primary, secondary 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, dimethyl ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known to those skilled in the art.

[0170] "Polymorph" refers to different solid crystalline phases of certain compounds of the present application that arise due to the presence of two or more different molecular arrangements in the solid state. Certain compounds of the present application can exist in more than one crystal form, and the present application is intended to include all such polymorphs and mixtures thereof.

[0171] In general, crystallization will produce solvates of the compounds of the present application. The term "solvate", as used herein, refers to an aggregate that comprises one or more molecules of a compound of the present application with one or more molecules of solvent. The solvent can be water, in which case the solvate is a hydrate. Alternatively, the solvent can be an organic solvent. Thus, the compounds of the present application can exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. The compounds of the present application can form true solvates, but in some cases can only retain a mixture of water or solvent that is not stoichiometrically determined. The compounds of the present application can be reacted or precipitated out of a solvent or crystallized from a solvent. Solvates of the compounds of the present application are also within the scope of the present application.

[0172] The present application also includes prodrugs of the above compounds. In the present application, the term "prodrug" means a compound that is convertible in vivo into a biologically active compound of the present application. Thus, the term "prodrug" refers to a pharmacologically acceptable metabolic precursor of a compound of the present application. When administered to a subject in need thereof, a prodrug can not be active, but is converted in vivo to the active compound of the present application. Prodrugs are typically rapidly transformed in vivo to yield the parent compound, e.g., by hydrolysis in the blood or plasma. Prodrug compounds often provide an advantage in solubility, tissue compatibility, or sustained release in a mammalian organism. Prodrugs include known amino- and carboxy-protecting groups.

[0173] In the present application, "pharmaceutical composition" refers to a preparation of a compound of the present application with a medium conventionally accepted in the art for the delivery of a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to the body and to facilitate absorption into the body for the purpose of exerting a biological activity.

[0174] The term "pharmaceutically acceptable" as used herein means a substance (such as a carrier or diluent) that does not interfere with the biological activity of the compounds of the present application and is relatively nontoxic, i.e., the material is not deleterious to the individual to whom it is administered, and does not interact with any of the components of the composition in a deleterious manner.

[0175] In the present application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, flow regulating agent, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surface-active agent, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsor that is approved by a relevant government regulatory agency for use in humans or domestic animals.

[0176] The "tumor", "cell proliferation abnormality-related disease", and the like described in the present application include, but are not limited to, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, renal cancer, oral cancer, and the like.

[0177] The terms "preventative", "prevention", and "preventing" as used herein include reducing the likelihood of the occurrence or worsening of a disease or condition in a subject.

[0178] The terms "treat", "treatment", and other similar synonyms as used herein include the following meanings:

[0179] (i) preventing the disease or condition from occurring in a subject, in particular, when such subject is predisposed to the disease or condition but has not yet been diagnosed as having it;

[0180] (ii) inhibiting the disease or condition, i.e., arresting its development;

[0181] (iii) relieving the disease or condition, i.e., causing the state of the disease or condition to regress; or

[0182] (iv) relieving the symptoms resulting from the disease or condition.

[0183] The term "effective amount", "therapeutically effective amount", or "pharmaceutically effective amount" as used herein refers to the amount of at least one agent or compound that, when administered, is sufficient to alleviate to some extent one or more symptoms of the disease or condition being treated. The result can be a reduction and / or alleviation of the signs, symptoms, or causes of a disease or disorder, or any other desired alteration of a biological

[0184] The terms "administering", "administered", "administration", and the like, as used herein, refer to the methods by which a compound or composition is delivered to the desired site of biological action. These methods include, but are not limited to, oral routes, transduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injections or infusion), topical administration, and transrectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

[0185] The terms "pharmaceutical combination", "pharmaceutical co-administration", "co-administration", "administering another therapeutic agent", "administering another therapeutic agent(s)", and the like, as used herein, refer to two or more active ingredients that are administered to a patient together in a fixed dosage form, or administered to a patient as separate dosage forms simultaneously or sequentially with no specific intervening time constraints. The term "fixed combination" means that all the components of the combination are administered to a patient as mutually associated in a single entity. The term "not fixed combination" means that the components of the combination are administered to a patient as separate entities either simultaneously or sequentially with no specific intervening time constraints. These also apply to cocktail therapies, e.g., the administration of three or more active ingredients.

[0186] Those skilled in the art will further appreciate that in the methods described below, the functional groups of intermediate compounds can need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amino, mercapto, and carboxylic acid. Suitable protecting groups for hydroxyl include trialkylsilyl or diarylalkylsilyl groups (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino, and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto include -C(O)-R" (where "R" is alkyl, aryl, or aralkyl), p-methoxybenzyl, trityl, and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl, or aralkyl esters.

[0187] Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. Protecting groups can also be polymeric resins.

[0188] Without deviating from the common knowledge in the art, the above-mentioned preferred conditions can be combined in any manner, thereby obtaining various preferred embodiments of the present application.

[0189] The reagents and starting materials used in the present application are commercially available.

[0190] The positive progress effect of the present application is that a nitrogen-containing heterocyclic compound is provided, which can be used as a KRAS G12C inhibitor; it can be used for preparing an antitumor drug for preventing and / or treating tumors. DETAILED DESCRIPTION

[0191] The inventors have prepared a novel nitrogen-containing heterocyclic compound having the structure shown in Formula I through long-term and in-depth research, and found that it has good KRAS G12C protein inhibitory activity, and the compound has quite excellent inhibitory activity on KRAS G12C related cell proliferation and downstream signal pERK (IC 50 even less than 10 nM) at a lower concentration, and thus can be used for treating diseases related to KRAS G12C mutation or abnormal expression, such as tumors. Based on the above findings, the inventors have completed the present application.

[0192] The present application is further illustrated by the following examples, but the present application is not limited to the scope of the examples. The experimental methods in the following examples, for which no specific conditions are indicated, are selected according to conventional methods and conditions, or according to the instructions of the product. The experimental methods in the following examples, for which no specific conditions are indicated, are generally selected according to conventional conditions, or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are weight percentages and weight parts.

[0193] Preparation of Intermediate Intermediate Al: 7-bromo-2,4,6-trichloro-8-fluoroquinazoline

[0194]

[0195] Step one: 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (1.5 g, 5.62 mmol) and urea (2.7 g, 44.9 mmol) were mixed and heated to 200 °C for 4 hours. Cooled to room temperature, then water (50 mL) was added, heated to 100 °C for another hour, filtered while hot. The solid was slurried with ethyl acetate (50 mL), the filtered solid was dried to give the red-brown intermediate product (1.3 g). LC-MS [M-H] - m / z 292.9. 1 HNMR (400 MHz, DMSO-d6): δ 11.50-11.3 (dt, 2H), 7.83 (s, 1H).

[0196] Step two: The above intermediate compound (413 mg, 1.41 mmol) was suspended in phosphorus oxychloride (POCl3) (20 mL), three drops of N,N-dimethylaniline were added, heated to reflux overnight, rotary evaporated, the residue was dissolved in dichloromethane (DCM) (10 mL) and added dropwise into saturated aqueous sodium bicarbonate (NaHCO3) solution, keeping the pH to 7-8, extracted with DCM (30 mL) three times. The combined organic phase was dried over anhydrous magnesium sulfate (MgSO4), filtered, concentrated under reduced pressure to give the yellow solid intermediate Al (219 mg). LC-MS [M+H] + m / z 328.8 / 330.8. 1 HNMR (400 MHz, DMSO-d6): δ 8.05 (s, 1H).

[0197] Preparation of Intermediate Al: 7-bromo-2,4,6-trichloro-8-fluoroquinazoline

[0198]

[0199] Step one: 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid methyl ester (710 mg, 2.51 mmol) and cyanoacetic acid (213 mg, 2.51 mmol) were dissolved in acetonitrile (10 mL), pyridine (1.98 g, 25.1 mmol) was added, cooled to around 5 °C, dropwise added phosphorus oxychloride (1.17 g, 7.53 mmol), stirred at room temperature for 2 hours, poured into water, adjusted the pH to around 5, filtered, dried to give the yellow solid intermediate product (510 mg). LC-MS [M-H] - m / z 349.1.

[0200] Step two: The above intermediate compound (100 mg, 0.29 mmol) was added to a freshly prepared sodium ethoxide (20 mg, 0.86 mmol) in ethanol (2 mL) and heated to reflux overnight. The solvent was evaporated and water was added. The pH was adjusted to about 4 with hydrochloric acid. A solid precipitated and the crude product was filtered and dried to give a yellow intermediate product (45 mg). LC-MS [M+H] + : m / z 316.9 / 318.9.

[0201] Step three: The above intermediate compound (370 mg, 1.16 mmol) was suspended in phosphorus oxychloride (10 mL) and one drop of N,N-dimethylformamide (DMF) was added. The mixture was heated to reflux overnight. The solvent was evaporated and the residue was dissolved in dichloromethane (DCM, 10 mL) and added dropwise to a saturated aqueous sodium bicarbonate (NaHCO3) solution to keep the pH basic. The mixture was extracted with DCM (30 mL) three times. The combined organic phase was dried over anhydrous magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure to give a yellow solid intermediate A2 (298 mg). LC-MS [M+H]+: m / z 352.8 / 354.8. 1H NMR (400 MHz, DMSO-d6): δ 8.43 (s, 1H).

[0202] Intermediate A3: 7-bromo-2,4,6-trichloro-8-fluoroquinazoline

[0203]

[0204] Step one: 4-amino-6-chloro-5-fluorobenzoic acid methyl ester (500 mg, 2.45 mmol) and cyanoacetic acid (208 mg, 2.45 mmol) were dissolved in acetonitrile (10 mL) and pyridine (19.4 g, 24.5 mmol) was added. The mixture was cooled to about 5 °C and phosphorus oxychloride (1.12 g, 7.35 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours, poured into water and the pH was adjusted to about 6. A solid precipitated and the crude product was filtered and dried to give a yellow intermediate product (530 mg). LC-MS [M+H] + : m / z 272.1.

[0205] Step two: To a solution of the above intermediate compound (500 mg, 1.84 mmol) in DMF (10 mL) was added NaH (60%, 200 mg, 5.0 mmol) under ice-bath cooling. The reaction was allowed to warm to room temperature and stirred overnight. Water was added to quench the reaction and the pH was adjusted to about 4 with 4 M aqueous hydrochloric acid. A solid precipitated and the crude product was filtered and dried to give a yellow intermediate product (200 mg). LC-MS [M+H] + : m / z 240.

[0206] Step 3: The above intermediate compound (150 mg, 0.63 mmol) was suspended in POCI3(10 mL) and a drop of DMF was added. The reaction was heated to reflux overnight. After the reaction was determined to be complete, the reaction was concentrated under reduced pressure. The residue was dissolved in DCM (10 mL) and was added dropwise to saturated aqueous NaHCO3solution and the pH was maintained at 7-8. The mixture was extracted with DCM (20 mL) three times. The combined organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure to give yellow solid intermediate A3 (219 mg). LC-MS [M+H] + m / z 276.1. 1 HNMR (400 MHz, DMSO-d6): δ 8.55 (s, 1H).

[0207] Intermediate A4: 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine

[0208]

[0209] Step 1: 2-chloro-3-fluoroisonicotinic acid (18 g, 103 mmol) was dissolved in a mixture of toluene (55 mL) and t-butanol (55 mL), and triethylamine (28.5 mL, 205 mmol), diphenylphosphoryl azide DPPA (23 mL, 107 mmol), Boc anhydride (2.2 mL, 10.2 mmol) were added. The reaction was stirred for 30 min under nitrogen atmosphere and heated to 80 °C for 8 h. After the reaction was completed, the reaction was cooled to room temperature, diluted with water, and extracted with ethyl acetate (200 mL). The organic phase was washed with saturated sodium bicarbonate solution and pure water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give the target compound (10 g, light yellow powder), ESI (M+H): 247.

[0210] Step 2: The solid (6 g) obtained in the above step was dissolved in tetrahydrofuran (50 mL) and cooled to -78 °C. n-butyllithium solution (24 mL, 60 mmol) was added dropwise under nitrogen atmosphere. After the addition was completed, the reaction was warmed to -20 °C and stirred for 1 h. Then, t-butyl isocyanate (29 mL, 48 mmol) was added dropwise. After the addition was completed, the reaction was warmed to room temperature and stirred for 1 h. Then, the reaction was heated to 70 °C and stirred overnight. The reaction was slowly poured into saturated sodium bicarbonate solution (60 mL) and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give the target compound (4 g, yellow solid).

[0211] Step three: The solid from the previous step (2.4 g, 8.8 mmol) was added slowly in portions to phosphorus oxychloride (30 mL) and N, N-diisopropylethylamine (4.4 mL) was added slowly dropwise with ice water cooling. The temperature was raised to 110 °C and the reaction was allowed to proceed overnight. After most of the phosphorus oxychloride was removed under reduced pressure, the residue was poured into a cooled saturated aqueous sodium bicarbonate solution (60 mL), extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was slurried in petroleum ether, filtered and the target compound, 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1.5 g) was obtained. 1 HNMR (400 MHz, DMSO-d6): δ 8.95 (s, 1H).

[0212] Intermediate A5: 7-Chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0213]

[0214] Step one: 4-Amino-2,6-dichloro-5-fluoronicotinic acid (15 g, 66.7 mmol) was dissolved in thionyl chloride (50 mL) and the reaction was stirred at 60 °C until the reaction was complete. The reaction was concentrated under reduced pressure to remove the solvent to obtain the target compound, which was used directly in the next step without purification.

[0215] Step two: The compound from the previous step was dissolved in anhydrous acetone (80 mL) and 15 g of ammonium thiocyanate was dissolved in 80 mL of anhydrous acetone and added slowly dropwise. The reaction was stirred at 50 °C for about 1 hour. The reaction was poured into 400 mL of water and stirred for 10 minutes. The solid was filtered and the filter cake was washed with water and dried to obtain the target compound (15 g, yellow solid).

[0216] Step three: The solid from the previous step was dissolved in methanol (120 mL) and iodomethane (12.7 g, 894 mmol) and 1 M sodium hydroxide aqueous solution (100 mL) were added sequentially. The mixture was stirred at room temperature for 3 hours and then poured into 400 mL of water. The pH was adjusted to ~ 6 with dilute hydrochloric acid and the solid was filtered and the filter cake was washed with water and dried to obtain the target compound (15 g, yellow solid). 1 HNMR (400 MHz, DMSO-d6): δ 13.31 (s, 1H), 2.59 (s, 3H).

[0217] Step four: Into a 250 mL reaction flask, methanol (2 mL) and anhydrous tetrahydrofuran (100 mL) were added, respectively, and then sodium hydride (2.9 g) was slowly added in batches under ice water bath cooling. After stirring for 10 minutes, the solid obtained in the previous step (4 g) was added in batches. After natural warming to room temperature, it was stirred for 15 minutes, and the reaction was shown to be complete. The reaction solution was cooled with an ice water bath, and then saturated ammonium chloride aqueous solution (100 mL) was slowly added dropwise to quench the reaction. Ethyl acetate was extracted three times, and the organic phase was dried and concentrated under reduced pressure to obtain the target compound (4 g). LC-MS [M+H] + : m / z 276.0.

[0218] Intermediate A6: 7-Chloro-8-fluoro-5-(methoxy-d3)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol

[0219]

[0220] Intermediate A7 was prepared according to the procedure of Step four of Intermediate A5, LC-MS [M+H] + : m / z 279.2.

[0221] Example Preparation

[0222] Example 1:

[0223]

[0224] Step one: N-Boc piperazine (558 mg, 3 mmol) and 2,4,7-trichloro-8-fluoropyrido[4,3d]pyrimidine (756 mg, 3 mmol) were dissolved in anhydrous dichloromethane (20 mL), and then DIEA (0.72 mL, 4.35 mmol) was slowly added under ice water bath cooling and nitrogen protection. After the dropwise addition was completed, the reaction was continued for 1 hour. The reaction solution was diluted with water (20 mL), extracted with dichloromethane (20 mL*2), and the organic phase was washed with saturated sodium chloride aqueous solution (20 mL). After drying over anhydrous sodium sulfate, it was concentrated under reduced pressure, and the residue was separated by flash silica gel column chromatography to obtain the target compound (1.02 g, light yellow solid). ESI-MS: 402.1 [M+1] + .

[0225] Second step: The solid from the previous step (1.02 g, 2.5 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidin-7a-ylmethanol (430 mg, 2.7 mmol) were dissolved in anhydrous tetrahydrofuran (100 mL), cooled in an ice water bath, and sodium tert-butoxide (240 mg, 2.5 mmol) was added slowly under nitrogen protection. After the addition was completed, the reaction was maintained at 0 °C for 1 h. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL*2). The organic phase was washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by flash silica gel column chromatography to obtain the target compound (600 mg, light yellow solid). ESI-MS: 525.2 [M+1].

[0226] Third step: The solid (105 mg, 0.2 mmol) was dissolved in a 1,4-dioxane / water (12 mL / 4 mL) solution at room temperature, and 2-amino-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophene-3-carbonitrile (70 mg, 0.22 mmol), tetrakis(triphenylphosphine)palladium (24 mg, 0.02 mmol), and sodium carbonate powder (Na2CO3) (56 mg, 0.53 mmol) were added successively under nitrogen protection. The reaction mixture was stirred at 100 °C overnight under nitrogen protection. After the reaction was completed, ethyl acetate was added for extraction, and the organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography to obtain the target compound (yellow solid, 60 mg). LC-MS m / z: 681.2 [M+H] + .

[0227] Fourth step: The solid (60 mg, 0.9 mmol) obtained in the previous step was dissolved in dichloromethane (DCM) (6 mL) under ice bath cooling, and trifluoroacetic acid (0.5 mL) was added dropwise under ice bath cooling. The reaction solution was warmed to room temperature and stirred for 4 h. The reaction solution was concentrated under reduced pressure to obtain a crude product which was directly used in the next step.

[0228] Fifth step: To the DCM (10 mL) solution of the product from the previous step (30 mg) was added triethylamine (Et3N) (6.6 mg, 0.066 mmol) and cooled to 0 °C, and acryloyl chloride (6 mg, 0.06 mmol) was added. The reaction mixture was slowly warmed to room temperature, and LC-MS monitoring showed that the reaction was complete. The reaction was quenched with saturated sodium bicarbonate (NaHCO3) (10 mL), extracted with ethyl acetate, washed with water, dried over Na2SO4, concentrated, and purified by reverse phase preparative chromatography to obtain the product (16 mg, yellow powder), ESI-MS m / z: 635.2 [M+H] + , 1H-NMR (400 MHz, DMSO-d6): δ 8.97 (s, 1H), 8.11 (s, 2H), 7.35 (dd, J = 8.4, 5.2 Hz, 1H), 7.17 (dd, J = 9.6, 8.4 Hz, 1H), 6.29 (dd, 1H), 5.82 (dd, 1H), 5.28 (m, 1H), 4.74-4.88 (m, 1H), 4.18-4.03 (m, 7H),, 3.95-3.80 (m, 2H), 3.16-3.00 (m, 4H), 2.88-2.78 (m, 1H), 2.15-2.10 (m, 1H), 2.08-2.06 (m, 1H), 2.05-1.97 (m, 1H), 1.88-1.73 (m, 3H).

[0229] The following example compounds were obtained using the general preparation method of the examples, following the procedure of Example 1:

[0230]

[0231]

[0232]

[0233]

[0234] Example 2:

[0235]

[0236] First step: 7-bromo-8-fluoro-2,4,6-trichloroquinazoline (984 mg, 3 mmol), DIPEA (580 mg, 4.5 mmol), N-Boc-piperazine (558 mg, 3 mmol) were dissolved in N,N-dimethylformamide (DMF) (15 mL), under Ar protection, heated to 60 °C for 20 hours. TLC monitoring of the reaction was complete, the reaction was cooled to room temperature, then water (20 mL) was added, extracted with ethyl acetate (10 mL*2), the organic phase was combined, saturated with sodium chloride, the organic phase was concentrated, and column chromatography was used for purification to give tert-butyl 4-(7-bromo-2,6-chlorodichloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate (white solid, 836 mg), ESI-MS m / z: 479.1 / 481.1 [M+H] + . 1 H-NMR (400 MHz, CDCl3) δ: 7.76 (d, J = 1.8 Hz, 1H), 3.90-3.87 (m, 4H), 3.67-3.64 (m, 4H), 1.49 (s, 9H).

[0237] Second step:

[0238] To a suspension of NaH (48 mg, 2 mmol) in THF (15 mL) at 0 °C, ((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (321 mg, 2 mmol) was added. After the reaction mixture was stirred at this temperature for half an hour, a solution of A2-2 (836 mg, 1.74 mmol) in THF (10 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. LC-MS showed the reaction was essentially complete. To the reaction mixture was added saturated aqueous NH4CI solution (50 mL), which was then extracted with EtOAc (50 mL) three times. The combined organic phase was dried and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 30: 1) to give the product (400 mg) as a yellow solid. LC-MS [M+H] + : m / z 602.1.

[0239] Third step: To a solution of A2-3 (120 mg, 0.2 mmol) in 1,4-dioxane / H2O (12 mL / 4 mL) was added a fluorosubstituted benzothiazolyl boronic acid starting material (178 mg, 0.1 mmol), tetrakis(triphenylphosphine)palladium (24 mg, 0.02 mmol) and sodium carbonate powder (Na2CO3) (108 mg, 1 mmol) at room temperature. The reaction mixture was stirred at 100 °C under argon overnight. After the reaction was completed, the reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give A2-4 (67 mg, yellow solid). ESI-MS m / z: 689.2 [M+H] + .

[0240] Fourth step: To a stirred solution of A2-4 (67 mg) in dichloromethane (DCM) (5 mL) was added trifluoroacetic acid (CF3COOH, TFA) (0.5 mL) under ice-bath cooling. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was used in the next step without further purification.

[0241] Fifth step: To a stirred solution of A2-5 (30 mg) in DCM (10 mL) was added triethylamine (Et3N) (6.6 mg, 0.066 mmol) and cooled to 0 °C. Acryloyl chloride (6 mg, 0.06 mmol) was added. The reaction mixture was slowly warmed to room temperature. LC-MS monitoring showed the reaction was complete. The reaction was quenched with saturated sodium bicarbonate (NaHCO3) (10 mL) and extracted with ethyl acetate. The organic phase was washed with water, dried over Na2SO4, concentrated and purified by reverse phase preparative chromatography to give the product (13 mg, yellow powder), ESI-MS m / z: 643.2 [M+H]+ . 1 HNMR (400 MHz, MeOD-d4): δ 7.96 (s, 1H), 7.20-7.24 (m, 1H), 6.83-7.02 (m, 2H), 6.29-6.26 (m, 1H), 5.82 (m, 1H), 4.74-4.88 (m, 1H), 4.26 (d, J = 10.5 Hz, 1H), 4.18 (d, J = 10.5 Hz, 1H), 3.99-3.89 (m, 4H), 3.69-3.59 (m, 4H), 3.31-3.12 (m, 3H), 3.01-2.93 (m, 1H), 2.25-2.18 (m, 1H), 2.14 (br dd, J = 14.7, 4.1 Hz, 1H), 1.99-1.80 (m, 3H).

[0242] Example 3:

[0243]

[0244] Step a: To a solution of intermediate Al (1.32 g, 4 mmol) in dichloromethane (DCM) (60 mL) was added 2-(cyanomethyl)piperazine-1-carboxylate benzyl ester (1.04 g, 4 mmol) and triethylamine (TEA) (2.02 g, 20 mmol) sequentially. The reaction mixture was stirred at room temperature overnight. The reaction was concentrated under reduced pressure and the resulting crude product was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 1:1) to give the product as a yellow solid (1.8 g). LC-MS [M+H] + : m / z 552.0.

[0245] Step b: To a suspension of sodium hydride (NaH) (71 mg, 2.95 mmol) in tetrahydrofuran (20 mL) was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (470 mg, 2.95 mmol) at 0 °C. After the reaction mixture was stirred at this temperature for half an hour, a solution of Al-2 (1.8 g, 3.25 mmol) in tetrahydrofuran (10 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. LC-MS indicated that the reaction was substantially complete. To the reaction mixture was added saturated aqueous ammonium chloride solution (50 mL) followed by extraction with ethyl acetate (100 mL) three times. The combined organic phase was dried and concentrated under reduced pressure. The resulting crude product was purified by column chromatography on silica gel (eluent: dichloromethane / methanol = 30:1) to give the product as a yellow solid (1.7 g). LC-MS [M+H] + : m / z 675.1.

[0246] Step c: To a solution of A1-3 (1 g, 1.48 mmol) in 1,4-dioxane / water (25 mL / 8 mL) was added tert-butyl (3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2- yl)carbamate (804 mg, 1.92 mmol), tetrakis(triphenylphosphine)palladium (180 mg, 0.15 mmol) and sodium carbonate powder (Na2CO3) (477 mg, 4.5 mmol) at room temperature. The reaction mixture was purged with argon for three times and stirred at 100 °C under argon overnight. LC-MS indicated the reaction was complete. The reaction was concentrated under reduced pressure. The crude product was purified by silica gel column (eluent: dichloromethane / methanol = 10:1) to give the product as a yellow solid (1.1 g). LC-MS m / z: 887.3 [M+H] + .

[0247] Step d: A1-4 (300 mg, 0.34 mmol) was dissolved in 6 mL of methanol, palladium on carbon (10 wt.%, 178 mg, 0.17 mmol) was purged with argon for three times and then hydrogen for three times. The reaction was stirred under hydrogen for 30 min. The reaction mixture was filtered through a Buchner funnel. The filtrate was concentrated to give the product A1 which was used directly in the next step. LC-MS m / z: 753.2 [M+H] + .

[0248] Step e: To a mixture of the above intermediate (50.0 mg, 0.07 mmol) and acryloyl chloride (7 mg, 0.08 mmol) in tetrahydrofuran (2 mL) and water (1 mL) was added potassium phosphate (21 mg, 0.1 mmol). The reaction mixture was stirred at zero degree for 2 hours. LC-MS indicated the reaction was almost complete. The reaction was diluted with water (20 mL). The product was extracted with ethyl acetate (30 mL) twice. The combined organic phase was dried over anhydrous magnesium sulfate and filtered. The crude product was purified by preparative HPLC to give the product as a yellow solid (23 mg).

[0249] Step f: To a solution of the above intermediate (23.0 mg, 0.03 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.5 ml). The reaction mixture was stirred at room temperature overnight. LCMS showed the reaction was essentially complete. The reaction was concentrated under reduced pressure to give a crude product, which was purified by preparative HPLC to give the product as a yellow solid (12 mg). 1H NMR (400 MHz, CD3OD) δ 7.85 (m, 1H), 7.21 (m, 1H), 7.15-6.81 (m, 2H), 6.25 (m, 1H) 5.81 (m, 1H), 5.29 (m, 1H), 4.97-4.85 (m, 1H), 4.58-4.49 (m, 1H), 4.49-4.39 (m, 1H), 4.26-4.03 (m, 3H), 3.87-3.73 (m, 2H), 3.27-3.15 (m, 3H), 3.15-3.03 (m, 3H), 2.92-2.81 (m, 1H), 2.22-1.97 (m, 3H), 1.89-1.73 (m, 3H). (ESI) m / z: 707.2 [M+H]+

[0250] The following example compounds were prepared using the general procedures of the examples, following the procedures of Example 2, 3:

[0251]

[0252]

[0253] Example 4:

[0254]

[0255] First step: N-Boc piperazine (614 mg, 3.3 mmol) and 2,4,7-trichloro-8-fluoro-1,6 naphthyridine-3-carbonitrile (822 mg, 3.0 mmol) were dissolved in anhydrous dichloromethane (20 mL), DIEA (1 mL, 6 mmol) was added slowly under ice water bath cooling and nitrogen protection, after dropwise addition was completed, the reaction was continued for 1 hour. The reaction solution was diluted with water (20 mL), extracted with dichloromethane (20 mL*2), the organic phase was washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, the residue was separated by flash silica gel column chromatography to obtain the target compound (900 mg, light yellow solid). ESI-MS: 427.1 [M+1] + .

[0256] Second step: A4-2 (900 mg, 2.1 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidin-7a- ylmethanol (366 mg, 2.3 mmol) were dissolved in anhydrous tetrahydrofuran (50 mL), cooled in an ice water bath, and sodium tert-butoxide (240 mg, 2.5 mmol) was slowly added under nitrogen protection. After the addition was completed, the reaction was maintained at 0 °C for 1 h. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL*2). The organic phase was washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by flash silica gel column chromatography to obtain the target compound (768 mg, light yellow solid). ESI-MS: 549.2 [M+1].

[0257] Third step: A4-3 (548 mg, 1 mmol) was dissolved in a 1,4-dioxane / water (20 mL / 7 mL) solution at room temperature. 2-amino-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophene-3-carbonitrile (381 mg, 1.2 mmol), tetrakis(triphenylphosphine)palladium (240 mg, 0.2 mmol), and sodium carbonate powder (Na2CO3) (210 mg, 2 mmol) were sequentially added under nitrogen protection. The reaction mixture was stirred at 100 °C for 4 h under nitrogen protection. After the reaction was completed, the reaction solution was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to obtain the target compound (yellow solid, 350 mg). LC-MS m / z: 705.2 [M+H] + .

[0258] Fourth step: A4-4 (70 mg, 0.1 mmol) was dissolved in dichloromethane (DCM) (6 mL) under ice bath cooling. Trifluoroacetic acid (0.5 mL) was added dropwise under ice bath cooling. After the addition was completed, the reaction solution was warmed to room temperature and stirred for 4 h. The reaction solution was concentrated under reduced pressure, and the crude product was directly used in the next step.

[0259] Fourth Step: To the above crude (60.0 mg, 0.1 mmol) and acryloyl chloride (10 mg, 0.11 mmol) in THF (2 mL) and water (1 mL) was added potassium phosphate (30 mg, 0.15 mmol). The reaction mixture was stirred at 0 °C for 2 h. After the reaction was completed as indicated by LC-MS, the reaction was diluted with water (20 mL). The product was extracted with ethyl acetate (30 mL) twice. The combined organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the product as a yellow solid (32 mg).1H NMR (400 MHz, CD3OD) δ 8.18 (s, 1H), 8.01-7.92 (m, 2H), 7.21-7.16 (m, 1H), 7.00-6.86 (m, 1H), 5.89-5.81 (m, 1H), 4.32-4.11 (m, 6H), 4.06-3.83 (m, 4H), 3.22-3.01 (m, 3H), 2.91-2.85 (m, 1H), 2.20-1.94 (m, 3H), 1.91-1.69 (m, 3H).

[0260] Example 5:

[0261]

[0262] First Step: To a solution of A5-1 (824 mg, 3 mmol) and N-Boc piperazine (577 mg, 3.1 mmol) in DMF (10 mL) was added DBU (1.5 mL) and PyBOP (2.4 g, 4.6 mmol) sequentially at room temperature. The reaction mixture was stirred at room temperature for 30 min. After the reaction was completed as indicated by LC-MS, the reaction was diluted with saturated brine (30 mL) and ethyl acetate (30 mL). The organic phase was washed with saturated brine three times, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (EA / PE = 0%-15%) to give the target compound (869 mg, yellow solid). ESIMS m / z: 444.1 [M+H].

[0263] Second Step: A5-2 (869 mg, 1.96 mmol) was dissolved in DCM (10 mL) and mCPBA (974 mg, 5.9 mmol) was added portionwise with ice water bath cooling. The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction was diluted with DCM (50 mL) and saturated NaHCO3 solution (20 mL). The organic phase was separated, and the aqueous phase was extracted with DCM (10 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (EA / PE = 0%-30%) to give the target compound (700 mg).

[0264] Step 3: A5-3 (700 mg, 1.47 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidin-7a(5H)-yl)methanol (340 mg, 1.5 mmol) were dissolved in anhydrous THF (20 mL) and cooled in an ice-water bath. To the above solution was added 1 M lithium bis(trimethylsilyl)amide in tetrahydrofuran (2 mL, 2 mmol) under nitrogen protection. After stirring for 1 h, the reaction was quenched by slowly adding saturated brine. The reaction mixture was extracted with ethyl acetate (50 mL) and the organic phase was dried over anhydrous sodium sulfate. The residue was purified by column chromatography to give the target compound (473 mg, yellow solid). ESI-MS m / z: 476.9 [M+H].

[0265] Step 4: To a 50 mL sealed tube were added the above solid (475 mg, 1 mmol), 2-amino-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophene-3-carbonitrile (343 mg, 1.1 mmol), K2CO3 powder (415 mg, 3 mmol), Pd(dppf)Cl2.DCM (38 mg, 0.05 mmol) and 20 mL dioxane / 7 mL water. After being replaced with nitrogen for 10 min, the reaction was carried out at 130 °C for 60 min. After the reaction was completed, the reaction mixture was cooled to room temperature and EA (20 mL x 3) was added to extract the product. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (EA / PE = 0%-30%) to give the target compound (300 mg, yellow solid). ESI-MS m / z: 710.3 [M+H].

[0266] Step 5: A5-6 (71 mg, 0.1 mmol) was dissolved in dichloromethane (DCM) (6 mL) and cooled in an ice bath. Trifluoroacetic acid (0.5 mL) was added dropwise. After the addition was completed, the reaction mixture was allowed to warm to room temperature and stirred for 4 h. The reaction mixture was concentrated under reduced pressure to give the crude product.

[0267] Step 6: To a mixture of the above crude product (61.0 mg, 0.1 mmol) and acryloyl chloride (10 mg, 0.11 mmol) in tetrahydrofuran (2 mL) and water (1 mL) was added potassium phosphate (30 mg, 0.15 mmol). The reaction mixture was stirred at 0 °C for 2 h. After the reaction was completed, the reaction mixture was diluted with water (20 mL). The product was then extracted with ethyl acetate (30 mL) twice. The combined organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the yellow solid product (28 mg). ESI-MS m / z: 665.2 [M+H]. 1H-NMR (400 MHz, DMSO-d6) δ 7.31-7.22 (m, 2H), 7.19-7.14 (m, 1H),.700-6.86 (m, 1H), 5.89-5.81 (m, 1H), 5.45-5.19 (m, 1H), 4.54-4.23 (m, 3H), 4.18-3.81 (m, 6H), 3.49-3.21 (m, 1H), 3.20-2.83 (m, 4H),, 2.41-2.21 (m, 3H), 2.11-2.01 (m, 3H), 1.97-1.71 (m, 3H).

[0268] The following example compounds were synthesized using the same method as in Example 5:

[0269]

[0270]

[0271]

[0272] Example 6:

[0273]

[0274] First step: 7-bromo-2,4,6-trichloro-8-fluoroquinoline-3-carbonitrile (1.1 g, 3 mmol) was dissolved in dichloromethane DCM (25 mL), then N-BOC piperazine (614 mg, 3.3 mmol) and triethylamine TEA (0.5 mL, 4.20 mmol) were added, and stirred at room temperature overnight. The reaction solution was rotary evaporated to get the crude product, which was purified by silica gel column chromatography to get the yellow solid product (1.2 g). ESI-MS m / z: 714.2 [M+H] + .

[0275] Second step: To a suspension of sodium hydride NaH (53 mg, 2.2 mmol) in tetrahydrofuran (20 mL) was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (353 mg, 2.2 mmol) at 0 degree. After the reaction mixture was stirred at this temperature for half an hour, a solution of A2-2 (1 g, 2 mmol) in tetrahydrofuran (10 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. LC-MS detection showed that the reaction was substantially complete. Saturated aqueous ammonium chloride solution (50 mL) was added to the reaction solution, which was then extracted with ethyl acetate (50 mL) three times. The combined organic phase was dried and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 30:1) to obtain the yellow solid product (398 mg). LC-MS [M+H] + : m / z 626.1.

[0276] Step 3: To a solution of A6-2 (313 mg, 0.5 mmol) in 1,4-dioxane / water (12 mL / 4 mL) was added fluorosubstituted benzothiazolyl boronic acid starting material (213 mg, 0.6 mmol), tetrakis(triphenylphosphine)palladium (24 mg, 0.02 mmol) and sodium carbonate powder (Na2CO3) (108 mg, 1 mmol) at room temperature. The reaction mixture was stirred at 100 °C under argon overnight. After the reaction was completed, the reaction mixture was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by flash column chromatography on silica gel to give A6-3 (200 mg, yellow solid). ESI-MS m / z: 714.2 [M+H] + .

[0277] Step 4: To a stirred solution of A6-3 (67 mg) in dichloromethane (DCM) (5 mL) was added trifluoroacetic acid (CF3COOH, TFA) (0.5 mL) under ice-bath cooling. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was used in the next step without further purification.

[0278] Step 5: To a stirred solution of A6-4 (30 mg) in DCM (10 mL) was added triethylamine (Et3N) (6.6 mg, 0.066 mmol) and cooled to 0 °C, acryloyl chloride (6 mg, 0.06 mmol) was added. The reaction mixture was slowly warmed to room temperature. LC-MS monitoring of the reaction showed that the reaction was complete. The reaction was quenched with saturated sodium bicarbonate (NaHCO3) (10 mL), extracted with ethyl acetate, washed with water, dried over Na2SO4, concentrated, and purified by reverse phase preparative chromatography to give the product (18 mg, yellow powder), 1 H-NMR (400 MHz, MeOD-d4): δ 7.96 (s, 1H), 7.20-7.24 (m, 2H), 6.97-7.02 (m, 1H), 6.29 (dd, 1H), 5.82 (dd, 1H), 5.37-5.20 (m, 1H), 4.84 (br s, 2H), 4.70 (br d, J = 12.3 Hz, 1H), 4.54 (br d, J = 12.3 Hz, 1H), 4.14 (dd, J = 10.4, 2.3 Hz, 1H), 4.05 (br d, J = 10.4 Hz, 1H), 3.90-3.70 (m, 2H), 3.15-3.01 (m, 3H), 2.87-2.80 (m, 1H), 2.18-1.90 (m, 3H), 1.89-1.74 (m, 3H).

[0279] The following example compounds were obtained using the general preparation method of the examples, following the similar procedure of Example 6:

[0280]

[0281]

[0282]

[0283] Example 51

[0284]

[0285] First step: N-Boc piperazine (558 mg, 3 mmol) and A51-1 (798 mg, 3 mmol) were dissolved in anhydrous dichloromethane (20 mL), and DIEA (0.72 mL, 4.35 mmol) was slowly added under ice water bath cooling and nitrogen protection. After dropwise addition was completed, the reaction was continued for 1 hour. The reaction solution was diluted with water (20 mL), extracted with dichloromethane (20 mL*2), and the organic phase was washed with saturated sodium chloride aqueous solution (20 mL). After drying over anhydrous sodium sulfate, it was concentrated under reduced pressure, and the residue was separated by flash silica gel column chromatography to obtain the target compound (980 mg, light yellow solid). ESI-MS: 416.1 [M+1] + .

[0286] Second step: The solid (832 mg, 2 mmol) obtained in the above step and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidin-7a-ylmethanol (398 mg, 2.5 mmol) were dissolved in anhydrous tetrahydrofuran (20 mL), cooled in an ice water bath, and sodium tert-butoxide (240 mg, 2.5 mmol) was slowly added under nitrogen protection. After addition, it was kept at 0°C for 1 hour. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 mL*2), and the organic phase was washed with saturated sodium chloride aqueous solution (20 mL). After drying over anhydrous sodium sulfate, it was filtered and concentrated under reduced pressure. The residue was separated by flash silica gel column chromatography to obtain the target compound (500 mg, light yellow solid). ESI-MS: 539.2 [M+1].

[0287] Step 3: A51-3 (270 mg, 0.5 mmol) was dissolved in 1,4-dioxane / water (12 mL / 4 mL) at room temperature, 2-amino-7-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[b]thiophene-3-carbonitrile (191 mg, 0.6 mmol), tetrakis(triphenylphosphine)palladium (60 mg, 0.05 mmol) and sodium carbonate powder (Na2CO3) (211 mg, 1 mmol) were added successively under nitrogen protection. The reaction mixture was stirred at 100 °C overnight under nitrogen protection. After the reaction was completed, ethyl acetate was extracted, the organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography to obtain the target compound (yellow solid, 183 mg). LC-MS m / z: 695.8 [M+H] + .

[0288] Step 4: The solid obtained in the previous step (180 mg, 0.26 mmol) was dissolved in dichloromethane (DCM) (6 mL) under ice bath cooling. Trifluoroacetic acid (0.5 mL) was added dropwise under ice bath cooling, and the reaction solution was warmed to room temperature and stirred for 4 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product which was directly used in the next step.

[0289] Step 5: To the stirred DCM (10 mL) solution of the product of the previous step A51-5 (59 mg), triethylamine (Et3N) (22 mg, 0.2 mmol) was added and cooled to 0 °C, and acryloyl chloride (10 mg, 0.11 mmol) was added. The reaction mixture was slowly warmed to room temperature, and LC-MS monitoring of the reaction showed that the reaction was complete. It was quenched with saturated sodium bicarbonate (NaHCO3) (10 mL), extracted with ethyl acetate, washed with water, dried over Na2SO4, concentrated, and purified by reverse phase preparative chromatography to obtain the product (16 mg, yellow powder), ESI-MS m / z: 635.2 [M+H] + , 1 H-NMR (400 MHz, DMSO-d6): δ 8.11 (s, 2H), 7.32 (dd, J = 8.6, 5.4 Hz, 1H), 7.21 (dd, J = 9.4, 8.2 Hz, 1H), 6.31 (dd, 1H), 5.86 (dd, 1H), 5.26 (m, 1H), 4.89-4.85 (m, 1H), 4.15-4.01 (m, 7H),, 3.96-3.81 (m, 2H), 3.13-3.01 (m, 4H), 2.89-2.80 (m, 1H), 2.71 (s, 3H), 2.19-1.97 (m, 3H), 1.84-1.69 (m, 3H).

[0290] The following example compounds were obtained by using the general preparation method of the examples, by analogy with the procedure of example 51:

[0291]

[0292]

[0293] Example 62

[0294]

[0295] Step one: To a solution of (S)-3-(hydroxymethyl)piperazine-1 -carboxylic acid tert-butyl ester (1.04 g, 4.8 mmol) in tetrahydrofuran (50 mL) was added sodium hydride (60% in mineral oil, 595 mg, 4.12 mmol) at room temperature. After the mixture was stirred at room temperature for 30 minutes, a solution of compound A62-1 (1.32 g, 4 mmol) in tetrahydrofuran (15 mL) was added. After the reaction mixture was heated to 60 degrees, the reaction was continued for 3 hours. After cooling to room temperature, the reaction was quenched by the addition of saturated aqueous ammonium chloride solution (30 mL) and the reaction was concentrated under reduced pressure to remove most of the organic solvent. To the residue was added ethyl acetate (50 mL) and water (20 mL). The separated aqueous phase was extracted with ethyl acetate twice. The combined organic phase was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 : 1) to give a yellow solid compound (1.05 g). LC-MS m / z: 525.0 [M+H] + .

[0296] Step two: To a solution of the above intermediate compound (1.05 g, 2 mmol) in dichloromethane (30 mL) was added BOP-Cl (763 mg, 3 mmol) and diisopropylethylamine (2.39 g, 18.5 mmol). The reaction mixture was stirred at room temperature for 4 hours. LC-MS showed that the reaction was substantially complete. The reaction was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2: 1) to give a yellow solid compound (0.75 g). LC-MS m / z: 506.0 [M+H] + .

[0297] Step three: To a solution of A62-3 (750 mg, 1.5 mmol) in N,N-dimethylformamide (30 mL) was added potassium fluoride (223 mg, 3 mmol) under nitrogen atmosphere. The reaction mixture was heated to 120 °C overnight. After the reaction was complete by LC-MS, water (60 mL) was added. The reaction was extracted with ethyl acetate (100 mL) twice. The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10: 1) to give the intermediate compound (498 mg) as a white solid. LC-MS m / z: 491.0 [M+H] + .

[0298] Step four: To a solution of the above intermediate compound (491 mg, 1 mmol) and N,N-bis(4-methoxybenzyl)-4-methyl-6-(tri-n-butylstannyl)pyridin-2-amine (650 mg, 1.02 mmol) in 1,4-dioxane (20 mL) was added tetrakis(triphenylphosphine)palladium (173 mg, 0.15 mmol), copper iodide (57 mg, 0.3 mmol) and lithium chloride (65 mg, 1.5 mmol) under nitrogen atmosphere. The reaction mixture was heated to 120 °C overnight. The reaction was complete by LC-MS. The reaction mixture was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2: 1) to give the compound (432 mg) as a white solid. LC-MS m / z: 759.3 [M+H] + .

[0299] Step five: To a solution of the above intermediate compound (432 mg, 0.57 mmol) in N,N-dimethylformamide (10 mL) was added N-iodosuccinimide (129 mg, 0.57 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was almost complete by LC-MS. The reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate (50 mL) twice. The combined organic phase was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3: 1) to give the compound (510 mg) as a white solid. LC-MS m / z: 885.2 [M+H] + .

[0300] Step six: To a solution of the above intermediate compound (510 mg, 0.58 mmol) in N,N-dimethylformamide (10 mL) was added cuprous iodide (385 mg, 2.02 mmol), hexamethylphosphoramide (1.20 g, 6.7 mmol) and methyl fluorosulfonyl difluoroacetate (1.29 g, 6.7 mmol) under nitrogen atmosphere. The reaction mixture was heated to 90 °C and stirred for 3 hours. After the reaction was completed by LC-MS detection, the reaction mixture was added with 50 mL of water, then extracted with ethyl acetate (50 mL) twice. The combined organic phase was dried over anhydrous sodium sulfate, then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3:1) to give a white solid compound (220 mg). LC-MS m / z: 827.3 [M+H] + .

[0301] Step seven: To a suspension of sodium hydride NaH (5.3 mg, 0.22 mmol) in tetrahydrofuran (5 mL) was added ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (35.3 mg, 0.22 mmol) at 0 °C. After the reaction mixture was stirred at this temperature for half an hour, a solution of A2-2 (165 mg, 0.2 mmol) in tetrahydrofuran (5 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction was substantially complete by LC-MS detection. To the reaction mixture was added saturated aqueous ammonium chloride solution (50 mL), then extracted with ethyl acetate (20 mL) three times. The combined organic phase was dried, then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 30:1) to give a yellow solid product (84 mg). LC-MS [M+H] + : m / z 966.4.

[0302] Step eight: The solid (84 mg) obtained in the previous step was dissolved in dichloromethane (DCM) (3 mL) under ice-bath cooling. Trifluoroacetic acid (0.5 mL) was added dropwise under ice-bath cooling. After the addition was completed, the reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure to give a crude product which was used directly in the next step.

[0303] Step nine: To a stirred solution of the product of previous step (30 mg) in DCM (10 mL) was added triethylamine (Et3N) (10 mg, 0.1 mmol) and cooled to 0 °C, acryloyl chloride (5 mg, 0.05 mmol) was added. The reaction mixture was slowly warmed to room temperature, LC-MS monitoring of the reaction showed the reaction to be complete, quenched with saturated sodium bicarbonate (NaHC03) (10 mL), extracted with ethyl acetate, washed with water, dried over Na2S04, concentrated, purified by reverse phase preparative chromatography to give the product (11 mg, yellow powder), ESI-MS m / z: 680.2 [M+H]+, 1H-NMR (400 MHz, DMSO-d6): δ 1H NMR (400 MHz, CD3OD) δ 7.98 (s, 1H), 6.97 (s, 1H),, 7.25 (dd, J = 9.6, 8.4 Hz, 1H), 6.64-6.60 (m, 1H), 5.94-5.86 (m, 1H), 5.28-5.24 (m, 1H), 4.90-4.86 (m, 1H), 4.18-4.08 (m, 8H), 3.99-3.88 (m, 2H), 3.16-3.09 (m, 4H), 2.91-2.88 (m, 1H), 2.51 (s, 3H), 2.21-1.98 (m, 3H), 1.89-1.67 (m, 3H).

[0304] The following example compounds were prepared using the general preparation methods of the examples, following procedures analogous to those of Example 62:

[0305]

[0306] Test Example 1: Effect of compounds of the present application on NCI-H358 cell proliferation and downstream signaling ERK phosphorylation

[0307] Test Method One (2D): NCI-H358 (lung cancer) (100 μL / well, 20,000 cells / mL) was seeded in 96-well plates and supplemented with 10% fetal bovine serum and 1% penicillin / streptomycin. Cells were treated with 0.5% dimethyl sulfoxide as a blank control and test compounds at a starting concentration of 10 μM, eight-fold dilutions in triplicate. Cells were incubated in a 5% CO2incubator for a certain period of time (5-7 days). At the end of the incubation, 10 μL of MTT stock solution (5 mg / mL) was added to each well. Plates were incubated at 37 °C for 4 h, and then the medium was removed. Dimethyl sulfoxide (100 μL) was added to each well, and then shaken thoroughly. The absorbance of the formazan product was measured at 570 nm on a Thermo Scientific Varioskan Flash multimode reader. IC 50 values were obtained by fitting the dose response data into a three-parameter nonlinear regression model using GraphPad Prism 6.0 software.

[0308] Results: The compounds of the examples provided by the present application have significant proliferation inhibitory activity against NCI-H358 cells, with IC 50 values of less than 100 nM; some of the example compounds, such as Examples 1, 2, 3, 4, 5, 6, 7, 10, 11, 12, 13, 15, 20, 25, 27, 29, 30, 32, 33, 35, 42, 44, 45, 51, 55, 60, 61, 64, 66, 67, 68, 71, 73, 74, have even more significant proliferation inhibitory activity against NCI-H358 cells, with IC 50 values of less than 20 nM, and some of the example compounds, such as Examples 1, 2, 3, 4, 5, 6, 13, 25, 32, 42, 66, 71, 74, have even more significant proliferation inhibitory activity against NCI-H358 cells, with IC

[0309] Test Method Two (3D): Tumor cells in the logarithmic growth phase were diluted with culture medium to a certain concentration and seeded in 96-well plates with ultra-low attachment surfaces, with 80 μL / well of culture medium. The cells were incubated at 37 °C in a humidity chamber overnight. The next day, serially diluted test compounds (10 concentrations, 3-fold dilutions) were added to the plates, 20 μL / well, and the plates were incubated in an incubator for 96 h. After the plates were removed and placed at room temperature, an equal volume of Cell Titer 3D reagent was incubated for 1 h, En Vision TMThe plate reader detects the signal. The signal is converted to percent inhibition using the following formula: % inhibition = 100 - [(test compound signal - median minimum signal) / (median maximum signal - median minimum signal) x 100]. The maximum signal is the signal value of the wells without inhibitor, and the minimum signal is the signal value of the wells containing the reference inhibitor sufficient to completely inhibit cell proliferation. The percent inhibition for each concentration of the compound is fitted to a curve by four-parameter nonlinear regression and the IC 50 .

[0310] Results: The compounds of the examples provided by the present application have an inhibitory activity on the proliferation of NCI-H358 cells, IC 50 all less than 100 nM, and some of the examples, such as Examples 1, 2, 3, 4, 5, 6, 7, 10, 11, 12, 15, 16, 20, 25, 27, 28, 29, 30, 31, 33, 35, 38, 42, 44, 45, 51, 55, 60, 61, 64, 66, 68, 71, 74, etc. have an inhibitory activity on the proliferation of NCI-H358 cells, IC 50 less than 10 nM, and some of the examples, such as Examples 2, 3, 7, 16, 25, 28, 31, 38, 42, 66, 74, etc. have an inhibitory activity on the proliferation of NCI-H358 cells, IC 50 even less than 2 nM.

[0311] Test method three (ERK phosphorylation): Cells of Miapaca-2 are seeded in 96-well plates at a certain concentration and incubated at 37°C, 5% CO2 in a cell incubator overnight. On the next day, the test compound is added to the wells in serial dilutions (5 concentrations, 3-fold dilution) for 24 h (Miapaca-2), and then the cells are lysed with lysis buffer containing protease and phosphatase inhibitors to extract proteins, and the level of p-ERK is detected by western blot method.

[0312] Results: The compounds of the examples provided by the present application, such as Examples 1, 2, 3, 4, 5, 6, 7, 11, 12, 13, 15, 19, 20, 21, 25, 26, 29, 31, 32, 34, 36, 37, 46, 55, 60, 64, 66, 68, 71, 74, etc. have a significant inhibitory effect on the phosphorylation of ERK of Miapaca-2, IC 50 all less than 20 nM, and some of the examples, such as Examples 1, 2, 3, 4, 5, 6, 20, 26, 32, 66, 74, etc. have an inhibitory activity on the phosphorylation of ERK of Miapaca-2, IC 50 even less than 2 nM.

[0313] Test example 2, pharmacokinetic experiment of the compound in mice

[0314] Test method: 1) The compound was weighed and added into 20% HP-B-CD in 50 mM pH 4.7 Acetate buffer, shaken and ultrasonicated to get a clear solution. 3 mice (ICR mice, male) were injected with the drug via tail vein after fasting overnight, and the dose was 2 mg / kg. 2) The compound was weighed and added into 0.5% CMC + 1% Tween 80, shaken and ultrasonicated to get a suspension. 3 mice (ICR mice, male) were orally administered with the drug after fasting overnight, and the dose was 10 mg / kg. 3) Sample collection: blood was collected from the eye orbit, and sodium heparin was used for anticoagulation. The collected sample was placed on ice, and the plasma was separated by centrifugation (8000 rpm, 6 min, 2-8°C) within 1 hour. 40 uL of the plasma sample was taken, 160 uL of cold acetonitrile containing an internal standard was added, vortexed for 1 min, and centrifuged at 18000 rpm for 10 min. The supernatant was transferred to a 96-well plate, and 5 uL was injected for analysis. 4) The drug concentration was analyzed by LC-MS / MS method, and the pharmacokinetic parameters were calculated by Phoenix WinNolin software.

[0315] All documents referred to in this disclosure are incorporated by reference as if each were individually incorporated. In addition, it is to be understood that various alterations and modifications will become apparent to the skilled artisan after reviewing the above teachings of the present application and that the same are intended to be encompassed by the present disclosure.

Claims

1. A nitrogen-containing heterocyclic compound having the structure of Formula (I), or a pharmaceutically acceptable salt, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph, or prodrug thereof, ###0001### Formula (I) wherein: R is selected from the group consisting of hydrogen, deuterium, halogen; and wherein the heteroatoms in the above heterocycloalkyl (heterocyclyl), heteroaryl (heteroaromatic) are independently selected from N, O, P, S, Se, Si and different oxidation states thereof, and the number of heteroatoms is independently 1, 2, or 3. wherein, which satisfies one or more of the following conditions: R 1 is selected from hydrogen, deuterium, halogen, substituted or unsubstituted groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, amino, hydroxyl, -SH, C 6-10 Aryl, 5-10 membered heteroaryl, the "substituted" refers to one or more (preferably 1, 2 or 3) R 11 Replacement, R 11 independently selected from deuterium, halogen, cyano, amino, C 1-4 Alkyl, C 1-4 Alkoxy, =O, =S, -C 0-4 Alkyl-SF5 is substituted by a substituent; the R 11 optionally further substituted with one or more groups independently selected from deuterium or halogen; R 2 To wherein n is independently selected from 0, 1, 2, 3, or 4; R a1 is independently selected from H, halogen (preferably F), or a substituted or unsubstituted group of -OH, C1-C4 alkyl, C1-C4 alkoxy, -C1-C4 alkyl-OH, amino, or multiple R a1 together with the atom to which they are attached form a 3-6 membered cycloalkyl or heterocycloalkyl; said "substituted" means substituted with 1, 2, or 3 R a11 , R a11 is independently selected from halogen, -OH, C1-C4 alkyl, C1-C4 alkoxy, (C 1-3 alkyl)2-N-(CO)-, (C 1-3 alkyl)-NH-(CO)-; R 4 selected from hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted: 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-SF5, C 3-18 cycloalkyl-C 1-6 alkyl-, 3-18 membered heterocyclyl-C 1-6 alkyl-, -C 1-8 alkyl-OH, -C 1-8 alkyl-NH2, -C 0-6 alkyl-(CO)-NH2, -C 0-6 alkyl-(CO)-C 1-6 alkyl, -C 0-6 alkyl-(CO)-O-C 1-6 alkyl, -C 0-6 alkyl-P(O)(C 1-6 alkyl)2, amino, hydroxyl, -SH; "substituted" means substituted with one or more (1, 2, 3, or 4) R 41 substituents, R 41 are independently selected from deuterium, halogen, cyano, amino, 3-6 membered cycloalkyl, 4-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl-CO-, C 1-4 alkyl-S(O) r -, NH2-S(O) r -; r is independently selected from 0, 1, or 2; said R 41 are optionally further substituted with one or more (preferably 1, 2, or 3) R 411 substituents, said R 411 are independently selected from deuterium or halogen; or R 4 with R 5c and the atom to which they are attached form a substituted or unsubstituted 5-12 membered heterocyclic ring, "substituted" meaning substituted with one or more (1, 2, or 3) groups independently selected from deuterium, halogen, cyano, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl; R 5a , R 5b , R 5c , and R 5d are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted amino, hydroxyl, -SH, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl; said "substituted" is substituted with one or more (1, 2, 3, or 4) R 51 , R 51 is independently selected from the group consisting of deuterium, halogen, cyano, amino, 3-6 membered cycloalkyl, 4-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl-CO-, C 1-4 alkyl-S(O) r -, NH2-S(O) r -; r is independently selected from 0, 1, or 2; said R 51 is optionally further substituted with one or more (preferably 1, 2, or 3) R 511 , R 511 is independently selected from deuterium or halogen; R 6a , R 6b each independently is selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted: 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-12 cycloalkyl-C 1-6 alkyl-, 3-12 membered heterocyclyl-C 1-6 alkyl-, C 1-8 alkoxy, -C 1-8 alkyl-OH, -C 1-8 alkyl-NH2, -C 0-6 alkyl-(CO)-NH2, -C 0-6 alkyl-(CO)-C 0-6 alkyl, -C 0-6 alkyl-(CO)-O-C 0-6 alkyl, -C 0-6 alkyl-P(O)(C 0-6 alkyl)2, amino, hydroxyl, -SH, C 0-4 alkyl-S(O) r -; said "substituted" means substituted with one or more (1, 2, 3, or 4) R 61 substituents, R 61 are independently selected from the group consisting of deuterium, halogen, cyano, amino, 3-6 membered cycloalkyl, 4-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl-CO-, C 1-4 alkyl-S(O) r -, NH2-S(O) r -; r is independently selected from 0, 1, or 2; said R 61 are optionally further substituted with one or more (preferably 1, 2, or 3) R 611 substituents, R 611 are independently selected from deuterium or halogen; Y is independently selected from N or CR Y , R Y is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl; said "substituted" means substituted with one or more (1, 2, 3, or 4) R Y1 substituents, R Y1 is independently selected from deuterium, halogen, cyano, amino, 3-6 membered cycloalkyl, 4-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl-CO-, C 1-4 alkyl-S(O) r -, NH2-S(O) r -; r is independently selected from 0, 1, or 2; said R Y1 is optionally further substituted with one or more (preferably 1, 2, or 3) R Y11 substituents, said R Y11 is independently selected from deuterium or halogen; Z and M are independently selected from N, CR Z1 ; Each R Z1 are each independently selected from hydrogen, halogen, cyano, deuterium, substituted or unsubstituted groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, the above "substituted" refers to one or more (1, 2 or 3) R Z11 Replacement, R Z11 independently selected from deuterium, halogen, cyano, nitro, azido, amino, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 0-4 Alkyl-CO-, C 0-4 Alkyl-CO-NH-, C 1-4 Alkyl-C(O)O-, C 0-4 Alkyl-S(O) r -、NH2-S(O) r -、C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; each r is independently selected from 0, 1 or 2; Ar is selected from a substituted or unsubstituted 5-12 membered aromatic or heteroaromatic ring, "substituted" meaning substituted with one or more (preferably 1, 2, 3, 4, or 5) R 3 substituted; each R 3 is independently selected from the group consisting of cyano, amino, halogen, deuterium, substituted or unsubstituted: amino, hydroxy, -SH, C 1-8 alkyl (methyl), C 1-8 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl (ethynyl), C 3-12 cycloalkyl (cyclopropyl), 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-SF5, C 3-12 cycloalkyl-C 1-6 alkyl-, 3-12 membered heterocyclyl-C 1-6 alkyl-, C 1-8 alkoxy, -C 1-8 alkyl-OH, -C 1-8 alkyl-NH2, -C 0-6 alkyl-(CO)-NH2, -C 0-6 alkyl-(CO)-C 1-6 alkyl, -C 0-6 alkyl-(CO)-O-C 1-6 alkyl, -C 0-6 alkyl-P(O)(C 1-6 alkyl)2; "substituted" means substituted with one or more (1, 2, 3, or 4) R 31 substituents, R 31 are independently selected from the group consisting of deuterium, halogen, cyano, amino, 3-6 membered cycloalkyl, 4-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl-CO-, C 1-4 alkyl-S(O) r -, NH2-S(O) r -; each r is independently selected from 0, 1, or 2; the R 31 are optionally further substituted with one or more (preferably 1, 2, or 3) R 311 substituents, the R 311 are independently selected from the group consisting of deuterium, halogen, or C 1-3 alkyl; (1) R is selected from the group consisting of hydrogen, deuterium, halogen; 2. The nitrogen-containing heterocyclic compound represented by the general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsomer, solvate, polymorph or prodrug thereof, characterized in that: which satisfies one or more of the following conditions: (1) R is selected from the group consisting of hydrogen, deuterium, halogen; (2) R 1 is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted: 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, amino, hydroxy, -SH, C 6-8 aryl, 5-8 membered heteroaryl, said "substituted" means substituted with one or more (preferably 1, 2 or 3) R 11 substituents; (3) R 11 independently selected from deuterium, halogen (preferably F, Cl); (4) R a1 independently selected from H, halogen (preferably F), and a group selected from the group consisting of -OH, C1-C4 alkyl, C1-C4 alkoxy; "substituted" means substituted with 1, 2, or 3 R a11 substituents; (5) R a11 independently selected from halogen, -OH, C1-C3 alkyl, C1-C3 alkoxy, (C 1-3 alkyl)2-N-(CO)-, (C 1-3 alkyl)-NH-(CO)-; (6) Y is independently selected from N or CR Y , R Y is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted groups: C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-5 Cycloalkyl, 3-6 membered heterocyclic group, C 6-9 Aryl, 5-9 membered heteroaryl; the "substituted" refers to one or more (1, 2, 3 or 4) R Y1 replace; (7) R Y1 independently selected from deuterium, halogen, cyano, amino, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, C1-6 alkyl, 6-9 aryl, 5-9 membered heteroaryl, C1-6 alkyl, 1-3 C1-6 alkyl, C1-6 alkoxy, 1-3 C1-6 alkyl, C1-6 alkoxy, 1-3 C1-6 alkyl, C1-6 alkoxy, 1-3 C1-6 alkyl, C1-6 alkoxy, r C1-6 alkyl, C1-6 alkoxy, r ; r is independently selected from 0, 1 or 2; said R Y1 optionally further substituted by one or more (preferably 1, 2 or 3) R Y11 substituents; (8) R Y11 independently selected from deuterium or halogen; (9) Z is N, M is N; Z is CR Z1 , M is N; Z is N, M is CR Z1 ; or Z is CR Z1 , M is CR Z1 ; (10) each R Z1 is independently selected from hydrogen, halogen, cyano, deuterium, a substituted or unsubstituted group: C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-9 aryl, 5-9 membered heteroaryl; said "substituted" means substituted with one or more (1, 2, or 3) R Z11 substituents; (11) R Z11 independently selected from deuterium, halogen, cyano, nitro, azido, amino, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, C 0-3 alkyl-CO-, C 0-3 alkyl-CO-NH-, C 1-3 alkyl-C(O)O-, C 0-3 alkyl-S(O) r -, NH2-S(O) r -, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-9 aryl, 5-9 membered heteroaryl; (12) Ar is selected from substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 6-10 membered aromatic heterocycle; the "substituted" means that Ar is substituted with one or more (preferably 1, 2, 3, 4, or 5) R 3 substituents; (13) each R 3 is independently selected from the group consisting of cyano, halo, deuterium, substituted or unsubstituted: amino, hydroxyl, -SH, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-9 aryl, 5-9 membered heteroaryl, -C 0-6 alkyl-SF5, C 3-6 cycloalkyl-C 1-3 alkyl-, 3-6 membered heterocyclyl-C 1-3 alkyl-, C 1-6 alkoxy, -C 1-6 alkyl-OH, -C 1-6 alkyl-NH2, -C 0-6 alkyl-(CO)-NH2, -C 0-4 alkyl-(CO)-C 1-3 alkyl, -C 0-4 alkyl-(CO)-O-C 1-3 alkyl, -C 0-4 alkyl-P(O)(C 1-3 alkyl)2; said "substituted" means substituted with one or more (1, 2, 3, or 4) R 31 substituents; (14) R 31 independently selected from deuterium, halogen, cyano, amino, 3- to 5-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, C 6-9 aryl, 5- to 9-membered heteroaryl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkyl-CO-, C 1-3 alkyl-S(O) r -, NH2-S(O) r ; each r is independently selected from 0, 1 or 2; said R 31 optionally further substituted by one or more (preferably 1, 2 or 3) R 311 substituents; (15) R 311 independently selected from deuterium, halogen or C 1-3 alkyl; (16) R 4 hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-9 aryl, 5-9 membered heteroaryl, -C 0-4 alkyl-SF5, C 3-6 cycloalkyl-C 1-4 alkyl-, 3-6 membered heterocyclyl-C 1-4 alkyl-, -C 1-6 alkyl-OH, -C 1-6 alkyl-NH2, -C 0-3 alkyl-(CO)-NH2, -C 0-3 alkyl-(CO)-C 1-3 alkyl, -C 0-3 alkyl-(CO)-O-C 1-3 alkyl, -C 0-3 alkyl-P(O)(C 1-3 alkyl)2, amino, hydroxyl, -SH; said "substituted" means substituted with one or more (1, 2, 3, or 4) R 41 substituents; (17) R 41 independently selected from deuterium, halogen, cyano, amino, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, C1-6alkyl, 6-9 aryl, 5-9 membered heteroaryl, C1-6alkyl, 1-4 C1-6alkyl, C1-6alkyl-, 1-4 C1-6alkyl, C1-6alkyl-, 1-4 C1-6alkyl, C1-6alkyl-, 1-4 C1-6alkyl, C1-6alkyl-, r C1-6alkyl, C1-6alkyl-, r ; r is independently selected from 0, 1 or 2; said R 41 optionally further substituted by one or more (preferably 1, 2 or 3) R 411 ; (18) R 411 independently selected from deuterium or halogen; (19)R 4 With R 5c and the atoms to which they are connected form a substituted or unsubstituted 6-9 membered heterocyclic ring; the "substituted" refers to one or more (1, 2, 3 or 4) R 41 replace; (20)R 5a (21)R 5b (22)R 5c (23)R 5d each independently is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted: amino, hydroxyl, -SH, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-9 aryl, 5-9 membered heteroaryl; said "substituted" means substituted with one or more (1, 2, 3, or 4) R 51 substituents; (21) R 51 independently selected from deuterium, halogen, cyano, amino, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, C1-6 alkyl, 6-9 aryl, 5-9 membered heteroaryl, C1-6 alkyl, 1-3 C1-6 alkyl, C1-6 alkoxy, 1-3 C1-6 alkyl, C1-6 alkoxy, 1-3 C1-6 alkyl, C1-6 alkyl-CO-, 1-3 C1-6 alkyl, C1-6 alkyl-S(O)r-, r C1-6 alkyl, C1-6 alkyl-S(O)r-, r ; r is independently selected from 0, 1 or 2; said R 51 optionally further substituted by one or more (preferably 1, 2 or 3) R 511 substituents; (22) said R 511 independently selected from deuterium or halogen; (23) R 6a (23) R 6b each independently is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted: 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-9 aryl, 5-9 membered heteroaryl, C 3-6 cycloalkyl-C 1-3 alkyl-, 3-6 membered heterocyclyl-C 1-3 alkyl-, C 1-6 alkoxy, -C 1-6 alkyl-OH, -C 1-6 alkyl-NH2, -C 0-4 alkyl-(CO)-NH2, -C 0-4 alkyl-(CO)-C 0-3 alkyl, -C 0-4 alkyl-(CO)-O-C 0-3 alkyl, -C 0-4 alkyl-P(O)(C 0-3 alkyl)2, amino, hydroxyl, -SH, C 0-4 alkyl-S(O) r -; said "substituted" means substituted with one or more (1, 2, 3, or 4) R 61 substituents; (24) R 61 independently selected from deuterium, halogen, cyano, amino, methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, and cyclobutoxy; said R 61 optionally further substituted by one or more (preferably 1, 2, or 3) R 611 substituents; (25) R 611 independently selected from deuterium or halogen.

3. The nitrogenous heterocyclic compound according to claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph, or prodrug thereof, wherein which satisfies one or more of the following conditions: (1) R is selected from the group consisting of hydrogen, deuterium, halogen; (2) R 1 selected from hydrogen, deuterium, halogen, cyano, and substituted or unsubstituted methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, methylthio, and ethylthio; (3) R 11 independently selected from deuterium, F, Cl; (4) R a11 independently selected from F, Cl, -OH, methyl, methoxy, methoxymethyl, (methyl)2-N-(CO)-, (methyl)-NH-(CO)-; (5) R 4 selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted: 1-4 alkyl, C 1-4 alkoxy, (C 1-4 alkyl)NH-, (C 1-4 alkyl)2NH-, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl; said "substituted" means substituted with one or more (1, 2, 3, or 4) R 41 substituents; (6) R 41 independently selected from deuterium, halogen, C 1-3 alkyl, C 1-3 alkoxy; said R 41 optionally further substituted by one or more (preferably 1, 2, or 3) R 411 substituents; (7) R 5a (8) R 5b (9) R 5c (10) R 5d each independently is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted amino, hydroxyl, -SH, C 1-4 alkyl, C 1-4 alkoxy; "substituted" means substituted with one or more (1, 2, 3, or 4) R 51 substituents; (8) R 51 independently selected from deuterium, halogen, C 1-3 alkyl, C 1-3 alkoxy.

4. The nitrogenous heterocyclic compound according to claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph, or prodrug thereof, wherein which satisfies one or more of the following conditions: (1) When R 4 With R 5c and the atoms to which they are connected form a substituted or unsubstituted heterocycle, wherein the "substituted" refers to being substituted by one or more (1, 2 or 3) groups independently selected from the following: deuterium, halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 alkyl halide; (2) R 6a , R 6b each independently is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted hydroxy, amino, C 1-6 alkyl; "substituted" means substituted with one or more (1, 2, 3, or 4) R 61 substituents; (3) R 611 independently selected from deuterium, F, Cl; (4) Y is independently selected from N or CR Y , R Y is selected from hydrogen, deuterium, halogen; (5) each R Z1 each independently selected from hydrogen, F, CI, cyano, deuterium, substituted or unsubstituted C 1-4 alkyl, C 1-4 alkoxy; (6) Ar is selected from the group consisting of substituted or unsubstituted phenyl, pyridyl, naphthyl, benzopyridyl, benzothiazolyl, benzothienyl, benzimidazolyl; "substituted" means that Ar is substituted with one or more (preferably 1, 2, 3, 4, or 5) R 3 substituents; (7) R 3 independently selected from deuterium, halogen, cyano, trifluoromethyl, substituted or unsubstituted: amino, hydroxy, -SH, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl; said "substituted" means substituted with one or more (1, 2, 3, or 4) R 31 substituents; (8) R 31 independently selected from halogen, amino, cyano, hydroxy, ethynyl, cyclopropyl, methyl, trifluoromethyl; (9) R 4 selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted amino, hydroxyl, -SH, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, methylthio, ethylthio, amino, monomethylamino, monoethylamino, and dimethylamino; "substituted" means substituted with one or more (1, 2, or 3) R 41 substituents; (10) R 5a , R 5b , R 5c , and R 5d are each independently selected from hydrogen, deuterium, halogen, cyano, a substituted or unsubstituted group selected from methyl, ethyl, said "substituted" by one or more (1, 2, 3, or 4) R 51 .

5. The nitrogenous heterocyclic compound according to claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph, or prodrug thereof, wherein (7) Z, M are independently selected from N, -C-Cl, -C-F, -C-CN; (1) R 2 selected from the following structures: (2) R 4 selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted: 1-4 alkyl, C 1-4 alkoxy; "substituted" means substituted with one or more (1, 2, 3, or 4) R 41 substituents; (4) R 5a , R 5b , R 5c and R 5d are each independently selected from hydrogen, F, Cl, cyano, methyl, methoxy; (5) R 6a , R 6b independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, cyclopropyl, cyclobutyl, oxetanyl, oxolanyl, azetidinyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy and cyclobutoxy, oxetanyl-CH2-, cyclopropyl-CH2-, pyrrolyl-CH2-, -(CO)-O-CH3, CH3-O-CH2-, CH3-SO2-CH2-, -CH2-NH2, -(CO)-CH3, -CO-NH2, -CH2-SH; said "substituted" means substituted with one or more (1, 2, 3 or 4) R 61 substituents; (6) Y is independently selected from N or CR Y , R Y is selected from hydrogen, deuterium, F, Cl; (8) Ar is selected from the following structures: ###0002### which satisfies one or more of the following conditions: wherein t is independently selected from 0, 1, 2, 3, 4, or 5; R 3 As defined in claim 1.

6. The nitrogenous heterocyclic compound according to claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph, or prodrug thereof, wherein (1) Ar is selected from the following structures: ###0003### 8. A pharmaceutical composition comprising an effective amount of a nitrogen-containing heterocyclic compound of any one of claims 1-7, or a pharmaceutically acceptable salt, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph, or prodrug thereof, and a pharmaceutically acceptable carrier. (2) R 2 selected from (3) R 4 selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted methoxy, ethoxy, methyl, ethyl; "substituted" means substituted with one or more (1, 2, 3, or 4) R 41 substituents; (4) R 6a (4) R 6b each independently is selected from hydrogen, methyl, ethyl, cyanomethyl, cyanoethyl.

7. The compound of any one of claims 1, or a pharmaceutically acceptable salt, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph, or prodrug thereof, wherein, The compound has the structure ​ 9. Use of the nitrogen-containing heterocyclic compound, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereoisomer, tautomer, rotamer, solvate, polymorph or prodrug thereof, or the pharmaceutical composition of claim 8 in the manufacture of a Ras mutant protein inhibitor or drug; the Ras mutant protein can be KRAS G12c ; the drug can be a drug for treating a disease associated with the activity or expression level of the Ras mutant protein; or the drug can be a drug for treating a tumor; the tumor is independently selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, intestinal cancer, cholangiocarcinoma, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, kidney cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer, pancreatic cancer.

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