Nucleoside compound as well as preparation method, composition and medical application thereof

Abstract

The invention relates to the technical field of medicines, in particular to a nucleoside compound, a preparation method thereof, a composition of the nucleoside compound and application of the nucleoside compound in medicines. The compound provided by the invention has a structure as shown in a formula (I). The compound or the pharmaceutically acceptable salt thereof can be used as an METTL3 inhibitor and has good activity. # imgabs0 #

Description

[0001] Related Applications

[0002] This application claims priority to Chinese patent application No. 2023112253556, filed on September 21, 2023, entitled “Nucleoside compounds, methods for their preparation, compositions thereof and their use in medicine”, the entire text of which is hereby incorporated by reference. Technical Field

[0003] The present invention relates to the field of medical technology, and in particular to nucleoside compounds, preparation methods thereof, compositions thereof, and their use in medicine. In particular, it relates to a compound having a structure represented by formula (I), or a pharmaceutically acceptable salt thereof, a preparation method thereof, a composition thereof, and their use in preparing a drug for treating or preventing a disease related to or mediated by METTL3 activity. Background Art

[0004] Among all RNA modifications, N 6 -methyladenine (m 6 A) is the most abundant chemical modification. This modification is distributed in all RNA types, including mRNA, lincRNA, pri-miRNA and rRNA, and plays a key role in physiological functions and disease occurrence by regulating gene expression. 6 METTL14 is a dynamic and reversible modification, which is regulated by methylase "writers" (METT3-METTL14, METTL16 and METTL5, etc.), methylation recognition proteins "readers" (YTHDF1-3, YTHDC1 and YTHDC2), and demethylase "erasers" (ALBH5 and FTO). 6 METTL3 is a key methylase for RNA modification. It uses S-adenosylmethionine (SAM) as a methyl donor to provide a methylation catalytic site for the substrate RNA, while METTL14 plays a role in recognizing the substrate and stabilizing the complex. The METTL3-METTL14 complex requires the assistance of Wilms't tumor-associated protein (WTAP) to ensure that it is located at the correct modification site. METTL3 specifically modifies target RNA, thereby regulating biological processes such as cell cycle, cell proliferation, differentiation, migration, invasion, apoptosis, metabolism and immune response.

[0005] Abnormal expression of METTL3 can induce the occurrence and development of various types of tumors, including acute myeloid leukemia (AML), breast cancer, liver cancer, malignant glioma, bladder cancer, gastric cancer, prostate cancer, lung cancer, colorectal cancer, pancreatic cancer, osteosarcoma, oral squamous cell carcinoma, thyroid cancer, uveal melanoma, ovarian cancer, head and neck squamous cell carcinoma, skin squamous cell carcinoma and nasopharyngeal carcinoma. In AML, the transcription factor CEBPZ stably recruits METTL3 to the promoter of specific active genomes, resulting in mRNA expression of the corresponding mRNA. 6 A methylation and increased its translation, one of the important targets SP1 regulates c-MYC expression. Therefore, METTL3 can be used as a potential therapeutic target for myeloid leukemia. + Specific knockout of the Mettl3 gene in T cells blocked the differentiation of T cells, thereby inhibiting the occurrence of enteritis in the enteritis model induced by adoptive transfer of T cells. During the outbreak of viral infection, METTL3 is overexpressed, regulates the methylation of IFNB mRNA and reduces its stability. When METTL3 is inhibited, the stability and expression of IFNB mRNA increase, mediating the expression of type I interferon. In autosomal dominant polycystic kidney disease (ADPKD), METTL3 is often highly expressed, and inhibition of METTL3 slows down the growth of cysts. Therefore, in addition to playing a key role in malignant tumors, METTL3 can also be used as a potential target for the treatment of autoimmune diseases, inflammatory diseases such as viral infections, and ADPKD. In summary, the development of METTL3 inhibitors has the potential to treat a variety of diseases.

[0006] Currently, no specific METTL3 inhibitor has been approved for marketing. Storm's small molecule STC-15, which has made the fastest progress, will enter Phase I clinical trials in November 2022. Therefore, there are significant unmet clinical needs in the relevant patient population. Summary of the invention

[0007] The purpose of the present invention is to provide a nucleoside compound that can be used as a METTL3 inhibitor and has good activity, a preparation method thereof, a composition thereof and a medical use thereof.

[0008] The first aspect of the present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof:

[0009]

[0010] in,

[0011] R 0 Selected from H or CN;

[0012] R 1 , R 2 are independently selected from H, halogen, C1-6 Alkyl, -OR 3 , cyano or amino;

[0013] R 3 Selected from H, C 1-6 Alkyl or -C(=O)C 1-6 ;

[0014] Q is selected from -N- or -CR 4 ;

[0015] X is selected from -O-, -S- or -CH2-;

[0016] Y is selected from -O-, -S-, -CR a R b or -NR c ;

[0017] R a and R b independently selected from H, deuterium, C 1-6 Alkyl or halogen;

[0018] R c Select from H or C 1-6 alkyl;

[0019] Z is selected from -(CH2) n -、 Among them, -(CH2) n -、 Each is optionally substituted by 1-3 independently selected halogens; n is an integer from 1 to 6, n1 and n2 are independently integers from 0 to 4, and n1+n2=4;

[0020] Ring A is selected from benzene, naphthalene, a 4- to 7-membered monocyclic heterocycloalkyl, a 5- to 6-membered monocyclic heteroaromatic ring, or an 8- to 10-membered bicyclic heteroaromatic ring, wherein the benzene, naphthalene, 4- to 7-membered monocyclic heterocycloalkyl, 5- to 6-membered monocyclic heteroaromatic ring, and 8- to 10-membered bicyclic heteroaromatic ring are each optionally substituted by 1-6 independently selected R 7 replace;

[0021] R 7 Each occurrence is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, halogen, -CN, =O, -OR 7a 、-NR 7a R 7b 、-OC(=O)R 7a 、-NR 7a C(=O)R 7a 、-NR7a C(=O)NR 7a R 7b 、-C(=O)NR 7a R 7b 、-C(=O)R 7a OR -C(=O)OR 7a , wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4 to 7 membered heterocycloalkyl, phenyl and 5 to 6 membered heteroaryl are each optionally substituted with 0 to 3 substituents independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, halogen, -CN, -OR 7a 、-NR 7a R 7b 、-C(=O)NR 7a R 7b 、-C(=O)R 7a 、-C(=O)OR 7a 、-NR 7a C(=O)R 7a or -OC(=O)R 7a ;

[0022] R 7a and R 7b Independently selected from H, C 1-6 Alkyl, -(CH2) n OC 1-6 Alkyl, -(CH2) n NC 1-6 Alkyl C 1-6 Alkyl, C 3-8 cycloalkyl, 4 to 6 membered heterocycloalkyl, phenyl or 5 to 6 membered heteroaryl, wherein the C 1-6 Alkyl, -(CH2) n OC 1-6 Alkyl, -(CH2) n NC 1-6 Alkyl C 1-6 Alkyl, C 3-8 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally substituted with 0-3 substituents independently selected from halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl or 4- to 7-membered heterocycloalkyl; or R 7a and R 7bTogether with the nitrogen atom to which they are attached, they form a 4- to 6-membered heterocycloalkyl group, or R 7a and R 7b Together with the N atom to which they are attached and a heteroatom additionally selected from O, N or S, they form a 4- to 6-membered heterocycloalkyl group, wherein the 4- to 6-membered heterocycloalkyl group is optionally substituted by 0-3 substituents independently selected from halogen, C 1-4 Alkyl or C 1-4 Haloalkyl; m is an integer of 1 to 6;

[0023] R 4 Selected from H, deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 5-8 Cycloalkenyl, 4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkenyl, phenyl, 5- to 6-membered heteroaryl, halogen, -CN, -OR 4a 、-NR 4a R 4b 、-C(=O)R 4a 、-NR 4a C(=O)R 4a 、-OC(=O)R 4a 、-C(=O)OR 4a or -C(=O)NR 4a R 4b , wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 5-8 The cycloalkenyl, 4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkenyl, phenyl and 5- to 6-membered heteroaryl are each optionally substituted with 0-3 substituents independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, halogen, -CN, -OR 4a 、-NR 4a R 4b 、-C(=O)R 4a 、-C(=O)NR 4a R 4b NR 4a C(=O)R 4a 、-OC(=O)R 4a OR -C(=O)OR 4a ;

[0024] R 4a and R 4bIndependently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl or 4- to 6-membered heterocycloalkyl; or R 4a and R 4b Together with the nitrogen atom to which they are attached, they form a 4- to 6-membered heterocycloalkyl group, or R 4a and R 4b Together with the N atom to which they are attached and a heteroatom additionally selected from O, N or S, they form a 4- to 6-membered heterocycloalkyl group, wherein the 4- to 6-membered heterocycloalkyl group is optionally substituted by 0-3 substituents independently selected from halogen, C 1-4 Alkyl or C 1-4 Haloalkyl;

[0025] R 5 Selected from H, amino, hydroxy, halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, -NR 5a R 5b 、-NR 5a CR 5b R 5c OR 5a ;

[0026] R 5a , R 5b and R 5c Independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 5-8 Cycloalkenyl, 4 to 7 membered heterocycloalkyl, 4 to 7 membered heterocycloalkenyl, phenyl, 5 to 6 membered heteroaryl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 5-8 Cycloalkenyl, 4 to 7 membered heterocycloalkyl, 4 to 7 membered heterocycloalkenyl, phenyl and 5 to 6 membered heteroaryl are each optionally substituted with 0-3 substituents independently selected from halogen, C 1-4 Alkyl or C 1-4 haloalkyl; or R 5a and R 5b Together with the nitrogen atom to which they are attached, they form a 4- to 6-membered heterocycloalkyl group, or R 5a and R 5b Together with the N atom to which they are attached and a heteroatom additionally selected from O, N or S, they form a 4- to 6-membered heterocycloalkyl group, wherein the 4- to 6-membered heterocycloalkyl group is optionally substituted by 0-3 substituents independently selected from halogen, C 1-4Alkyl or C 1-4 Haloalkyl;

[0027] R 6 Selected from H, halogen, amino or C 1-6 alkyl.

[0028] In some embodiments, the R 0 Selected from H.

[0029] In some embodiments, the R 1 and R 2 Independently selected from CH3, H or OH.

[0030] In some embodiments, the R 1 and R 2 Independently selected from H or OH.

[0031] In some embodiments, the R 1 is H or CH3, the R 2 For OH.

[0032] In some embodiments, the R 3 For H.

[0033] In some embodiments, Q is -CR 4 .

[0034] In some embodiments, the R 4 Selected from H, halogen or one of the following groups:

[0035]

[0036] In some embodiments, X is -O-.

[0037] In some embodiments, said Y is -O-.

[0038] In some embodiments, Z is -CH2-.

[0039] In some embodiments, the ring A is selected from quinoline, quinazoline, 2,3-naphthyridine, quinoxaline, cinnoline, 1,5-naphthyridine, pyridopyrimidine, pyridopyrazine, pteridine, indole, isoindole, indolizine, indazole, benzimidazole, benzotriazole, benzoxazole, benzisoxazole, benzothiazole, benzofuran, isobenzofuran, benzothiophene, benzothiadiazole, azaindole, purine, imidazopyridine, pyrrolopyrimidine, imidazopyridazine, imidazopyrazine, pyrazolopyrimidine, pyrazolopyridine, pyrazolotriazine, oxazolopyridine, isoxazolopyridine, thiazolopyridine, isothiazolopyridine, thienopyridine, pyridine, piperidine or benzene, wherein The quinoline, quinazoline, 2,3-naphthyridine, quinoxaline, cinnoline, 1,5-naphthyridine, pyridopyrimidine, pyridopyrazine, pteridine, indole, isoindole, indolizine, indazole, benzimidazole, benzotriazole, benzoxazole, benzisoxazole, benzothiazole, benzofuran, isobenzofuran, benzothiophene, benzothiadiazole, azaindole, purine, imidazopyridine, pyrrolopyrimidine, imidazopyridazine, imidazopyrazine, pyrazolopyrimidine, pyrazolopyridine, pyrazolotriazine, oxazolopyridine, isoxazolopyridine, thiazolopyridine, isothiazolopyridine, thienopyridine, pyridine, piperidine and benzene are each optionally replaced by 1-6 independently selected R 7 replace.

[0040] In some embodiments, the compound has a structure shown in any one of Formula (II)-1 to Formula (II)-10:

[0041]

[0042]

[0043] Here, p is an integer from 0 to 3.

[0044] In some embodiments, the R 7 Each occurrence is independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen, =O, OR 7a or -NR 7a R 7b .

[0045] In some embodiments, the R 7a and R 7b Independently selected from H, C 1-6 Alkyl, -(CH2) m OC 1-6 Alkyl, -(CH2) m NC 1-6 Alkyl C 1-6 Alkyl or C 3-8 Cycloalkyl, or R 7a and R7b Together with the nitrogen atom to which they are attached, they form a 4- to 6-membered heterocycloalkyl group, wherein the 4- to 6-membered heterocycloalkyl group is substituted by 0-3 substituents independently selected from halogen or C 1-6 alkyl.

[0046] In some embodiments, the R 7a and R 7b The 4- to 6-membered heterocycloalkyl group substituted with 0-3 substituents formed together with the N atom to which they are attached is selected from one of the following groups:

[0047]

[0048] In some embodiments, the R 5 is -NH2.

[0049] In some embodiments, the R 6 is -H.

[0050] In some embodiments, the compound has a structure shown in any one of formulas (III)-1 to (III)-12:

[0051]

[0052]

[0053] In some embodiments, the compound is selected from one of the structures in Table 1:

[0054] Table 1

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061] The second invention of the present invention provides a method for preparing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0062] Under acidic conditions, removing the protecting group from the compound having the structure represented by formula (I-1) to obtain a compound having the structure represented by formula (I-2), and obtaining a compound having the structure represented by formula (I) through the compound having the structure represented by formula (I-2);

[0063]

[0064] Among them, the R 0 , R 1 , R 2 , R 3 , Q, X, Y, Z, Ring A, R 5 and R 6 As described in the first aspect of the present invention.

[0065] In some embodiments, the acid used in the acidic condition is selected from trifluoroacetic acid or hydrochloric acid, preferably trifluoroacetic acid.

[0066] The third aspect of the present invention provides a pharmaceutical composition, which comprises the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

[0067] The fourth aspect of the present invention provides the use of the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition described in the third aspect of the present invention in the preparation of a drug for treating and / or preventing diseases related to or mediated by METTL3 activity.

[0068] In some embodiments, the disease is selected from cancer, autoimmune disease, inflammatory disease or autosomal dominant polycystic kidney disease. Preferably, it is cancer.

[0069] In some embodiments, the cancer is selected from acute myeloid leukemia, breast cancer, liver cancer, malignant glioma, bladder cancer, gastric cancer, prostate cancer, lung cancer, colorectal cancer, pancreatic cancer, osteosarcoma, oral squamous cell carcinoma, thyroid cancer, uveal melanoma, ovarian cancer, head and neck squamous cell carcinoma, skin squamous cell carcinoma or nasopharyngeal carcinoma. Preferably, it is acute myeloid leukemia.

[0070] The fifth aspect of the present invention provides the use of the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition described in the third aspect of the present invention in combination with one or more other anti-tumor drugs in the preparation of a drug for treating and / or preventing cancer associated with or mediated by METTL3 activity.

[0071] In some embodiments, the anti-tumor drug is selected from alkylating agents (cyclophosphamide, ifosfamide, melphalan, busulfan, nimustine, ranimustine, dacarbazine, temozolomide, nitrogen mustard hydrochloride, dibromomannitol, etc.), platinum complex agents (cisplatin, carboplatin, oxaliplatin, etc.), metabolic antagonists (methotrexate, 5-fluorouracil, tegafur, gemcitabine, capecitabine, fulvestrant, pemetrexed, etc.), plant alkaloids (vincristine, vinblastine, vindesine, etoposide, docetaxel, paclitaxel, irinotecan, vinorelbine, mitoxantrone, vinflunine, topotecan, etc.), hormone anticancer agents (leuprorelin, goserelin, exemestane, letrozole, etc.), , anastrozole, dutasteride, etc.), antibody drugs (trastuzumab, pertuzumab, rituximab, cetuximab, panitumumab, bevacizumab, etc.), VEGFR or EGFR inhibitors (sunitinib, sorafenib, imatinib, gefitinib, erlotinib, vandetanib, pazopanib, lapatinib, etc.), mTOR inhibitors (everolimus, sirolimus, zotarolimus, etc.), PI3K kinase inhibitors (BKM-120, XL-147, BEZ-235, etc.), B-Raf inhibitors (vemurafenib, GSK-2118436, etc.) or AKT inhibitors (perifosine, MK-2206, etc.), etc.

[0072] Beneficial effects:

[0073] The present invention provides a series of novel nucleoside compounds, which can be used as METTL3 inhibitors with good activity and can be used as drugs for treating and / or preventing diseases related to or mediated by METTL3 activity. DETAILED DESCRIPTION

[0074] Definition of terms

[0075] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0076] The term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon group. Preferably, the alkyl group contains 1 to 20 carbon atoms, more preferably 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl or, n-decyl, etc.

[0077] The term "alkenyl" refers to an unsaturated branched or straight chain group having at least one double bond. Preferably, the alkenyl group contains 2 to 20 carbon atoms, more preferably 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms or 2 to 4 carbon atoms. Alkenyl includes but is not limited to propenyl, 1,3-butadienyl, 1-butenyl, hexenyl, pentenyl, heptenyl, octenyl, etc.

[0078] The term "alkynyl" refers to an unsaturated branched or straight chain group having at least one triple bond. Preferably, the alkynyl group contains 2 to 20 carbon atoms, more preferably 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms or 2 to 4 carbon atoms. Alkynyl includes, but is not limited to, propynyl, 1-butynyl, hexynyl, pentynyl, hexynyl, heptynyl, octynyl, etc.

[0079] The term "cycloalkyl" refers to a fully saturated monocyclic, bicyclic or tricyclic hydrocarbon radical of 3-12 carbon atoms, preferably 3-9 or more preferably 3-8 carbon atoms. Exemplary monocyclic carbocyclic radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl. Exemplary bicyclic carbocyclic radicals include bornyl, decahydronaphthyl, bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.1] heptenyl, 6,6-dimethyl bicyclo [3.1.1] heptyl, 2,6,6-trimethyl bicyclo [3.1.1] heptyl, bicyclo [1.1.1] pentane or bicyclo [2.2.2] octyl. Exemplary tricyclic carbocyclic radicals include adamantyl.

[0080] The term "cycloalkenyl" refers to a partially unsaturated monocyclic, bicyclic or tricyclic hydrocarbon radical having 3-12 ring carbon atoms, preferably 3-9, or more preferably 3-8 carbon atoms and having one or more double bonds. Exemplary monocyclic cycloalkenyls include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, etc. Exemplary bicyclic cycloalkenyls include, but are not limited to, bicyclo[2.2.1]hept-5-enyl and bicyclo[2.2.2]oct-2-enyl.

[0081] The term "haloalkyl" refers to an alkyl group as defined herein that is substituted with one or more halogen groups as defined herein. Preferably, haloalkyl can be monohaloalkyl, dihaloalkyl or polyhaloalkyl, including perhaloalkyl. Monohaloalkyl can have an iodine, bromine, chlorine or fluorine substituent. Dihaloalkyl and polyhaloalkyl can be substituted with two or more identical halogen groups or a combination of different halogen groups. Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. Perhaloalkyl refers to an alkyl group in which all hydrogen atoms are replaced by halogen atoms. Preferred haloalkyls are trifluoromethyl and difluoromethyl.

[0082] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0083] The term "heterocycloalkyl" refers to a fully saturated monocyclic, bicyclic or tricyclic heterocyclyl containing 3-15 ring members, wherein at least one ring member is a heteroatom and wherein up to 10 ring members may be heteroatoms, wherein the heteroatoms are independently selected from O, S and N, and wherein N and S may be optionally oxidized to various oxidation states. In one embodiment, the heterocyclyl is a 4 to 7 membered heterocycloalkyl. Examples of heterocyclic groups include dihydrofuranyl, [1,3] dioxolane, 1,4-dioxane, 1,4-dithiane, piperazinyl, 1,3-dioxolane, imidazolidinyl, imidazolinyl, pyrrolidine, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathianyl, thiomorpholinyl, oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, azepine, Azepinyl, oxa Oxapinyl, oxazepine Oxazepinyl and diazepine Base (diazepinyl).

[0084] The term "heterocycloalkenyl" refers to a partially unsaturated monocyclic, bicyclic or tricyclic heterocyclic radical comprising 3-15 ring members, having at least one double bond, at least one ring member being a heteroatom, and wherein up to 10 ring members may be heteroatoms, wherein the heteroatoms are independently selected from O, S and N, and wherein N and S may be optionally oxidized to various oxidation states. In one embodiment, the heterocyclic radical is a 4 to 7 membered heterocycloalkenyl radical. Examples of heterocycloalkenyl radicals include 1,2,3,4-tetrahydropyridyl, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridyl, 1,4,5,6-tetrahydropyrimidyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, 3,4-dihydro-2H-pyran, dihydrofuranyl, fluoro-dihydro-furanyl, dihydro-thienyl and dihydro-thiopyranyl.

[0085] The term "heteroaryl" refers to a 5-14 membered monocyclic, bicyclic or tricyclic ring system having 1 to 10 heteroatoms independently selected from N, O or S, wherein the N and S may be optionally oxidized to various oxidation states, and wherein at least one ring in the ring system is aromatic. Examples of monocyclic heteroaryl groups include pyridyl, thienyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl. Bicyclic heteroaryl groups in which at least one ring is aromatic include quinolinyl, quinazolinyl, 2,3-naphthyridinyl, quinoxalinyl, cinnolinyl, 1,5-naphthyridinyl, pyridopyrimidinyl, pyridopyrazinyl, pteridinyl, indolyl, isoindolyl, indolizinyl, indazolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, benzothiadiazolyl, azaindolyl, purine, imidazopyridinyl, pyrrolopyrimidinyl, imidazopyridazinyl, imidazopyrazinyl, pyrazolopyrimidinyl, pyrazolopyridinyl, pyrazolotriazinyl, oxazolopyridinyl, isoxazolopyridinyl, thiazolopyridinyl, isothiazolopyridinyl, indolyl, benzofuranyl, quinoline, isoquinolyl, indazolyl, indolinyl, isoindolinyl, indolizinyl, benzimidazolyl and quinolinyl.

[0086] The term "alkoxy" refers to alkyl-O-, wherein alkyl is as defined above. Alkoxy includes, but is not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy, cyclohexyloxy, and the like. Preferably, the alkoxy has about 1-6 carbon atoms, more preferably about 1-4 carbon atoms.

[0087] In the chemical structure of the compound described in the present invention, the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be or Or include both configurations.

[0088] The compounds of the present invention may contain one or more asymmetric centers and may produce diastereomers and optical isomers, including all possible diastereomers and racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers and pharmaceutically acceptable salts thereof.

[0089] When the compound represented by the general formula (I) exists in tautomerism, unless otherwise stated, the present invention includes any possible tautomerism and pharmaceutically acceptable salts thereof, and mixtures thereof.

[0090] The term "substituted" or "substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, which are independently replaced by a corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions (by experiment or theory) without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0091] In the present invention, the single bond to which the substituent is connected runs through the corresponding ring, indicating that the substituent can be connected to any position of the ring, for example R is connected to any substitutable position of the benzene ring.

[0092] In the present invention Indicates connections to other atoms.

[0093] The term "optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "C optionally (optionally) substituted with halogen or cyano" 1-6 The term "alkyl" means that halogen or cyano may but need not be present, and the description includes the case where the alkyl is substituted with halogen or cyano and the case where the alkyl is not substituted with halogen and cyano.

[0094] The term "pharmaceutical composition" refers to a mixture containing one or more compounds described herein or their pharmaceutically acceptable salts and other chemical components, as well as other components such as pharmaceutically acceptable carriers, diluents or excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0095] The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which may be selected from an inorganic salt or an organic salt. Such salts are safe and effective when used in mammals and have the desired biological activity. Salts may be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

[0096] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0097] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given only for illustrative purposes and not for limitation.

[0098] The term "prevention and / or treatment" includes not only preventing and / or treating a disease, but also generally includes preventing the onset of a disease, slowing or reversing the progression of a disease, preventing or slowing the onset of one or more symptoms associated with a disease, reducing and / or alleviating one or more symptoms associated with a disease, reducing the severity and / or duration of the disease and / or any symptoms associated therewith and / or preventing a further increase in the severity of the disease and / or any symptoms associated therewith, preventing, reducing or reversing any physiological damage caused by the disease, and generally any pharmacological effect that is beneficial to the patient being treated.

[0099] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0100] The meanings of the abbreviations in the following examples are shown in Table 2:

[0101] Table 2

[0102] abbreviation meaning ACN Acetonitrile DCM Dichloromethane DIPEA N,N-Diisopropylethylamine DMAP 4-Dimethylaminopyridine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide MeOH Methanol <![CDATA[PdCl2(dppf)]]> 1,1-Bis(diphenylphosphine)ferrocenepalladium(II) chloride <![CDATA[Pd2(dba)3]]> Tris(dibenzylideneacetone)dipalladium Pre-HPLC Preparative HPLC TFA Trifluoroacetic acid THF Tetrahydrofuran

[0103] The structures of the compounds in the following examples were confirmed by hydrogen nuclear magnetic resonance spectroscopy and / or mass spectrometry (MS). The unit of NMR shift (δ) is 10 -6 (ppm). NMR was measured using Buker AVANCE III-400 and Buker AVANCE III-600 nuclear magnetic resonance spectrometers, with deuterated chloroform (Chloroform-d), deuterated dimethyl sulfoxide (DMSO-d6) and deuterated methanol (methanol-d4) as the solvents, and tetramethylsilane (TMS) as the internal standard. MS was measured using Finnigan LCQ Deca XP liquid chromatography-mass spectrometer or Agilent LC / MSD iQ mass liquid chromatography-mass spectrometer.

[0104] The thin layer chromatography silica gel plates in the following examples use Shanghai Test Silica Gel Prefabricated Plate GF254, and the silica gel plates used in thin layer chromatography (TLC) have a specification of 0.2 mm to 0.25 mm.

[0105] The silica gel column chromatography in the following examples uses Shanghai test 200-300 mesh silica gel as the stationary phase.

[0106] The known starting materials in the following examples can be synthesized by methods known in the art, or can be purchased from companies such as Bitmain Pharmaceutical Technology, Haohong Biopharmaceutical Technology, and Sinopharm Reagents.

[0107] In the following examples, unless otherwise specified, the anhydrous solvents used in the reactions were all treated with molecular sieves.

[0108] In the following examples, unless otherwise specified, the reactions can be carried out under an argon or nitrogen atmosphere, wherein the argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen balloon with a volume of about 1 L.

[0109] In the following examples, hydrogen atmosphere refers to a reaction bottle connected to a hydrogen generator under normal pressure.

[0110] In the following examples, unless otherwise specified, the reaction temperature is room temperature, 20°C to 30°C.

[0111] In the following examples, the pre-HPLC separation and purification conditions used are: Instrument model: EasySep TM 1050, chromatographic column: Globalsil TM C18-AP, 20*250mm, 5μm; mobile phase A: CAN (0.1% TFA); mobile phase B: water (0.1% TFA); flow rate: 10mL / min; elution gradient: 5% A to 30% A in 50min; wavelength: 214nm.

[0112] Intermediate A1: ((3aR,4R,6S,6aS)-6-(4-(((E)-(dimethylamino)methylene)amino)-5-iodopyrrolo[2,1-f][1,2,4]triazine-7-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxy-4-yl)methyl-4-methylbenzenesulfonate

[0113]

[0114] Step a: Preparation of intermediate A1-1

[0115] 4-Amino-7-bromopyrrolo[2,1-f][1,2,4]triazine (1.0 g, 4.69 mmol) was placed in a Schlenk flask, argon was replaced three times, anhydrous THF (40 mL) was added, and the mixture was stirred at room temperature for 5 minutes. An anhydrous THF solution (5 mL) of 1,2-bis(chlorodimethylsilyl)ethane (1.1 g, 5.16 mmol) was added dropwise to the reaction system, and the mixture was stirred at room temperature for 10 minutes. Diisopropylamine (522.5 mg, 5.16 mmol) was added dropwise to the reaction system, and the mixture was stirred at room temperature for 5 minutes. The reaction system was placed in a -78°C low-temperature reactor, and n-BuLi (2.5 mol / L in hexane, 20.2 mmol) was slowly added dropwise, stirred for 15 minutes, and then (3R, 4R, 5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)dihydrofuran-2(3H)-one (3.9 g, 9.39 mmol) in anhydrous THF (5 mL) was added dropwise, and stirring was continued at -78°C for 2 hours. TLC detected that the raw material reaction was complete. The reaction system was warmed to room temperature, quenched by slowly adding 1.0 M citric acid, extracted with ethyl acetate (50 mL*3), washed with water, saturated sodium bicarbonate and saturated brine respectively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. It was separated and purified by silica gel column chromatography (PE / EA=1 / 1) to obtain a yellow foamy solid (1.8 g, yield 70%).

[0116] ESI-MS m / z:553.0[M+H] + .

[0117] Step b: Preparation of intermediate A1-2

[0118] The intermediate A1-1 (1.8 g, 3.26 mmol) was dissolved in anhydrous DCM (50 mL), and triethylsilane (1.89 mg, 16.29 mmol) and boron trifluoride ether solution (1.2 mL, 9.77 mmol) were added in sequence at 0°C. The mixture was stirred at 0°C for 1 hour, and the raw material was completely consumed after TLC detection. Saturated sodium bicarbonate was added to quench, and the mixture was extracted with DCM, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography (PE / EA=3 / 7) to obtain a yellow oily liquid (1.7 g, yield 95%).

[0119] ESI-MS m / z:537.1[M+H] + .

[0120] 1H NMR(600MHz,Chloroform-d)δ7.90(s,1H),7.29(dt,J=19.7,6.5Hz,15H),6.67(d,J=4.4Hz,1 H),6.49(d,J=4.4Hz,1H),5.73(s,2H),5.68(d,J=4.1Hz,1H),4.78–4.68(m,2H),4.60(d,J=12 .0Hz,1H),4.57–4.51(m,2H),4.44(d,J=11.9Hz,1H),4.40(dt,J=7.3,3.9Hz,1H),4.28(t,J= 4.6Hz, 1H), 4.13 (t, J = 5.8Hz, 1H), 3.78 (dd, J = 10.8, 3.4Hz, 1H), 3.66 (dd, J = 10.8, 4.0Hz, 1H).

[0121] Step c: Preparation of intermediate A1-3

[0122] Dissolve intermediate A1-2 (4.9 g, 9.09 mmol) in anhydrous THF (150 mL), add triethylamine (6.3 mL, 45.47 mmol) and DMAP (555.5 mg, 4.55 mmol) in turn at room temperature. Cool the reaction system to 0°C, add di-tert-butyl dicarbonate (9.9 g, 45.47 mmol) dropwise under argon protection, stir for 10 minutes, slowly warm to room temperature, and stir overnight at room temperature. TLC detection shows that the raw material is completely consumed, and no post-treatment is required, and it is directly used for the next step reaction.

[0123] ESI-MS m / z:737.2[M+H] + .

[0124] Step d: Preparation of Intermediate A1-4

[0125] Add 3.0M sodium hydroxide aqueous solution (200mL) to the reaction solution obtained in step c and stir at 60°C for 16 hours. TLC detection shows that the raw material is completely consumed. Dilute with water, extract with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. Separate and purify by silica gel column chromatography (PE / EA=5 / 1) to obtain a yellow oily liquid (5.0g, two-step yield: 86%).

[0126] ESI-MS m / z:637.2[M+H] + .

[0127] Step e: Preparation of Intermediate A1-5

[0128] Dissolve intermediate A1-4 (5.0 g, 7.83 mmol) in anhydrous DCM (150 mL), slowly add boron trichloride solution (1.0 M in DCM, 31.33 mmol) at 0°C under argon protection. Continue stirring the reaction system at 0°C for 2 hours. TLC shows that the raw material is completely consumed. Add MeOH at 0°C to quench, remove the solvent under reduced pressure to obtain a white solid, which is used directly in the next step without purification.

[0129] Step f: Preparation of Intermediate A1-6

[0130] Intermediate A1-5 was suspended in anhydrous acetone (60 mL), and p-toluenesulfonic acid (2.7 g, 15.70 mmol) and 2,2-dimethoxypropane (60 mL) were added in sequence at room temperature, and stirred overnight at room temperature. TLC detected that the raw material was completely consumed. Saturated sodium bicarbonate was added to quench, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. It was separated and purified by silica gel column chromatography (DCM / MeOH=60:1) to obtain a white foamy solid (1.4 g, yield 58%).

[0131] ESI-MS m / z:306.9[M+H] + .

[0132] 1 H NMR(400MHz,Chloroform-d)δ7.86(s,1H),6.66(d,J=4.5Hz,1H),6.54(d,J=4.5Hz,1H),6.13(s,2H),5.21–5.15(m,2H),5.01(ddd,J=4.8,2. 5,1.0Hz,1H),4.88–4.56(m,1H),4.37(q,J=2.3Hz,1H),3.91(dd,J=12.2,2.2Hz,1H),3.76(dd,J=12.1,2.2Hz,1H),1.62(s,3H),1.36(s,3H).

[0133] Step g: Preparation of intermediate A1-7

[0134] A1-6 (2.0 g, 6.53 mmol) was dissolved in anhydrous DMF (45 mL), N-iodosuccinimide (2.2 g, 9.79 mmol) was added, and the mixture was stirred at room temperature overnight. TLC detected that the reaction of the raw material was complete. The reaction solution was poured into water (100 mL), extracted with ethyl acetate (50 mL*3), the organic phases were combined, washed with saturated sodium thiosulfate (50 mL*2) and saturated brine (50 mL*3) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (DCM / MeOH=60 / 1) to obtain a white solid (2.4 g, yield 85%).

[0135] ESI-MS m / z:433.23[M+H] + .

[0136] 1 H NMR (400MHz, Methanol-d4) δ7.83 (s, 1H), 6.99 (s, 1H), 5.34 (d, J = 4.6Hz, 1H), 5.04 (dd, J = 6.5, 4.6Hz, 1H), 4.83 (dd, J=6.5, 3.8Hz, 1H), 4.15 (q, J=4.3Hz, 1H), 3.82–3.61 (m, 2H), 1.59 (s, 3H), 1.37 (s, 3H).

[0137] Step h: Preparation of Intermediate A1-8

[0138] A1-7 (400.0 mg, 925.46 μmol) was dissolved in anhydrous toluene (12 mL), and N,N-dimethylformamide dimethyl acetal (0.9 mL, 827.1 mg, 6.94 mmol) was added dropwise at room temperature. The reaction solution was heated to 60 ° C and stirred for 1 hour. TLC detected that the raw material reacted completely. The reaction solution was cooled to room temperature and the solvent was removed under reduced pressure to obtain a yellow oily liquid crude product, which was directly used in the next step without purification.

[0139] ESI-MS m / z:488.29[M+H] + .

[0140] Step i: Preparation of intermediate A1

[0141] The crude product of A1-8 was dissolved in anhydrous DCM (20 mL), and DMAP (113.1 mg, 925.45 μmol) and triethylamine (0.6 mL, 468.2 mg, 4.63 mmol) were added in sequence at room temperature. The reaction solution was placed in an ice bath at 0°C, and p-toluenesulfonyl chloride (882.1 mg, 4.63 mmol) was added in batches under argon protection and stirred for 5 minutes. The ice bath was removed, and the reaction solution was slowly warmed to room temperature and stirred for 2 hours. TLC detected that the raw material reaction was complete. The crude product of the reaction solution was concentrated under reduced pressure and separated and purified by silica gel column chromatography (DCM / MeOH=100 / 1) to obtain a light yellow solid intermediate A1 (550.0 mg, two-step yield 93%).

[0142] ESI-MS m / z:642.24[M+H] + .

[0143] Intermediate A2: (E)-N'-(7-((3aS,4S,6R,6aR)-6-((2-((2,4-dimethoxybenzyl)(methyl)amino)quinolin-7-yl)oxy)methyl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxy-4-yl)-5-iodopyrrolo[2,1-f][1,2,4]triazine-4-yl)-N,N-dimethylformamide

[0144]

[0145] At room temperature, under the protection of argon, cesium carbonate (914.3 mg, 2.81 mmol) was added to a solution of A1 (600.0 mg, 935.33 μmol) and B2 (333.7 mg, 1.03 mmol) in anhydrous DMF (15 mL). The temperature was then raised to 60°C and stirred vigorously for 30 minutes. TLC detected that the raw material reaction was complete. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 mL*3), the organic phases were combined, washed with saturated brine (50 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (DCM / MeOH=100 / 1-80 / 1) to obtain a yellow solid intermediate A2 (580.0 mg, yield 78%).

[0146] ESI-MS m / z:794.21[M+H] + .

[0147] Intermediate A3: (E)-N'-(7-((3aS,4S,6R,6aR)-6-((2-(cyclobutylamino)quinolin-7-yl)oxy)methyl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxy-4-yl)-5-iodopyrrolo[2,1-f][1,2,4]triazine-4-yl)-N,N-dimethylformamide

[0148]

[0149] Intermediate A3 was prepared as a yellow solid from Intermediate A1 and Intermediate B3 using the method described for Intermediate A2.

[0150] ESI-MS m / z: 684.20 [M+H]+.

[0151] Intermediate A4: (E)-N'-(7-((3aS,4S,6R,6aR)-6-((2-(azetidin-1-yl)quinolin-7-yl)oxy)methyl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxy-4-yl)-5-iodopyrrolo[2,1-f][1,2,4]triazine-4-yl)-N,N-dimethylformamide

[0152]

[0153] Intermediate A4 was prepared as a yellow solid from Intermediate A1 and Intermediate B4 using the method described for Intermediate A2.

[0154] ESI-MS m / z:670.22[M+H] + .

[0155] Intermediate A5: ((3aR,4R,6S,6aS)-6-(5-bromo-4-(((E)-(dimethylamino)methylene)amino)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl-4-methylbenzenesulfonate

[0156]

[0157] Step a: Preparation of intermediate A5-1

[0158] A1-6 (250.0 mg, 816.13 μmol) was dissolved in anhydrous DMF (10 mL), N-bromosuccinimide (159.8 mg, 897.75 μmol) was added, and the mixture was stirred at room temperature overnight. TLC detected that the raw material reaction was complete. Dilute with water, extract with ethyl acetate (30 mL*3), combine the organic phases, wash with saturated sodium thiosulfate (30 mL*2) and saturated brine (50 mL*3) in turn, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (DCM / MeOH=60 / 1) to obtain a white solid intermediate (259.0 mg, yield 82%).

[0159] ESI-MS m / z:384.8,386.8[M+H] + .

[0160] 1 H NMR (400MHz, Methanol-d4) δ7.79(s,1H),6.86(s,1H),5.33(d,J=4.6Hz,1H),5.02(dd,J=6.5,4.6Hz, 1H), 4.81 (dd, J=6.5, 3.7Hz, 1H), 4.13 (q, J=4.3Hz, 1H), 3.81–3.64 (m, 2H), 1.57 (s, 3H), 1.36 (s, 3H).

[0161] Step b: Preparation of intermediate A5-2

[0162] Intermediate A5-2 was prepared from Intermediate A5-1 as a yellow oily liquid using the method described for Intermediate A1-8.

[0163] ESI-MS m / z:439.9,441.9[M+H] + .

[0164] Step c: Preparation of Intermediate A5

[0165] Intermediate A5 (340.3 mg, two-step yield: 99%) was prepared as a light yellow foamy solid from Intermediate A5-2 using the method described in Intermediate A1.

[0166] ESI-MS m / z:594.0,596.0[M+H] + .

[0167] Intermediate A6: ((3aR,4R,6S,6aS)-6-(5-chloro-4-(((E)-(dimethylamino)methylene)amino)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl-4-methylbenzenesulfonate

[0168]

[0169] Step a: Preparation of intermediate A6-1

[0170] A1-6 (300.0 mg, 979.36 μmol) was dissolved in anhydrous DMF (10 mL), N-chlorosuccinimide (143.9 mg, 1.08 mmol) was added, and the temperature was raised to 60 ° C and stirred for 1 hour. TLC detected that the raw material reaction was complete. Dilute with water, extract with ethyl acetate (30 mL*3), combine the organic phases, wash with saturated brine (50 mL*3), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (DCM / MeOH=60 / 1) to obtain a white solid intermediate (196.0 mg, yield 59%).

[0171] ESI-MS m / z:341.0,342.9[M+H] + .

[0172] 1 H NMR (400MHz, Chloroform-d) δ7.84(s,1H),6.64(s,1H),6.36(s,2H),5.14(t,J=6.2Hz,1H),5.07(d,J=6.1Hz,1H),5.00(dd,J=6. 2,2.4Hz,1H),4.37(q,J=2.3Hz,1H),4.32(s,1H),3.89(dd,J=12.2,2.2Hz,1H),3.75(d,J=12.2Hz,1H),1.61(s,3H),1.36(s,3H).

[0173] Step b: Preparation of intermediate A6-2

[0174] Intermediate A6-2 was prepared from Intermediate A6-1 as a yellow oily liquid using the method described for Intermediate A1-8.

[0175] ESI-MS m / z:395.9,397.9[M+H] + .

[0176] Step c: Preparation of intermediate A6

[0177] Intermediate A6 (312.3 mg, two-step yield: 99%) was prepared as a brown oily liquid from Intermediate A6-2 using the method described in Intermediate A1.

[0178] ESI-MS m / z:549.9,552.0[M+H] + .

[0179] Intermediate B1: 2-Chloroquinolin-7-ol

[0180]

[0181] Dissolve B1-1 (4.0 g, 24.82 mmol) in anhydrous DMF (40 mL), slowly add thionyl chloride (11.8 g, 7.2 ml, 99.28 mmol) under argon protection, and stir at room temperature for 0.5 hours. Then heat the reaction solution to 70 ° C and continue stirring for 2 hours. TLC detection shows that the raw material has reacted completely. After cooling the reaction solution to room temperature, slowly pour it into water (300 mL), adjust the pH value to 8 with saturated sodium bicarbonate solution, solid precipitates, filter, wash with distilled water, and vacuum dry to obtain a yellow solid intermediate (4.1 g, yield 92%).

[0182] ESI-MS m / z:180.23[M+H] + .

[0183] 1 H NMR (400MHz, DMSO-d6) δ10.46(s,1H),8.27(d,J=8.5Hz,1H),7.87(d,J=8.8Hz, 1H),7.32(d,J=8.5Hz,1H),7.19(dd,J=8.8,2.4Hz,1H),7.16(d,J=2.3Hz,1H).

[0184] Intermediate B2: 2-((2,4-dimethoxybenzyl)(methyl)amino)quinolin-7-ol

[0185]

[0186] In a 15mL sealed tube, add B1 (1.0g, 5.57mmol), DIPEA (2.9mL, 2.2g, 16.70mmol), and B2-1 (997.1μL, 1.0g, 5.57mmol) in sequence at room temperature. Seal the tube and stir the reaction solution at 120°C for 16 hours. TLC detected that the raw material reaction was complete. The reaction solution was cooled to room temperature, diluted with ethyl acetate (5mL), poured into water (50mL), extracted with ethyl acetate (50mL*3), combined the organic phases, washed with saturated brine (50mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (PE / EA=2 / 1) to obtain a light yellow solid intermediate (1.1g, yield 60%).

[0187] ESI-MS m / z:325.11[M+H] + .

[0188] 1 H NMR (400MHz, DMSO-d6) δ9.79(s,1H),7.80(d,J=9.1Hz,1H),7.46(d,J=8.6Hz,1H),6.89(d,J=8.3Hz,1H),6.80(d,J=2.4Hz,1H ),6.76–6.67(m,2H),6.57(d,J=2.4Hz,1H),6.41(dd,J=8.3,2.4Hz,1H),4.68(s,2H),3.80(s,3H),3.70(s,3H),3.11(s,3H).

[0189] Intermediate B3: 2-(Cyclobutylamino)quinolin-7-ol

[0190]

[0191] Intermediate B3 was prepared as a yellow solid from Intermediate B1 and cyclobutylamine (B3-1) using the method described for Intermediate B2.

[0192] ESI-MS m / z:215.22[M+H] + .

[0193] Intermediate B4: 2-(azetidin-1-yl)quinolin-7-ol

[0194]

[0195] Intermediate B4 was prepared as a yellow solid from Intermediate B1 and azetidine (B4-1) using the method described for Intermediate B2.

[0196] ESI-MS m / z:201.27[M+H] + .

[0197] 1 H NMR (400MHz, DMSO-d6) δ9.72 (s, 1H), 7.83 (dd, J = 8.9, 0.7Hz, 1H), 7.49 (d, J = 8.6Hz, 1H), 6.83 (d, J = 2. 4Hz,1H),6.73(dd,J=8.6,2.4Hz,1H),6.42(d,J=8.8Hz,1H),4.03(t,J=7.4Hz,4H),2.41–2.24(m,2H).

[0198] Intermediate B5: 2-((2,4-dimethoxybenzyl)amino)quinolin-7-ol

[0199]

[0200] Intermediate B5 was prepared as a yellow oily liquid from Intermediate B1 and 2,4-dimethoxybenzylamine (B5-1) using the method described for Intermediate B2.

[0201] ESI-MS m / z:311.0[M+H] + .

[0202] Intermediate B6: 2-(Ethylamino)quinolin-7-ol

[0203]

[0204] Intermediate B6 was prepared as a yellow solid from Intermediate B1 and ethylamine alcohol solution (B6-1) using the method described for Intermediate B2.

[0205] ESI-MS m / z:188.8[M+H] + .

[0206] Intermediate B7: 2-(Isopropylamino)quinolin-7-ol

[0207]

[0208] Dissolve intermediate B1 (600.0 mg, 3.34 mmol) in n-butanol (2 mL), and add isopropylamine B7-1 (3 mL) dropwise at room temperature. Seal the tube, stir overnight at 150°C, cool to room temperature, and TLC indicates that the reaction of the raw material is complete. Concentrate the solvent under pressure, separate and purify by silica gel column chromatography (DCM / MeOH=60 / 1) to obtain a yellow foamy solid (361.8 mg, yield 54%).

[0209] ESI-MS m / z:202.8[M+H] + .

[0210] Intermediate B8: 2-(tert-butylamino)quinolin-7-ol

[0211]

[0212] Dissolve the intermediate B1 (300 mg, 1.67 mmol) in n-butanol (2 mL), and add DIPEA (1 mL) and tert-butylamine B8-1 (5 mL) dropwise at room temperature. Seal the tube, stir overnight at 150°C, cool to room temperature, and detect that the raw material has reacted completely by TLC. Concentrate the solvent under pressure, separate and purify by silica gel column chromatography (DCM / MeOH=60 / 1) to obtain the intermediate as a yellow solid (95.5 mg, yield 26%).

[0213] ESI-MS m / z:216.9[M+H] + .

[0214] Intermediate B9: 2-(Cyclopropylamino)quinolin-7-ol

[0215]

[0216] Dissolve the intermediate B1 (400 mg, 1.67 mmol) in n-butanol (9 mL), add cyclopropylamine B9-1 (1.3 g, 22.27 mmol) and concentrated hydrochloric acid (1.5 mL) at room temperature. Seal the tube, stir overnight at 150°C, cool to room temperature, and detect that the raw material has reacted completely by TLC. Concentrate the solvent under pressure, separate and purify by silica gel column chromatography (DCM / MeOH=50 / 1) to obtain the intermediate (409.0 mg, yield 92%) as a yellow solid.

[0217] ESI-MS m / z:200.8[M+H] + .

[0218] 1 H NMR (400MHz, Methanol-d4) δ8.13(d,J=9.2Hz,1H),7.70(d,J=8.7Hz,1H),7.32(s,1H),7.00(dd,J=8.7 ,2.3Hz,1H),6.83(d,J=9.1Hz,1H),2.88(tt,J=7.0,3.7Hz,1H),1.14–1.06(m,2H),0.83–0.77(m,2H).

[0219] Intermediate B10: 2-(3,3-difluorocyclobutyl)amino)quinolin-7-ol

[0220]

[0221] Intermediate B10 was prepared as a yellow foamy solid from Intermediate B1 and 3,3-difluorocyclobutanamine (B10-1) using the method described for Intermediate B2.

[0222] ESI-MS m / z:250.8[M+H] + .

[0223] Intermediate B11: 2-(Bicyclo[1.1.1]pentan-1-ylamino)quinolin-7-ol

[0224]

[0225] Intermediate B11 was prepared as a yellow solid from Intermediate B1 and bicyclo[1.1.1]-1-pentylamine hydrochloride (B11-1) using the method described for Intermediate B7.

[0226] ESI-MS m / z:226.8[M+H] + .

[0227] 1 H NMR (400MHz, Methanol-d4) δ8.28(dd,J=9.3,0.8Hz,1H),7.75(d,J=8.8Hz,1H),7.12–7.05(m,2H),7.03(dd,J=8.8,2.3Hz,1H),2.63(s,1H),2.34(s,6H).

[0228] Intermediate B12: 2-(Cyclopentylamino)quinolin-7-ol

[0229]

[0230] Intermediate B12 was prepared as a yellow oily liquid from Intermediate B1 and cyclopentylamine (B12-1) using the method described for Intermediate B2.

[0231] ESI-MS m / z:228.8[M+H] + .

[0232] Intermediate B13: 2-(Cyclohexylamino)quinolin-7-ol

[0233]

[0234] Intermediate B13 was prepared as a yellow oily liquid from Intermediate B1 and cyclohexylamine (B13-1) using the method described for Intermediate B2.

[0235] ESI-MS m / z:242.8[M+H] + .

[0236] Intermediate B14: 2-((4,4-difluorocyclohexyl)amino)quinolin-7-ol

[0237]

[0238] Intermediate B14 was prepared as a yellow oily liquid from Intermediate B1 and 4,4-difluorocyclohexylamine (B14-1) using the method described for Intermediate B2.

[0239] ESI-MS m / z:278.8[M+H] + .

[0240] Intermediate B15: 2-((Tetrahydro-2H-pyran-4-yl)amino)quinolin-7-ol

[0241]

[0242] Intermediate B15 was prepared as a yellow oily liquid from Intermediate B1 and 4-aminotetrahydropyran (B15-1) using the method described for Intermediate B2.

[0243] ESI-MS m / z:244.9[M+H] + .

[0244] Intermediate B16: 2-(Dimethylamino)quinolin-7-ol

[0245]

[0246] Intermediate B16 was prepared as a yellow solid from Intermediate B1 and aqueous dimethylamine solution (B16-1) using the method described for Intermediate B2.

[0247] ESI-MS m / z:188.9[M+H] + .

[0248] 1 H NMR(600MHz,Chloroform-d)δ7.76(d,J=9.1Hz,1H),7.44(d,J=8.8Hz,1H),7.18 (s,1H),6.80(d,J=8.6Hz,1H),6.70(d,J=9.1Hz,1H),3.49(s,1H),3.23(s,6H).

[0249] Intermediate B17: 2-(cyclobutyl(methyl)amino)quinolin-7-ol

[0250]

[0251] Intermediate B17 was prepared as a brown oily liquid from Intermediate B1 and cyclobutylmethylamine hydrochloride (B17-1) using the method described for Intermediate B7.

[0252] ESI-MS m / z:228.8[M+H] + .

[0253] 1 H NMR(400MHz, Methanol-d4)δ7.88(d,J=9.2Hz,1H),7.50(dt,J=8.7,2.1Hz,1H),7.05–7.00(m,1H ),6.81(ddt,J=8.7,3.6,1.3Hz,2H),4.77(p,J=8.5Hz,1H),2.47–2.24(m,4H),1.87–1.70(m,2H).

[0254] Intermediate B18: 2-(Pyrrolidin-1-yl)quinolin-7-ol

[0255]

[0256] Intermediate B18 was prepared as a tan solid from Intermediate B1 and tetrahydropyrrole (B18-1) using the method described for Intermediate B2.

[0257] ESI-MS m / z:214.9[M+H] + .

[0258] 1 H NMR(600MHz,Chloroform-d)δ7.48(s,1H),7.38(d,J=9.1Hz,1H),7.03(d,J=8.5Hz,1 H), 6.51 (d, J = 8.5Hz, 1H), 6.25 (d, J = 9.0Hz, 1H), 3.54 (s, 4H), 1.99 (d, J = 6.1Hz, 4H).

[0259] Intermediate B19: 2-Morpholinequinolin-7-ol

[0260]

[0261] Intermediate B19 was prepared as a yellow solid from intermediate B1 and morpholine (B19-1) using the method described for intermediate B2.

[0262] ESI-MS m / z:230.8[M+H] + .

[0263] 1 H NMR (400 MHz, Methanol-d4) δ 7.88 (d, J = 9.1 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 6.99 (d, J = 2.4 Hz, 1H), 6.90 (d, J = 9.1 Hz, 1H), 6.85–6.79 (m, 1H), 3.91–3.76 (m, 4H), 3.64 (dd, J = 5.8, 3.9 Hz, 4H). Intermediate C1: 2-((2,4-dimethoxybenzyl)(methyl)amino)quinazolin-7-ol

[0264]

[0265] Step a: Preparation of intermediate C1-1

[0266] Dissolve 7-bromo-2-chloroquinazoline (200.0 mg, 821.40 μmol) in 1,4-dioxane (3 mL), add DIPEA (318.5 mg, 2.46 mmol) and 1-(2,4-dimethoxyphenyl)-N-methylmethylamine (223.3 mg, 1.23 mmol) at room temperature. Seal the tube, stir overnight at 120°C, cool to room temperature, and TLC detects that the raw material has reacted completely. Concentrate the solvent under reduced pressure, separate and purify by silica gel column chromatography (PE / EA=10 / 1) to obtain a yellow oily liquid (322.3 mg, yield 100%).

[0267] ESI-MS m / z:387.9,389.8[M+H] + .

[0268] 1 H NMR(400MHz,Chloroform-d)δ8.94(d,J=0.8Hz,1H),7.80–7.74(m,1H),7.47(d,J=8.5Hz,1H),7.26–7.19(m,1H),7.14 –6.91(m,1H),6.48(d,J=2.4Hz,1H),6.39(dd,J=8.3,2.4Hz,1H),4.95(s,2H),3.82(s,3H),3.78(s,3H),3.25(s,3H).

[0269] Step b: Preparation of intermediate C1

[0270] The intermediate C1-1 (322.3 mg, 830.10 μmol) and 2-di-tert-butylphospho-3,4,5,6-tetramethyl-2',4',6'-triisopropylbiphenyl (79.8 mg, 166.02 μmol) were dissolved in 1,4-dioxane (6 mL), and KOH aqueous solution (6 mL, 139.7 mg, 2.49 mmol) was added at room temperature, and argon was bubbled into the reaction system for 5 minutes. Under argon protection, Pd2(dba)3 (76.0 mg, 83.01 μmol) was added, the tube was sealed, and stirred at 100°C overnight. TLC detected that the raw material reacted completely. The pH of the reaction solution was adjusted to neutral with 1N HCl aqueous solution, and the reaction solution was concentrated under reduced pressure. The intermediate (196.9 mg, yield 73%) was prepared by separation and purification by silica gel column chromatography (DCM / MeOH=80 / 1).

[0271] ESI-MS m / z:325.9[M+H] + .

[0272] 1 H NMR(400MHz,Chloroform-d)δ8.57(s,1H),7.13(dd,J=18.0,8.5Hz,3H),6.52–6.46 (m,1H),6.42(d,J=8.6Hz,2H),4.90(s,2H),3.77(s,3H),3.76(s,4H),3.16(s,3H).

[0273] Intermediate C2: 2-(azetidin-1-yl)quinazolin-7-ol

[0274]

[0275] Step a: Preparation of intermediate C2-1

[0276] Intermediate C2-1 was prepared as a white solid from 7-bromo-2-chloroquinazoline and azetidine using the procedure described for Intermediate C1-1.

[0277] ESI-MS m / z:263.7,265.8[M+H] + .

[0278] 1 H NMR (600MHz, Chloroform-d) δ8.94 (d, J = 1.5 Hz, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.49 (dd, J = 8. 5,1.5Hz,1H),7.28(dt,J=8.5,1.7Hz,1H),4.27(td,J=7.6,1.6Hz,4H),2.54–2.35(m,2H).

[0279] Step b: Preparation of intermediate C2

[0280] Intermediate C2 was prepared as a yellow solid from Intermediate C2-1 using the method described for Intermediate C1.

[0281] ESI-MS m / z:201.8[M+H] + .

[0282] 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),8.89(d,J=0.8Hz,1H),7.65(d,J=8.7Hz,1H),6.78 (dd,J=8.7,2.3Hz,1H),6.71(d,J=2.3Hz,1H),4.08(t,J=7.5Hz,4H),2.39–2.24(m,2H).

[0283] Intermediate C3: 2-(Cyclobutylamino)quinazolin-7-ol

[0284]

[0285] Step a: Preparation of intermediate C3-1

[0286] Intermediate C3-1 was prepared as a light yellow solid from 7-bromo-2-chloroquinazoline and cyclobutylamine using the procedure described for Intermediate C1-1.

[0287] ESI-MS m / z:277.7,279.8[M+H] + .

[0288] 1 H NMR(600MHz,Chloroform-d)δ8.90(s,1H),7.76(s,1H),7.48(d,J=8.4Hz,1H),7.29(dt,J=8.5,1.7Hz,1H),5 .52(s,1H),4.60(q,J=8.1Hz,1H),2.57–2.43(m,2H),1.99–1.90(m,2H),1.78(ddt,J=17.8,10.9,6.4Hz,2H).

[0289] Step b: Preparation of intermediate C3

[0290] Intermediate C3 was prepared as a tan solid from Intermediate C3-1 using the method described for Intermediate C1.

[0291] ESI-MS m / z:215.8[M+H]+ .

[0292] Intermediate D1: 2-Ethylquinolin-7-ol

[0293]

[0294] Step a: Preparation of intermediate D1-1

[0295] Dissolve intermediate B1 (200.0 mg, 1.11 mmol) and potassium carbonate (384.8 mg, 2.78 mmol) in anhydrous DMF (3 mL), add benzyl bromide (285.7 mg, 1.67 mmol) dropwise, and stir the reaction system at room temperature for 3 hours. TLC detected that the raw material reacted completely. Dilute with water (50 mL), extract with ethyl acetate (50 mL*3), wash with saturated brine (50 mL*3), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. Separate and purify by silica gel column chromatography (PE / EA=15 / 1) to prepare a white solid (259.1 mg, yield 86%).

[0296] ESI-MS m / z:270.19,272.18[M+H] + .

[0297] 1 H NMR (400 MHz, Chloroform-d) δ 8.01 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 8.9 Hz, 1H), 7.52–7.44 (m, 2H), 7.44–7.38 (m, 3H), 7.37–7.32 (m, 1H), 7.28 (dd, J = 9.0, 2.6 Hz, 1H), 7.24 (s, 1H), 5.20 (s, 2H). Step b: Preparation of intermediate D1-2

[0298] Intermediate D1-1 (50.0 mg, 185.37 μmol), potassium carbonate (76.9 mg, 556.12 μmol) and Pd(dppf)Cl2 (13.6 mg, 18.54 μmol) were placed in a Shlenk bottle, argon was replaced 3 times, and anhydrous THF (3 mL) and diethylzinc (27.5 mg, 222.45 μmol) were added in sequence at room temperature. Under argon protection, the reaction system was heated to 70°C and stirred overnight. TLC detected that the raw material reacted completely. The solvent was concentrated under reduced pressure and separated and purified by silica gel column chromatography (PE / EA=10 / 1) to prepare a colorless oily liquid (38.7 mg, yield 79%).

[0299] ESI-MS m / z:264.24[M+H] + .

[0300] 1 H NMR(400MHz,Chloroform-d)δ7.99(d,J=8.3Hz,1H),7.67(d,J=8.9Hz,1H),7.52–7.44(m,3H),7.44–7.37 (m,2H),7.37–7.31(m,1H),7.24–7.16(m,2H),5.20(s,2H),2.97(q,J=7.7Hz,2H),1.40(d,J=7.6Hz,3H).

[0301] Step c: Preparation of intermediate D1

[0302] The intermediate D1-2 (213.8 mg, 811.88 μmol) was dissolved in TFA (3 mL) and heated under reflux at 75°C for 3 hours. TLC detected that the raw material reaction was complete. The reaction solution was cooled to 0°C, and ammonia methanol solution was added to neutralize it to weak acidity. The solvent was concentrated under reduced pressure and separated and purified by silica gel column chromatography (DCM / MeOH=15 / 1) to prepare a yellow oily liquid (150.1 mg, yield 100%).

[0303] ESI-MS m / z:174.31[M+H] + .

[0304] Intermediate D2: 4-chloro-2-ethylquinolin-7-ol

[0305]

[0306] Step a: Preparation of intermediate D2-1

[0307] Dissolve the intermediate D1-2 (2.1 g, 7.97 mmol) in anhydrous DCM (40 mL), add m-chloroperbenzoic acid (2.1 g, 11.96 mmol) at 0 ° C, slowly return the reaction system to room temperature, and stir overnight at room temperature. TLC detection shows that the raw material has reacted completely. Add saturated sodium bicarbonate to quench, extract with DCM (100 mL * 3), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. Separate and purify by silica gel column chromatography (PE / EA = 1 / 1) to obtain a white solid (2.1 mg, yield 96%).

[0308] ESI-MS m / z:280.29[M+H] + .

[0309] Step b: Preparation of intermediate D2-2

[0310] Dissolve the intermediate D2-1 (2.1 g, 7.62 mmol) in anhydrous chloroform (40 mL), add phosphorus oxychloride (12 mL) dropwise at room temperature, and reflux and stir at 80 ° C for 3 hours. TLC detected that the raw material reaction was complete. Cool to room temperature, pour the reaction solution into ice water, slowly neutralize with saturated sodium bicarbonate solution, extract with DCM (100 mL * 3), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. Separate and purify by silica gel column chromatography (PE / EA = 12 / 1) to prepare a white solid (1.5 g, yield 66%).

[0311] ESI-MS m / z:298.27,300.25[M+H] + .

[0312] 1 H NMR(400MHz,Chloroform-d)δ8.08(d,J=9.2Hz,1H),7.52–7.45(m,3H),7.44–7.33( m,3H),7.32–7.27(m,2H),5.21(s,2H),2.94(q,J=7.6Hz,2H),1.38(t,J=7.6Hz,3H).

[0313] Step c: Preparation of intermediate D2

[0314] Intermediate D2 was prepared as a white solid from Intermediate D2-2 using the method described for Intermediate D1.

[0315] ESI-MS m / z:208.37,210.35[M+H] + .

[0316] Intermediate D3: 4-amino-2-ethylquinolin-7-ol

[0317]

[0318] Step a: Preparation of intermediate D3-1

[0319] Dissolve the intermediate D2-2 (200.0 mg, 671.63 μmol) in anhydrous DMSO (1 mL), add DIPEA (1 mL) and 2,4-dimethoxybenzylamine (1 mL) in turn at room temperature, seal the tube, and stir at 150°C overnight. TLC detected that the raw material reaction was complete. Dilute with water (10 mL), extract with ethyl acetate (20 mL*3), wash with saturated brine (20 mL*3), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. Separate and purify by silica gel column chromatography (DCM / MeOH=100 / 1) to prepare a yellow oily liquid (203.1 mg, yield 71%).

[0320] ESI-MS m / z:429.23[M+H] + .

[0321] Step b: Preparation of intermediate D3

[0322] Intermediate D3 was prepared from Intermediate D3-1 as a yellow oily liquid using the method described for Intermediate D1.

[0323] ESI-MS m / z:189.33[M+H] + .

[0324] Intermediate D4: 2-ethyl-4-(methylamino)quinolin-7-ol

[0325]

[0326] Step a: Preparation of intermediate D4-1

[0327] Intermediate D4-1 was prepared as a yellow oily liquid from Intermediate D2-2 and 2,4-dimethoxy-N-methylbenzylamine using the method described for Intermediate D3-1.

[0328] ESI-MS m / z:443.24[M+H] + .

[0329] Step b: Preparation of intermediate D4

[0330] Intermediate D4 was prepared from Intermediate D4-1 as a yellow oily liquid using the method described for Intermediate D3.

[0331] ESI-MS m / z:203.36[M+H] + .

[0332] Intermediate D5: 4-(Dimethylamino)-2-ethylquinolin-7-ol

[0333]

[0334] Step a: Preparation of intermediate D5-1

[0335] Intermediate D5-1 was prepared as a yellow oily liquid from intermediate D2-2 and aqueous dimethylamine using the method described for intermediate D3-1.

[0336] ESI-MS m / z:307.25[M+H] + .

[0337] Step b: Preparation of intermediate D5

[0338] Intermediate D5 was prepared as a yellow solid from Intermediate D5-1 using the method described for Intermediate D3.

[0339] ESI-MS m / z:217.34[M+H] + .

[0340] Intermediate D6: 4-(Cyclopropylamino)-2-ethylquinolin-7-ol

[0341]

[0342] Step a: Preparation of intermediate D6-1

[0343] Intermediate D6-1 was prepared as a yellow oily liquid from intermediate D2-2 and cyclopropylamine using the method described for intermediate D3-1.

[0344] ESI-MS m / z:319.27[M+H] + .

[0345] Step b: Preparation of intermediate D6

[0346] Intermediate D6 was prepared from Intermediate D6-1 as a brown oily liquid using the method described for Intermediate D3.

[0347] ESI-MS m / z:229.34[M+H] + .

[0348] Intermediate D7: 4-(azetidin-1-yl)-2-ethylquinolin-7-ol

[0349]

[0350] Step a: Preparation of intermediate D7-1

[0351] Intermediate D7-1 was prepared as a yellow oily liquid from intermediate D2-2 and azetidine using the method described for intermediate D3-1.

[0352] ESI-MS m / z:319.26[M+H] + .

[0353] Step b: Preparation of intermediate D7

[0354] Intermediate D7 was prepared as a white solid from Intermediate D7-1 using the method described for Intermediate D3.

[0355] ESI-MS m / z:229.28[M+H] + .

[0356] Intermediate D8: 2-ethyl-4-(pyrrolidin-1-yl)quinolin-7-ol

[0357]

[0358] Step a: Preparation of intermediate D8-1

[0359] Intermediate D8-1 was prepared as a yellow oily liquid from Intermediate D2-2 and tetrahydropyrrole using the method described for Intermediate D3-1.

[0360] ESI-MS m / z:333.30[M+H] + .

[0361] Step b: Preparation of intermediate D8

[0362] Intermediate D8 was prepared as a light yellow solid from Intermediate D8-1 using the method described for Intermediate D3.

[0363] ESI-MS m / z:243.41[M+H] + .

[0364] Intermediate D9: 2-ethyl-4-morpholinequinolin-7-ol

[0365]

[0366] Step a: Preparation of intermediate D9-1

[0367] Intermediate D9-1 was prepared as a yellow oily liquid from intermediate D2-2 and morpholine using the method described for intermediate D3-1.

[0368] ESI-MS m / z:349.30[M+H] + .

[0369] Step b: Preparation of intermediate D9

[0370] Intermediate D9 was prepared as a light yellow solid from Intermediate D9-1 using the method described for Intermediate D3.

[0371] ESI-MS m / z:259.38[M+H] + .

[0372] Intermediate D10: 2-ethyl-4-(4-methylpiperazin-1-yl)quinolin-7-ol

[0373]

[0374] Step a: Preparation of intermediate D10-1

[0375] Intermediate D10-1 was prepared as a yellow oily liquid from intermediate D2-2 and N-methylpiperazine using the method described for intermediate D3-1.

[0376] ESI-MS m / z:362.36[M+H] + .

[0377] Step b: Preparation of intermediate D10

[0378] Intermediate D10 was prepared as a bright yellow solid from Intermediate D10-1 using the method described for Intermediate D3.

[0379] ESI-MS m / z:272.38[M+H] + .

[0380] Intermediate D11: 4-(4,4-difluoropiperidin-1-yl)-2-ethylquinolin-7-ol

[0381]

[0382] Step a: Preparation of intermediate D11-1

[0383] Intermediate D11-1 was prepared as a yellow oily liquid from intermediate D2-2 and 4,4-difluoropiperidine using the method described for intermediate D3-1.

[0384] ESI-MS m / z:383.33[M+H] + .

[0385] Step b: Preparation of intermediate D11

[0386] Intermediate D11 was prepared as a light yellow solid from Intermediate D11-1 using the method described for Intermediate D3.

[0387] ESI-MS m / z:293.38[M+H] + .

[0388] Intermediate D12: 4-((2-(dimethylamino)ethyl)amino)-2-ethylquinolin-7-ol

[0389]

[0390] Step a: Preparation of intermediate D12-1

[0391] Intermediate D12-1 was prepared as a yellow oily liquid from intermediate D2-2 and N,N-dimethylethylenediamine using the method described for intermediate D3-1.

[0392] ESI-MS m / z:350.31[M+H]+ .

[0393] 1 H NMR(400MHz,Chloroform-d)δ7.65(d,J=9.1Hz,1H),7.48(dt,J=6.2,1.5Hz,2H),7.43–7.36(m,3H),7.36–7.30(m,1H),7.09(dd,J=9.1,2.6Hz,1H) ,6.24(s,1H),5.74(s,1H),5.17(s,2H),3.29(dt,J=6.4,4.7Hz,2H),2.8 4(q,J=7.6Hz,2H),2.71–2.65(m,2H),2.30(s,7H),1.37(t,J=7.6Hz,3H).

[0394] Step b: Preparation of intermediate D12

[0395] Intermediate D12 was prepared as a white solid from Intermediate D12-1 using the method described for Intermediate D3.

[0396] ESI-MS m / z:260.27[M+H] + .

[0397] Intermediate D13: 2-ethyl-4-((2-methoxyethyl)amino)quinolin-7-ol

[0398]

[0399] Step a: Preparation of intermediate D13-1

[0400] Intermediate D13-1 was prepared as a brown solid from intermediate D2-2 and 2-methoxyethylamine using the method described for intermediate D3-1.

[0401] ESI-MS m / z:337.28[M+H] + .

[0402] Step b: Preparation of intermediate D13

[0403] Intermediate D13 was prepared as a white solid from Intermediate D13-1 using the method described for Intermediate D3.

[0404] ESI-MS m / z:247.32[M+H] + .

[0405] Intermediate D14: 2-ethyl-4-((2-methoxyethyl)(methyl)amino)quinolin-7-ol

[0406]

[0407] Step a: Preparation of intermediate D14-1

[0408] Intermediate D14-1 was prepared as a light yellow oily liquid from Intermediate D2-2 and N-(2-methoxyethyl)methylamine using the method described for Intermediate D3-1.

[0409] ESI-MS m / z:351.32[M+H] + .

[0410] Step b: Preparation of intermediate D14

[0411] Intermediate D14 was prepared as a yellow oil from Intermediate D14-1 using the method described for Intermediate D3.

[0412] ESI-MS m / z:261.36[M+H] + .

[0413] Intermediate E1: 2-(2,4-dimethoxybenzyl)(methyl)amino)-4-(2-methoxyethyl)amino)quinolin-7-ol

[0414]

[0415] Step a: Preparation of intermediate E1-1

[0416] 7-Benzyloxy-4-hydroxyquinoline (1.1g, 4.18mmol) was dissolved in anhydrous toluene (20mL), phosphorus oxychloride (1.15mL, 12.54mmol) was added dropwise at room temperature, and the reaction system was refluxed at 120°C for 1 hour. TLC detected that the raw material reaction was complete. The reaction solution was slowly poured into ice water, neutralized with 3N NaOH aqueous solution to neutrality, extracted with ethyl acetate (50mL*3), washed with saturated brine (50mL*3), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. It was separated and purified by silica gel column chromatography (PE / EA=3 / 1) to prepare a white solid (1.0g, yield 90%).

[0417] ESI-MS m / z:270.23,272.18[M+H] + .

[0418] 1 H NMR (400MHz, Chloroform-d) δ8.69(d,J=4.8Hz,1H),8.13(d,J=9.3Hz,1H),7.55–7.47(m,3H),7.45–7.33(m,5H),5.22(s,2H).

[0419] Step b: Preparation of intermediate E1-2

[0420] Dissolve the intermediate E1-1 (1.0 g, 3.75 mmol) in anhydrous chloroform (33 mL), add m-chloroperbenzoic acid (3.23 g, 18.73 mmol) at 0°C, slowly warm to room temperature, and stir overnight. TLC detected that the raw material reacted completely. Add saturated sodium bicarbonate solution to neutralize, extract with DCM (100 mL*3), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. Separate and purify by silica gel column chromatography (DCM / MeOH=60 / 1) to prepare a light yellow solid (745.8 mg, yield 70%).

[0421] ESI-MS m / z:286.22,288.20[M+H] + .

[0422] Step c: Preparation of intermediate E1-3

[0423] Dissolve the intermediate E1-2 (745.8 mg, 2.61 mmol) in anhydrous chloroform (20 mL), add phosphorus oxychloride (2.4 mL, 26.10 mmol) dropwise at room temperature, heat to 80 ° C, and stir for 2 hours. TLC detected that the raw material reaction was complete. Slowly pour the reaction solution into ice water, neutralize with saturated sodium bicarbonate solution to neutrality, extract with DCM (50 mL * 3), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. Separate and purify by silica gel column chromatography (DCM / MeOH=50 / 1) to prepare a white solid (696.7 mg, yield 88%).

[0424] ESI-MS m / z:304.23,306.17,308.16[M+H] + .

[0425] 1 H NMR (400MHz, Chloroform-d) δ8.09 (d, J = 9.2Hz, 1H), 7.49–7.45 (m, 2H), 7.45–7.39 (m, 3H), 7.39–7.33 (m, 3H), 5.20 (s, 2H).

[0426] Step d: Preparation of intermediate E1-4

[0427] The intermediate E1-3 (1.0 g, 3.29 mmol) was dissolved in anhydrous 1,4-dioxane (8 mL), and DIPEA (1.72 mL, 9.86 mmol) and 2,4-dimethoxy-N-methylbenzylamine (715.0 mg, 3.95 mmol) were added in sequence at room temperature, and the tube was sealed and stirred at 120°C for 24 hours. TLC detected that the raw material reacted completely. The solvent was concentrated under reduced pressure, and separated and purified by silica gel column chromatography (DCM / MeOH=200 / 1) to prepare a yellow oily liquid (1.1 g, yield 75%).

[0428] ESI-MS m / z:449.0,451.0[M+H] + .

[0429] 1 H NMR(400MHz,Chloroform-d)δ7.86(d,J=9.0Hz,1H),7.53–7.46(m,2H),7.45– 7.38(m,2H),7.37–7.29(m,1H),7.18(d,J=2.5Hz,1H),7.03(d,J=8.3Hz,1H),6 .98(dd,J=9.0,2.5Hz,1H),6.83(s,1H),6.49(d,J=2.4Hz,1H),6.40(dd,J=8.3 ,2.4Hz,1H),5.18(s,2H),4.73(s,2H),3.84(s,3H),3.79(s,3H),3.23(s,3H).

[0430] Step e: Preparation of intermediate E1-5

[0431] The intermediate E1-4 (1.0 g, 2.32 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (269.0 mg, 464.87 μmol) and cesium carbonate (1.5 g, 4.65 mmol) were dissolved in anhydrous 1,4-dioxane (20 mL), 2-methoxyethylamine (1.8 g, 23.24 mmol) was added at room temperature, argon gas was blown for 5 minutes, and then palladium acetate (52.2 mg, 232.43 μmol) was added, the tube was sealed, and stirred at 120°C overnight. TLC detected that the raw material reacted completely. The solvent was concentrated under reduced pressure, separated and purified by silica gel column chromatography (DCM / MeOH=30 / 1), and a yellow oily liquid (1.1 g, yield 91%) was prepared.

[0432] ESI-MS m / z:488.0[M+H] + .

[0433] 1H NMR(600MHz,Chloroform-d)δ7.49(d,J=7.5Hz,2H),7.45(d,J=9.0Hz,1H),7.40(t,J=7.5Hz,2H),7. 33(t,J=7.4Hz,1H),7.22(dt,J=14.3,6.9Hz,1H),7.17(s,1H),7.07(d,J=8.4Hz,1H),6.84(dd,J=8.9 , 2.6 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H), 6.39 (dd, J = 8.4, 2.4 Hz, 1H), 5.16 (s, 2H), 4.74 (s, 2H), 3.85 (s, 3H), 3.78 (s, 3H), 3.63 (t, J = 5.2 Hz, 2H), 3.39 (s, 3H), 3.32 (q, J = 5.2 Hz, 2H), 3.26 (s, 3H). Step f: Preparation of Intermediate E1

[0434] The intermediate E1-6 (1.0 g, 2.05 mmol) was dissolved in MeOH (20 mL), 10% Pd-C (750 mg) was added, and the mixture was stirred for 24 hours under a hydrogen atmosphere and room temperature. TLC detected that the reaction of the raw material was complete. The mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and separated and purified by silica gel column chromatography (DCM / MeOH=15 / 1) to obtain a brown foamy solid (804.2 mg, yield 99%).

[0435] ESI-MS m / z:398.1[M+H] + .

[0436] Intermediate E2: 2-(azetidin-1-yl)-4-((2-methoxyethyl)amino)quinolin-7-ol

[0437]

[0438] Step a: Preparation of intermediate E2-1

[0439] Intermediate E2-1 was prepared as a white solid from Intermediate E1-3 and azetidine using the procedure described for Intermediate E1-4.

[0440] ESI-MS m / z:324.9,326.9[M+H] + .

[0441] Step b: Preparation of intermediate E2-2

[0442] Intermediate E2-2 was prepared as a yellow oil from intermediate E2-1 using the procedure described for intermediate E1-5.

[0443] ESI-MS m / z:364.0[M+H] + .

[0444] Step c: Preparation of intermediate E2

[0445] Intermediate E2 was prepared as a light yellow solid from Intermediate E2-2 using the method described for Intermediate E1.

[0446] ESI-MS m / z:273.9[M+H] + .

[0447] 1 H NMR (400MHz, Methanol-d4) δ7.90(d,J=9.0Hz,1H),6.97(d,J=2.4Hz,1H),6.87(dd,J=9.1,2.4Hz,1H),5.35(d,J=4 .2Hz,1H),4.31(t,J=7.6Hz,4H),3.68(t,J=5.3Hz,2H),3.57(t,J=5.4Hz,2H),3.40(s,3H),2.53(q,J=7.8Hz,2H).

[0448] Intermediate F1: 2-((2,4-dimethoxybenzyl)(methyl)amino)-4-(2-methoxyethyl)amino)quinazolin-7-ol

[0449]

[0450] Step a: Preparation of intermediate F1-1

[0451] Dissolve 2,4-dichloro-7-bromoquinazoline (2.0g, 7.20mmol) in anhydrous DMF (20mL), add DIPEA (1.86g, 14.39mmol) and 2-methoxyethylamine (810.8mg, 10.79mmol) in turn, and stir at room temperature for 3 hours. TLC detected that the raw material reacted completely. Dilute with water, extract with ethyl acetate (50mL*3), wash with saturated brine (50mL*3), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. Separate and purify by silica gel column chromatography (PE / EA=3 / 1) to prepare a light yellow solid (2.1g, yield 92%).

[0452] ESI-MS m / z:315.8,317.8,319.8[M+H] + .

[0453] 1H NMR(400MHz,Chloroform-d)δ7.92(dd,J=1.8,0.6Hz,1H),7.58–7.51(m,2H),6. 38(s,1H),3.86(td,J=5.2,4.4Hz,2H),3.65(dd,J=5.5,4.5Hz,2H),3.43(s,3H).

[0454] Step b: Preparation of intermediate F1-2

[0455] The intermediate F1-1 (500.0 mg, 1.58 mmol) was dissolved in n-butanol (6 mL), and DIPEA (612.4 mg, 4.74 mmol) and 2,4-dimethoxy-N-methylbenzylamine (429.4 mg, 2.37 mmol) were added in sequence, and the tube was sealed and stirred at 120°C overnight. TLC detected that the raw material had reacted completely. The solvent was concentrated under reduced pressure, and separated and purified by silica gel column chromatography (PE / EA=2 / 1) to prepare a yellow oily liquid (680.0 mg, yield 93%).

[0456] ESI-MS m / z:461.0,462.9[M+H] + .

[0457] 1 H NMR(400MHz,Chloroform-d)δ7.64(d,J=2.0Hz,1H),7.32(d,J=8.6Hz,1H),7.09(dd,J=8.6,2.0Hz,1H),6.47(d,J=2.4Hz,1H),6.3 8(dd,J=8.3,2.4Hz,1H),5.77(s,1H),4.88(s,2H),3.82(s,3H),3.77(s,3H),3.71(s,2H),3.54(s,2H),3.35(s,3H),3.19(s,3H).

[0458] Step c: Preparation of intermediate F1

[0459] Intermediate F1-2 (811.3 mg, 1.76 mmol) and 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropylbiphenyl (226.8 mg, 351.70 μmol) were dissolved in 1,4-dioxane (6 mL), and KOH aqueous solution (6 mL, 296.0 mg, 5.28 mmol) was added at room temperature, and argon was bubbled into the reaction system for 5 minutes. Under argon protection, Pd2(dba)3 (161.0 mg, 175.85 μmol) was added, the tube was sealed, and stirred at 100°C overnight. TLC detected that the raw material reacted completely. The pH of the reaction solution was adjusted to neutral with 1N HCl aqueous solution, and the reaction solution was concentrated under reduced pressure. The brown oily liquid (580.0 mg, yield 83%) was prepared by separation and purification by silica gel column chromatography (DCM / MeOH=20 / 1).

[0460] ESI-MS m / z:399.1[M+H] + .

[0461] Intermediate F2: 2-(azetidin-1-yl)-4-((2-methoxyethyl)amino)quinazolin-7-ol

[0462]

[0463] Step a: Preparation of intermediate F2-1

[0464] Intermediate F2-1 was prepared as a white solid from Intermediate F1-1 and azetidine using the method described for Intermediate F1-2.

[0465] ESI-MS m / z:336.8,338.8[M+H] + .

[0466] 1 H NMR(400MHz,Chloroform-d)δ7.66(d,J=1.9Hz,1H),7.34(d,J=8.6Hz,1H),7.13(dd,J=8.6,2.0Hz,1H),5.85( s,1H),4.17(t,J=7.5Hz,4H),3.78(q,J=5.2Hz,2H),3.62(t,J=5.1Hz,2H),3.41(s,3H),2.33(q,J=7.5Hz,2H).

[0467] Step b: Preparation of intermediate F2

[0468] Intermediate F2 was prepared as a yellow solid from Intermediate F2-1 using the method described for Intermediate F1.

[0469] ESI-MS m / z:275.0[M+H] + .

[0470] Intermediate G: ((3aR,4R,6S,6aS)-6-(4-(((E)-(dimethylamino)methylene)amino)-5-iodopyrrolo[2,1-f][1,2,4]triazine-7-yl)-2,2,6a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl-4-methylbenzenesulfonate

[0471]

[0472] Step a: Preparation of intermediate G-1

[0473] Dissolve (3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)-3-methyldihydrofuran-2(3H)-one (2.0g, 12.33mmol) in anhydrous DMF (28mL), place the reaction system in an ice bath, add sodium hydride (1.73g, 43.17mmol) in batches under argon protection, and stir at 0℃ for 1 hour. Slowly add benzyl bromide (8.44g, 49.34mmol), gradually warm to room temperature, and stir at room temperature for 3 hours. TLC detection shows that the raw material reaction is complete. Slowly pour the reaction solution into ice water, extract with ethyl acetate (50mL*3), wash with saturated brine (50mL*3), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Separate and purify by silica gel column chromatography (PE / EA=15 / 1) to prepare a colorless liquid (3.9g, yield 73%).

[0474] ESI-MS m / z:433.0[M+H] + .

[0475] 1 H NMR(400MHz,Chloroform-d)δ7.44–7.22(m,15H),4.80(d,J=11.7Hz,1H),4.68(d,J=4.5Hz,2H),4.66–4. 45(m,4H),4.06(d,J=7.5Hz,1H),3.80(dd,J=11.5,2.4Hz,1H),3.62(dd,J=11.5,3.5Hz,1H),1.54(s,3H).

[0476] Step b: Preparation of intermediate G-2

[0477] Dissolve 4-amino-7-bromopyrrolo[2,1-f][1,2,4]triazine (5.0 g, 23.47 mmol) in anhydrous THF (100 mL), add triethylamine (11.9 g, 117.35 mmol), DMAP (286.7 mg, 2.35 mmol) and di-tert-butyl dicarbonate (15.4 g, 70.41 mmol) in turn, and stir at room temperature overnight. TLC detection shows that the raw material is completely reacted. No post-treatment is required and it is directly used in the next step.

[0478] Step c: Preparation of intermediate G-3

[0479] Add 3M NaOH aqueous solution (100 mL) to the reaction solution of intermediate G-2, heat to 60°C, and stir for 36 hours. TLC detected that the raw material reacted completely. Extract with ethyl acetate (200 mL*3), wash with saturated brine (200 mL*3), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. Separate and purify by silica gel column chromatography (PE / EA=10 / 1) to prepare a white solid (5.7 g, two-step yield 78%).

[0480] ESI-MS m / z:256.7,258.8[M- t Bu+H] + .

[0481] 1 H NMR (400MHz, DMSO-d6) δ10.59(s,1H),8.31(s,1H),7.53–7.15(m,1H),7.00(d,J=4.8Hz,1H),1.51(s,9H).

[0482] Step d: Preparation of intermediate G-4

[0483] Intermediate G-3 (4.0 g, 12.77 mmol) was placed in a Schlenk flask, argon was replaced 3 times, anhydrous THF (100 mL) was added, cooled to -30 ° C, lithium diisopropylamide (2.0 M in THF, 8.3 mL, 16.61 mmol) was slowly added dropwise, and stirred at -30 ° C for 50 minutes. Then the reaction system was cooled to -78 ° C, n-butyl lithium (2.5 M in hexane, 12.7 mL, 31.93 mmol) was slowly added dropwise, and stirred at -78 ° C for 5 minutes. Anhydrous THF solution (200 mL) of intermediate G1 (16.6 g, 38.32 mmol) was added dropwise, and stirred at -78 ° C for 2 hours. TLC detected that the raw material reaction was complete. At -78°C, saturated ammonium chloride solution was added dropwise to quench, the mixture was heated to room temperature, extracted with ethyl acetate (200 mL*3), washed with saturated brine (200 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The product was separated and purified by silica gel column chromatography (PE / EA=2 / 1) to obtain a light yellow oily liquid (8.3 g, yield 97%).

[0484] ESI-MS m / z:667.1[M+H] + .

[0485] Step e: Preparation of intermediate G-5

[0486] Dissolve the intermediate G-4 (8.3 g, 12.45 mmol) in anhydrous DCM (80 mL), add triethylsilane (5.8 g, 49.79 mmol) dropwise at -10 ° C, stir for 5 minutes, add boron trifluoride ether solution (3.1 mL, 24.90 mmol), slowly warm to room temperature, and stir for 1 hour. TLC detected that the raw material reacted completely. Add saturated sodium bicarbonate solution to quench, extract with DCM (200 mL*3), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. Separate and purify by silica gel column chromatography (PE / EA=1 / 1) to prepare a yellow oily liquid (3.7 g, yield 46%).

[0487] ESI-MS m / z:551.0[M+H] + .

[0488] 1H NMR(600MHz,Chloroform-d)δ7.89(s,1H),7.50–7.20(m,15H),6.89(d,J=4.5H z,1H),6.52(d,J=4.5Hz,1H),5.91(s,1H),5.69(s,2H),4.91(d,J=12.1Hz,1H) ,4.81(d,J=12.1Hz,1H),4.71–4.54(m,4H),4.44–4.38(m,1H),4.08(d,J=8.7H z,1H),3.91(dd,J=10.9,2.5Hz,1H),3.73(dd,J=10.9,3.6Hz,1H),1.04(s,3H).

[0489] Step f: Preparation of intermediate G-6

[0490] Dissolve intermediate G-5 (3.7 g, 6.70 mmol) in anhydrous THF (70 mL), add triethylamine (3.39 g, 33.52 mmol), DMAP (409.5 mg, 3.35 mmol) and di-tert-butyl dicarbonate (7.32 g, 33.52 mmol) in sequence, and stir at room temperature overnight. TLC detection shows that the raw material is completely reacted. No post-treatment is required and it is directly used in the next step.

[0491] Step g: Preparation of intermediate G-7

[0492] Add 3M NaOH aqueous solution (70mL) to the reaction solution of intermediate G-6, heat to 60°C, and stir for 36 hours. TLC detected that the raw material reacted completely. Extract with ethyl acetate (200mL*3), wash with saturated brine (200mL*3), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. Separate and purify by silica gel column chromatography (PE / EA=5 / 1) to prepare a light yellow oily liquid (3.4g, two-step yield 78%).

[0493] 1H NMR(400MHz,Chloroform-d)δ9.27(s,1H),8.19(s,1H),7.48–7.25(m,15H),7. 12(d,J=4.8Hz,1H),5.99(s,1H),4.93(d,J=12.2Hz,1H),4.84(d,J=12.0Hz,1H ),4.73–4.56(m,5H),4.45(dt,J=8.8,3.0Hz,1H),4.09(d,J=8.7Hz,1H),3.94( dd,J=10.9,2.5Hz,1H),3.75(dd,J=10.9,3.5Hz,1H),1.60(s,9H),1.05(s,3H).

[0494] Step h: Preparation of intermediate G-8

[0495] The intermediate G-7 (3.4 g, 5.22 mmol) was dissolved in anhydrous DCM (70 mL), cooled to 0 ° C, and a boron trichloride solution (1.0 M in DCM, 20.9 ml, 20.90 mmol) was added dropwise, and stirred at 0 ° C for 1 hour. TLC detected that the raw material reacted completely. Methanol was added at 0 ° C to quench, and the solvent was concentrated under reduced pressure to prepare a light yellow solid, which was directly used in the next step without purification.

[0496] ESI-MS m / z:280.8[M+H] + .

[0497] Step i: Preparation of intermediate G-9

[0498] The crude G-8 was suspended in anhydrous acetone (72 mL), and 2,2-dimethoxypropane (36 mL) and p-toluenesulfonic acid (1.8 g) were added in sequence, and stirred at room temperature overnight. TLC detected that the raw material reaction was complete. Saturated sodium bicarbonate solution was added to quench, extracted with ethyl acetate (100 mL*3), washed with saturated brine (100 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. It was separated and purified by silica gel column chromatography (DCM / MeOH=40 / 1) to obtain a white foamy solid (1.2 g, two-step yield 73%).

[0499] ESI-MS m / z:320.9[M+H] + .

[0500] 1H NMR(400MHz,Chloroform-d)δ7.93(s,1H),6.68(d,J=4.5Hz,1H),6.62(d,J=4.5Hz,1H),5.70(s,2H),5.56(s,1H),4.63(d,J=2.5 Hz,1H),4.34(q,J=2.5Hz,1H),3.98(dd,J=12.2,2.8Hz,1H),3.80(dd,J=12.2,2.3Hz,1H),1.65(s,3H),1.42(s,3H),1.28(s,3H).

[0501] Step j: Preparation of intermediate G-10

[0502] Dissolve the intermediate G-9 (1.2 g, 3.82 mmol) in anhydrous DMF (30 mL), add N-iodosuccinimide (1.3 g, 5.73 mmol), and stir at room temperature overnight. TLC detected that the raw material reacted completely. Quench with saturated sodium thiosulfate, dilute with water, extract with ethyl acetate (100 mL*3), wash with saturated brine (100 mL*3), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. Separate and purify by silica gel column chromatography (DCM / MeOH=60 / 1) to obtain a white foamy solid (1.4 g, yield 85%).

[0503] ESI-MS m / z:446.8[M+H] + .

[0504] 1 H NMR(400MHz,Chloroform-d)δ7.89(s,1H),6.81(s,1H),6.33(s,1H),5.51(s,1H),4.56(d,J=2.6Hz,1H),4.31(q,J=2.7 Hz,1H),3.95(dd,J=12.1,3.0Hz,1H),3.79(dd,J=12.1,2.8Hz,1H),1.74–1.56(m,3H),1.42–1.36(m,3H),1.27(s,3H).

[0505] Step k: Preparation of intermediate G-11

[0506] Dissolve the intermediate G-10 (88.0 mg, 197.20 μmol) in anhydrous toluene (3 mL), add N,N-dimethylformamide dimethyl acetal (188.0 mg, 1.58 mmol) dropwise, raise the temperature to 60°C, and stir for 1 hour. TLC detection shows that the raw material has reacted completely, the solvent is concentrated under reduced pressure, and it is directly used for the next step without purification.

[0507] ESI-MS m / z:502.0[M+H] + .

[0508] Step 1: Preparation of Intermediate G

[0509] Dissolve the intermediate G-11 in anhydrous DCM, add triethylamine (99.8 mg, 985.99 μmol), DMAP (24.1 mg, 197.20 μmol) and p-toluenesulfonyl chloride (188.0 mg, 985.99 μmol) in sequence, and stir at room temperature for 4 hours. TLC detected that the raw material reacted completely. The solvent was concentrated under reduced pressure and separated and purified by silica gel column chromatography (DCM / MeOH=100 / 1) to obtain a yellow foamy solid (105.2 mg, two-step yield 81%).

[0510] ESI-MS m / z:655.9[M+H] + .

[0511] Intermediate H: ((3aR,4R,6R,6aR)-6-cyano-6-(4-(((E)-(dimethylamino)methylene)amino)-5-iodopyrrolo[2,1-f][1,2,4]triazine-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)4-methylbenzenesulfonic acid methyl ester

[0512]

[0513] Step a: Preparation of intermediate H-1

[0514] Dissolve (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxolane-4-carbonitrile (200.0 mg, 603.62 μmol) in anhydrous DMF (5 mL), add N-iodosuccinimide (271.6 mg, 1.21 mmol), and stir at room temperature overnight. TLC detected that the raw material reaction was complete. Dilute with water, extract with ethyl acetate (50 mL*3), wash with saturated brine (50 mL*3), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to a crude product. Separate and purify by silica gel column chromatography (DCM / MeOH=60 / 1) to obtain a white foamy solid (273.2 mg, yield 99%).

[0515] ESI-MS m / z:457.8[M+H] + .

[0516] 1H NMR(400MHz,Chloroform-d)δ7.86(s,1H),7.19(s,1H),6.77(s,2H),5.37(d,J=6.6Hz,1H),5.18(dd,J=6.6,2.5Hz,1H), 4.63(q,J=2.1Hz,1H),4.31(s,1H),3.94(dd,J=12.5,2.0Hz,1H),3.82(d,J=12.6Hz,1H),1.77(s,3H),1.40–1.32(m,3H).

[0517] Step b: Preparation of intermediate H-2

[0518] Dissolve intermediate H-1 (273.2 mg, 597.51 μmol) in anhydrous toluene (6 mL), add N,N-dimethylformamide dimethyl acetal (0.4 mL, 2.99 mmol), and heat to 60 °C and stir for 1 hour. TLC detected that the raw material reacted completely. The solvent was concentrated under reduced pressure and used directly in the next step without purification.

[0519] Step c: Preparation of intermediate H

[0520] The crude intermediate H-2 was dissolved in anhydrous DCM (10 mL), triethylamine (302.3 mg, 2.99 mmol), DMAP (73.0 mg, 597.51 μmol) and p-toluenesulfonyl chloride (569.6 mg, 2.99 mmol) were added in sequence, and stirred at room temperature for 4 hours. TLC detected that the raw material had reacted completely. The solvent was concentrated under reduced pressure, and separated and purified by silica gel column chromatography (DCM / MeOH=100 / 1) to obtain a yellow foamy solid (364.2 mg, two-step yield 91%).

[0521] Intermediate I: ((3aR,4R,6S,6aS)-6-(4-(((E)-(dimethylamino)methylene)amino)imidazo[2,1-f][1,2,4]triazine-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl-4-methylbenzenesulfonate

[0522]

[0523] Step a: Preparation of intermediate I-1

[0524] Dissolve ((3aR,4R,6S,6aS)-6-(4-aminoimidazo[2,1-f][1,2,4]triazine-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (300.0 mg, 976.21 μmol) in anhydrous toluene (8 mL), add N,N-dimethylformamide dimethyl acetal (0.6 mL, 4.88 mmol), heat to 60 °C and stir for 1 hour. TLC detected that the raw material reacted completely. The solvent was concentrated under reduced pressure and used directly in the next step without purification.

[0525] ESI-MS m / z:363.1[M+H] + .

[0526] Step b: Preparation of Intermediate I

[0527] The crude intermediate I-1 was dissolved in anhydrous DCM (10 mL), triethylamine (493.9 mg, 4.88 mmol), DMAP (119.3 mg, 976.21 μmol) and p-toluenesulfonyl chloride (930.5 mg, 4.88 mmol) were added in sequence, and stirred at room temperature for 4 hours. TLC detected that the raw material had reacted completely. The solvent was concentrated under reduced pressure, separated and purified by silica gel column chromatography (DCM / MeOH=100 / 1) to obtain a yellow foamy solid (504.0 mg, two-step yield 99%).

[0528] ESI-MS m / z:517.0[M+H] + .

[0529] Example 1: (2S,3R,4S,5R)-2-(4-amino-5-iodopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-((2-(methylamino)quinolin-7-yloxy)methyl)tetrahydrofuran-3,4-diol (Compound 1)

[0530]

[0531] Intermediate A2 (60.1 mg, 81.37 μmol) was dissolved in a mixed solvent of TFA (1.8 mL) and water (0.2 mL) and stirred at room temperature for 2 hours. TLC detected that the raw material was completely consumed. In an ice bath at 0°C, ammonia methanol solution was added dropwise to the reaction solution, the pH value was adjusted to neutral, the solvent was concentrated under reduced pressure, and separated and purified by silica gel column chromatography (DCM / MeOH=25 / 1) to obtain white solid compound 1 (25.0 mg, yield 56%).

[0532] ESI-MS m / z:549.13[M+H] + .

[0533] 1 H NMR (600MHz, Methanol-d4) δ7.81(s,1H),7.76(d,J=8.9Hz,1H),7.51(d,J=8.7Hz,1H),7.17(d,J=2.4Hz,1H),6.94(s,1H),6.90(dd,J=8.7,2.5Hz,1H), 6.59(d,J=8.9Hz,1H),5.40(d,J=4.7Hz,1H),4.42(t,J=5.0Hz,2H),4.36(t, J=5.3Hz,1H),4.34–4.32(m,1H),4.27(dd,J=10.7,4.0Hz,1H),3.00(s,3H).

[0534] Example 2: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-((2-(methylamino)quinolin-7-yloxy)methyl)tetrahydrofuran-3,4-diol (Compound 2)

[0535]

[0536] Step a: Preparation of intermediate 2-1

[0537] At room temperature, PdCl2(dppf) (6.37 mg, 8.71 μmol) was added to a mixed solution of A2 (69.1 mg, 87.06 μmol), 1-methylpyrazole-3-boronic acid pinacol ester (21.7 mg, 104.48 μmol) and potassium carbonate (24.1 mg, 174.13 μmol) in dioxane (4 mL) and water (1 mL), and the argon gas was replaced three times, and the temperature was raised to 80 ° C and stirred for 2 hours. TLC detected that the raw material reacted completely. The reaction solution was cooled, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (DCM / MeOH=100 / 1) to obtain yellow oily liquid intermediate 2-1 (36.1 mg, yield 60%).

[0538] ESI-MS m / z:693.27[M+H] + .

[0539] Step b: Preparation of compound 2

[0540] Using the method described for compound 1, compound 2 (13.0 mg, yield 50%) was prepared from intermediate 2-1 as a light grey solid.

[0541] ESI-MS m / z:503.32[M+H] + .

[0542] 1 H NMR(400MHz, Methanol-d4)δ7.72(dd,J=9.0,2.0Hz,2H),7.53–7.43(m,2H),7.19(d,J=2.4 Hz,1H),6.98(d,J=2.0Hz,1H),6.89(dt,J=8.8,2.3Hz,1H),6.56(dd,J=8.8,2.0Hz,1H),6. 41(d,J=2.2Hz,1H),5.43(dd,J=4.9,1.9Hz,1H),4.50(td,J=5.0,1.9Hz,1H),4.39(dddd,J =19.4,12.4,5.2,2.7Hz,3H),4.28(ddd,J=10.5,4.2,2.0Hz,1H),3.89(s,3H),2.98(s,3H).

[0543] Example 3: (2S,3R,4S,5R)-2-(4-amino-5-(5-methylfuran-2-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-((2-(methylamino)quinolin-7-yloxy)methyl)tetrahydrofuran-3,4-diol (Compound 3)

[0544]

[0545] Step a: Preparation of intermediate 3-1

[0546] Intermediate 3-1 (96.0 mg, 100% yield) was prepared from Intermediate A2 and 2-methylfuran-5-boronic acid pinacol ester as a yellow oily liquid using the method described in Intermediate 2-1.

[0547] ESI-MS m / z:748.33[M+H] + .

[0548] Step b: Preparation of compound 3

[0549] Compound 3 (31.0 mg, yield 48%) was prepared from intermediate 3-1 as a yellow solid using the method described for compound 1.

[0550] ESI-MS m / z:503.23[M+H] + .

[0551] 1H NMR (600MHz, Methanol-d4) δ7.78(d,J=1.3Hz,1H),7.74(d,J=8.8Hz,1H),7.49(d,J=8.8Hz,1 H),7.19(d,J=2.5Hz,1H),6.93–6.88(m,2H),6.58(d,J=8.9Hz,1H),6.38(d,J=3.2Hz,1H),6. 12(d,J=3.2Hz,1H),5.43(d,J=4.8Hz,1H),4.47(t,J=4.9Hz,1H),4.45(s,1H),4.39(t,J=5.4 Hz,1H),4.35(dt,J=5.8,3.5Hz,1H),4.29(dd,J=10.7,4.2Hz,1H),2.99(s,3H),2.38(s,3H).

[0552] Example 4: (2S,3R,4S,5R)-2-(4-amino-5-cyclopentylpyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-((2-(methylamino)quinolin-7-yloxy)methyl)tetrahydrofuran-3,4-diol (Compound 4)

[0553]

[0554] Step a: Preparation of intermediate 4-1

[0555] Intermediate 4-1 (90.0 mg, 97% yield) was prepared from Intermediate A2 and 1-cyclopenteneboronic acid pinacol ester as a yellow oily liquid using the method described in Intermediate 2-1.

[0556] ESI-MS m / z:734.33[M+H] + .

[0557] Step b: Preparation of intermediate 4-2

[0558] The intermediate 4-1 (90.0 mg, 122.64 μmol) was dissolved in methanol (3 mL), and a palladium carbon catalyst (9.0 mg, 10% wt) was added. The reaction solution was stirred at 40 ° C for 6 hours under a hydrogen atmosphere. TLC detected that the raw material reaction was complete. The reaction solution was filtered through diatomaceous earth to remove the palladium carbon, and the filtrate was concentrated under reduced pressure to obtain the intermediate crude product 4-2, which was directly used in the next step without purification.

[0559] Step c: Preparation of compound 4

[0560] Compound 4 (5.0 mg, 8% yield for two steps) was prepared from intermediate 4-2 as a light yellow solid using the method described for compound 1.

[0561] ESI-MS m / z:491.27[M+H] + .

[0562] 1 H NMR (600MHz, Methanol-d4) δ7.92(d,J=9.2Hz,1H),7.68(s,1H),7.60(d,J=8.8Hz,1H),7.26( d,J=2.4Hz,1H),7.00(dt,J=8.4,2.6Hz,1H),6.70(d,J=9.1Hz,1H),6.55(s,1H),5.40(d,J=4 .9Hz,1H),4.49–4.45(m,1H),4.44(t,J=5.1Hz,1H),4.38(t,J=5.3Hz,1H),4.33–4.28(m,2H) ,3.36(d,J=8.0Hz,1H),3.07(s,3H),2.09–1.95(m,3H),1.74–1.70(m,2H),1.62–1.46(m,3H).

[0563] Example 5: (2S,3R,4S,5R)-2-(4-amino-5-iodopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-((2-(cyclobutylamino)quinolin-7-yloxy)methyl)tetrahydrofuran-3,4-diol (Compound 5)

[0564]

[0565] Compound 5 (52.1 mg, 43% yield) was prepared from intermediate A3 as a white solid using the method described for compound 1.

[0566] ESI-MS m / z:589.21[M+H] + .

[0567] 1H NMR (600MHz, Methanol-d4) δ7.82(s,1H),7.78(d,J=8.8Hz,1H),7.52(d,J=8.7Hz,1H),7.14( d,J=2.5Hz,1H),6.96(s,1H),6.92(dd,J=8.7,2.5Hz,1H),6.59(d,J=8.8Hz,1H),5.42(d,J=4. 7Hz,1H),4.52(p,J=7.8Hz,1H),4.45–4.39(m,2H),4.39–4.36(m,1H),4.36–4.33(m,1H),4.2 8(dd,J=10.6,4.1Hz,1H),2.53–2.42(m,2H),1.99(dt,J=11.5,8.8Hz,2H),1.87–1.76(m,2H).

[0568] Example 6: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-((2-(cyclobutylamino)quinolin-7-yloxy)methyl)tetrahydrofuran-3,4-diol (Compound 6)

[0569]

[0570] Step a: Preparation of intermediate 6-1

[0571] Intermediate 6-1 (98.9 mg, 88% yield) was prepared from Intermediate A3 and 1-methylpyrazole-3-boronic acid pinacol ester as a yellow oily liquid using the method described in Intermediate 2-1.

[0572] ESI-MS m / z:583.32[M+H] + .

[0573] Step b: Preparation of compound 6

[0574] Compound 6 (48.5 mg, 53% yield) was prepared from intermediate 6-1 as a white solid using the method described for compound 1.

[0575] ESI-MS m / z:543.29[M+H] + .

[0576] 1H NMR (600MHz, Methanol-d4) δ7.74(dd,J=8.9,2.5Hz,1H),7.72(d,J=1.5Hz,1H),7.51(t,J=2.1Hz,1H),7.47(dd,J=8.7,2.5Hz,1H ),7.14(d,J=2.4Hz,1H),6.99(d,J=1.7Hz,1H),6.90(dt,J=8.7,2.2Hz,1H),6.56(dd,J=8.8,2.0Hz,1H),6.41(d,J=2.4Hz,1H),5 .43(d,J=5.0Hz,1H),4.49(q,J=5.3Hz,2H),4.43(dd,J=10.7,2.9Hz,1H),4.39(t,J=5.3Hz,1H),4.35(ddd,J=5.6,4.3,2.9Hz,1H ), 4.29(dd,J=10.6,4.3Hz,1H),3.91(s,3H),2.44(dtd,J=11.1,7.3,3.6Hz,2H),2.02–1.93(m,2H),1.78(tt,J=10.2,4.4Hz,2H).

[0577] Example 7: (2S,3R,4S,5R)-2-(4-amino-5-(5-methylfuran-2-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-((2-(cyclobutylamino)quinolin-7-yloxy)methyl)tetrahydrofuran-3,4-diol (Compound 7)

[0578]

[0579] Step a: Preparation of intermediate 7-1

[0580] Intermediate 7-1 (115.6 mg, 86% yield) was prepared from Intermediate A3 and 2-methylfuran-5-boronic acid pinacol ester as a yellow oily liquid using the method described in Intermediate 2-1.

[0581] ESI-MS m / z:638.32[M+H] + .

[0582] Step b: Preparation of compound 7

[0583] Compound 7 (44.7 mg, 45% yield) was prepared from intermediate 7-1 as a white solid using the method described for compound 1.

[0584] ESI-MS m / z:543.28[M+H] + .

[0585] 1 H NMR (600MHz, Methanol-d4) δ7.78(s,1H),7.75(d,J=8.9Hz,1H),7.48(dd,J=8.7,2.4Hz,1H),7.14(d,J=2.4Hz,1H),6. 90–6.88(m,2H),6.56(d,J=8.9Hz,1H),6.37(d,J=3.2Hz,1H),6.13–6.10(m,1H),5.43(dd,J=4.8,2.5Hz,1H),4.51–4. 48(m,1H),4.46(t,J=4.9Hz,1H),4.43(dd,J=10.8,2.9Hz,1H),4.38(t,J=5.3Hz,1H),4.35(q,J=5.0,4.4Hz,1H),4.29 (dd,J=10.6,4.4Hz,1H),2.45(dq,J=7.3,3.9Hz,2H),2.38(s,3H),1.98(t,J=9.9Hz,2H),1.79(dt,J=10.0,6.4Hz,2H).

[0586] Example 8: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-((2-(azetidin-1-yl)quinolin-7-yloxy)methyl)tetrahydrofuran-3,4-diol (Compound 8)

[0587]

[0588] Step a: Preparation of intermediate 8-1

[0589] Intermediate 8-1 (123.0 mg, 100% yield) was prepared from Intermediate A4 and 1-methylpyrazole-3-boronic acid pinacol ester using the method described in Intermediate 2-1.

[0590] ESI-MS m / z:569.34[M+H] + .

[0591] Step b: Preparation of compound 8

[0592] Compound 8 (52.3 mg, 46% yield) was prepared from intermediate 8-1 as a white solid using the method described for compound 1.

[0593] ESI-MS m / z:529.35[M+H] + .

[0594] 1H NMR (600MHz, Methanol-d4) δ7.84(d,J=8.8Hz,1H),7.71(s,1H),7.59–7.47(m,2H),7.17(d,J=2. 5Hz,1H),6.95–6.89(m,2H),6.45(d,J=8.9Hz,1H),6.38(d,J=2.3Hz,1H),5.42(d,J=5.1Hz,1H), 4.48(t,J=5.1Hz,1H),4.44(dd,J=10.8,2.9Hz,1H),4.39(t,J=5.3Hz,1H),4.35(ddd,J=5.5,4.2 ,2.8Hz,1H),4.29(dd,J=10.8,4.2Hz,1H),4.16(t,J=7.5Hz,4H),3.90(s,3H),2.49–2.29(m,2H).

[0595] Example 9: (2S,3R,4S,5R)-2-(4-amino-5-(5-methylfuran-2-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-((2-(azetidin-1-yl)quinolin-7-yloxy)methyl)tetrahydrofuran-3,4-diol (Compound 9)

[0596]

[0597] Step a: Preparation of intermediate 9-1

[0598] Intermediate 9-1 (142.0 mg, 100% yield) was prepared from Intermediate A4 and 2-methylfuran-5-boronic acid pinacol ester as a yellow oily liquid using the method described in Intermediate 2-1.

[0599] ESI-MS m / z:624.36[M+H] + .

[0600] Step b: Preparation of compound 9

[0601] Using the method described for compound 1, pre-HPLC preparative purification from intermediate 9-1 gave compound 9 as a trifluoroacetate salt as a white solid.

[0602] ESI-MS m / z:529.35[M+H] + .

[0603] 1H NMR (600MHz, Methanol-d4) δ8.12(d,J=9.3Hz,1H),7.92(s,1H),7.68(d,J=8.8Hz,1H),7.22(d,J=2.4Hz,1H),7.08(dd,J=8.8,2.4H z,1H),6.85(s,1H),6.64(d,J=9.3Hz,1H),6.58(d,J=3.3Hz,1H),6.23(dd,J=3.3,1.2Hz,1H),5.37(d,J=4.3Hz,1H),4.58–4.53(m, 1H), 4.48–4.44 (m, 5H), 4.41 (t, J = 5.3 Hz, 1H), 4.36–4.31 (m, 2H), 2.62 (p, J = 7.8 Hz, 2H), 2.43 (d, J = 1.0 Hz, 3H). Example 10: (2S, 3R, 4S, 5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-((4-(2-(dimethylamino)ethyl)amino)-2-ethylquinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 10)

[0604]

[0605] Step a: Preparation of intermediate 10-1

[0606] Intermediate 10-1 (140.0 mg, yield 23%) was prepared from Intermediate A1 and Intermediate D12 as a yellow oily liquid.

[0607] ESI-MS m / z:729.35[M+H] + .

[0608] 1H NMR (400MHz, Methanol-d4) δ8.62(s,1H),7.92(s,1H),7.87(d,J=9.2Hz,1H),7.13(d,J=2.6Hz,1H),6.97(dd,J=9.2,2 .6Hz,1H),6.92(s,1H),6.31(s,1H),5.48(d,J=3.8Hz,1H),5.15(dd,J=6.4,3.8Hz,1H),4.99(dd,J=6.4,3.7Hz,1H),4. 52–4.47(m,1H),4.26(dd,J=10.4,4.2Hz,1H),4.20(dd,J=10.4,5.4Hz,1H),3.43(t,J=6.7Hz,2H),3.27(d,J=0.7Hz,3H ),3.19(s,3H),2.76(q,J=7.6Hz,2H),2.65(t,J=6.7Hz,2H),2.32(s,6H),1.60(s,3H),1.38(s,3H),1.34–1.30(m,3H).

[0609] Step b: Preparation of intermediate 10-2

[0610] Intermediate 10-2 (47.0 mg, 39% yield) was prepared from Intermediate 10-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a yellow oily liquid.

[0611] ESI-MS m / z:628.46[M+H] + .

[0612] Step c: Preparation of compound 10

[0613] The trifluoroacetic acid salt of compound 10 was prepared from intermediate 10-2 by pre-HPLC separation and purification using the method described for compound 1 as a white solid.

[0614] ESI-MS m / z:588.44[M+H] + .

[0615] 1H NMR (600MHz, Methanol-d4) δ8.17(d,J=9.3Hz,1H),7.91(s,1H),7.68(d,J=2.3Hz,1H),7.26(dd,J=9.3, 2.5Hz,1H),7.23(d,J=2.5Hz,1H),7.07(s,1H),6.71(s,1H),6.63(d,J=2.4Hz,1H),5.39(d,J=4.4Hz,1H ),4.59(dd,J=11.0,2.2Hz,1H),4.49(t,J=4.7Hz,1H),4.43(t,J=5.4Hz,1H),4.40(s,2H),4.00(d,J=6. 3Hz, 2H), 3.98 (s, 3H), 3.56 (t, J = 6.3Hz, 2H), 3.01 (s, 6H), 2.93 (q, J = 7.6Hz, 2H), 1.42 (t, J = 7.7Hz, 3H).

[0616] Example 11: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-((2-ethyl-4-((2-methoxyethyl)amino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 11)

[0617]

[0618] Step a: Preparation of intermediate 11-1

[0619] Intermediate 11-1 (350.0 mg, yield 56%) was prepared from Intermediate A1 and Intermediate D13 as a yellow oily liquid.

[0620] ESI-MS m / z:716.31[M+H] + .

[0621] Step b: Preparation of intermediate 11-2

[0622] Intermediate 11-2 (240.0 mg, 80% yield) was prepared from Intermediate 11-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a yellow oily liquid.

[0623] ESI-MS m / z:615.43[M+H] + .

[0624] Step c: Preparation of compound 11

[0625] The trifluoroacetic acid salt of compound 11 was prepared from intermediate 11-2 by pre-HPLC separation and purification using the method described for compound 1 as a white solid.

[0626] ESI-MS m / z:575.40[M+H] + .

[0627] 1 H NMR (600MHz, Methanol-d4) δ8.11(d,J=9.3Hz,1H),7.89(s,1H),7.66(d,J=2.4Hz,1H),7.21(dd, J=9.3,2.5Hz,1H),7.17(d,J=2.5Hz,1H),6.97(s,1H),6.63(s,1H),6.55(d,J=2.4Hz,1H),5.38( d,J=4.4Hz,1H),4.64–4.56(m,1H),4.49(d,J=4.9Hz,1H),4.45(t,J=5.4Hz,1H),4.41–4.34(m,2 H), 3.98 (s, 3H), 3.72 (d, J = 1.4Hz, 4H), 3.41 (s, 3H), 2.86 (q, J = 7.6Hz, 2H), 1.39 (t, J = 7.6Hz, 3H).

[0628] Example 12: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-((2-ethyl-4-morpholinoquinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 12)

[0629]

[0630] Step a: Preparation of intermediate 12-1

[0631] Intermediate 12-1 (406.2 mg, yield 80%) was prepared from Intermediate A1 and Intermediate D9 as a yellow oily liquid.

[0632] ESI-MS m / z:728.32[M+H] + .

[0633] Step b: Preparation of intermediate 12-2

[0634] Intermediate 12-2 (300.0 mg, 86% yield) was prepared from Intermediate 12-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a yellow foamy solid.

[0635] ESI-MS m / z:627.43[M+H] + .

[0636] Step c: Preparation of compound 12

[0637] The trifluoroacetic acid salt of compound 12 was prepared from intermediate 12-2 using the method described for compound 1 by pre-HPLC separation and purification as a white solid.

[0638] ESI-MS m / z:587.40[M+H] + .

[0639] 1 H NMR (600MHz, Methanol-d4) δ7.96(d,J=9.4Hz,1H),7.91(s,1H),7.68(d,J=2.3Hz,1H),7.30(d,J=2.5Hz ,1H),7.25(dd,J=9.4,2.5Hz,1H),7.01(s,1H),6.91(s,1H),6.60(d,J=2.4Hz,1H),5.36(d,J=4.6Hz,1H ),4.61(dd,J=11.5,2.5Hz,1H),4.48(t,J=4.9Hz,1H),4.45–4.39(m,2H),4.37(ddd,J=6.2,4.0,2.5Hz, 1H),3.98(s,3H),3.92(t,J=4.8Hz,4H),3.77–3.67(m,4H),2.95(q,J=7.6Hz,2H),1.41(t,J=7.6Hz,3H).

[0640] Example 13: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-((2-ethyl-4-(pyrrolidin-1-yl)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 13)

[0641]

[0642] Step a: Preparation of Intermediate 13-1

[0643] Intermediate 13-1 (294.8 mg, 46% yield) was prepared from Intermediate A1 and Intermediate D8 as a yellow foamy solid.

[0644] ESI-MS m / z:712.33[M+H]+ .

[0645] Step b: Preparation of intermediate 13-2

[0646] Intermediate 13-2 (175.0 mg, 69% yield) was prepared from Intermediate 13-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a yellow oily liquid.

[0647] ESI-MS m / z:611.43[M+H] + .

[0648] Step c: Preparation of compound 13

[0649] The trifluoroacetic acid salt of compound 13 was prepared from intermediate 13-2 by pre-HPLC separation and purification using the method described for compound 1 as a white solid.

[0650] ESI-MS m / z:571.43[M+H] + .

[0651] 1 H NMR (600MHz, Methanol-d4) δ8.32(d,J=9.5Hz,1H),7.89(s,1H),7.68(d,J=2.3Hz,1H),7.16( d,J=2.6Hz,1H),7.13(dd,J=9.5,2.7Hz,1H),6.95(s,1H),6.59(d,J=2.3Hz,1H),6.44(s,1H), 5.37(d,J=4.0Hz,1H),4.67–4.59(m,1H),4.48(p,J=5.0Hz,2H),4.39(d,J=3.6Hz,2H),3.98( s,3H),3.91(s,4H),2.83(q,J=7.7Hz,2H),2.15(dq,J=6.7,3.2Hz,4H),1.38(t,J=7.6Hz,3H).

[0652] Example 14: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-((2-ethyl-4-((2-methoxyethyl)(methyl)amino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 14)

[0653]

[0654] Step a: Preparation of intermediate 14-1

[0655] Intermediate 14-1 (432.8 mg, yield 69%) was prepared from Intermediate A1 and Intermediate D14 as a yellow oily liquid using the method described in Intermediate A2.

[0656] ESI-MS m / z:730.32[M+H] + .

[0657] Step b: Preparation of intermediate 14-2

[0658] Intermediate 14-2 (242.2 mg, 65% yield) was prepared from Intermediate 14-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a brown oily liquid.

[0659] ESI-MS m / z:629.41[M+H] + .

[0660] Step c: Preparation of compound 14

[0661] The trifluoroacetic acid salt of compound 14 was prepared from intermediate 14-2 by pre-HPLC separation and purification using the method described for compound 1 as a white solid.

[0662] ESI-MS m / z:589.41[M+H] + .

[0663] 1 H NMR (600MHz, Methanol-d4) δ8.25(d,J=9.5Hz,1H),7.90(s,1H),7.67(d,J=2.3Hz,1H),7.22(d,J=2.6Hz,1H) ,7.17(dd,J=9.5,2.6Hz,1H),6.99(s,1H),6.78(s,1H),6.58(d,J=2.4Hz,1H),5.36(d,J=4.5Hz,1H),4.59(d d,J=11.2,2.1Hz,1H),4.48(t,J=4.8Hz,1H),4.43(t,J=5.3Hz,1H),4.41–4.35(m,2H),3.97(s,3H),3.93(t, J=5.1Hz,2H),3.81(t,J=5.1Hz,2H),3.42(s,3H),3.38(s,3H),2.87(q,J=7.6Hz,2H),1.38(t,J=7.6Hz,3H).

[0664] Example 15: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-ethyl-4-(4-methylpiperazin-1-yl)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 15)

[0665]

[0666] Step a: Preparation of intermediate 15-1

[0667] Intermediate 15-1 (298.4 mg, 62% yield) was prepared from Intermediate A1 and Intermediate D10 as a yellow oily liquid.

[0668] ESI-MS m / z:741.43[M+H] + .

[0669] Step b: Preparation of intermediate 15-2

[0670] Intermediate 15-2 (166.9 mg, 65% yield) was prepared from Intermediate 15-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a brown oily liquid.

[0671] ESI-MS m / z:640.44[M+H] + .

[0672] Step c: Preparation of compound 15

[0673] The intermediate 15-2 was separated and purified by silica gel column chromatography using the method described in Compound 1 to prepare Compound 15 (119.9 mg, yield 77%) as a yellow solid.

[0674] ESI-MS m / z:600.44[M+H] + .

[0675] Example 16: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-ethylquinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 16)

[0676]

[0677] Step a: Preparation of intermediate 16-1

[0678] Intermediate 16-1 (258.8 mg, 62% yield) was prepared from Intermediate A1 and Intermediate D1 as a yellow foamy solid.

[0679] ESI-MS m / z:643.13[M+H] + .

[0680] Step b: Preparation of intermediate 16-2

[0681] Intermediate 16-2 (171.7 mg, 79% yield) was prepared from Intermediate 16-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a yellow oily liquid.

[0682] ESI-MS m / z:542.27[M+H] + .

[0683] Step c: Preparation of compound 16

[0684] The method described in Compound 1 was used to separate and purify the intermediate 16-2 by silica gel column chromatography to prepare Compound 16 (60.0 mg, yield 38%) as a white solid.

[0685] ESI-MS m / z:502.24[M+H] + .

[0686] Example 17: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-((quinolin-7-yloxy)methyl)tetrahydrofuran-3,4-diol (Compound 17)

[0687]

[0688] Step a: Preparation of Intermediate 17-1

[0689] Intermediate 17-1 (223.0 mg, 80% yield) was prepared from Intermediate A1 and 7-hydroxyquinoline as a yellow oily liquid using the method described in Intermediate A2.

[0690] ESI-MS m / z:615.10[M+H] + .

[0691] Step b: Preparation of Intermediate 17-2

[0692] Intermediate 17-2 (150.0 mg, 80% yield) was prepared from Intermediate 17-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a yellow oily liquid.

[0693] ESI-MS m / z:514.23[M+H] + .

[0694] Step c: Preparation of compound 17

[0695] The method described in Compound 1 was used to separate and purify the intermediate 17-2 by silica gel column chromatography to prepare Compound 17 (76.1 mg, yield 55%) as a white solid.

[0696] ESI-MS m / z:474.21[M+H] + .

[0697] Example 18: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-methylquinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 18)

[0698]

[0699] Step a: Preparation of Intermediate 18-1

[0700] Intermediate 18-1 (232.8 mg, 91% yield) was prepared from Intermediate A1 and 2-methyl-7-hydroxyquinoline as a yellow foamy solid using the method described in Intermediate A2.

[0701] ESI-MS m / z:629.15[M+H] + .

[0702] Step b: Preparation of intermediate 18-2

[0703] Intermediate 18-2 (150.6 mg, 77% yield) was prepared from Intermediate 18-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a yellow oily liquid.

[0704] ESI-MS m / z:528.25[M+H] + .

[0705] Step c: Preparation of compound 18

[0706] The method described in Compound 1 was used to separate and purify the intermediate 18-2 by silica gel column chromatography to prepare Compound 18 (76.3 mg, yield 55%) as a white solid.

[0707] ESI-MS m / z:488.23[M+H] + .

[0708] Example 19: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-ethyl-4-(methylamino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 19)

[0709]

[0710] Step a: Preparation of Intermediate 19-1

[0711] Intermediate 19-1 (216.7 mg, yield 36%) was prepared from Intermediate A1 and Intermediate D4 as a pale yellow oily liquid.

[0712] ESI-MS m / z:672.27[M+H] + .

[0713] Step b: Preparation of intermediate 19-2

[0714] Intermediate 19-2 (76.0 mg, 41% yield) was prepared from Intermediate 19-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a brown oily liquid.

[0715] ESI-MS m / z:571.36[M+H] + .

[0716] Step c: Preparation of compound 19

[0717] The trifluoroacetic acid salt of compound 19 was prepared from intermediate 19-2 by pre-HPLC separation and purification using the method described for compound 1 as a white solid.

[0718] ESI-MS m / z:531.38[M+H] + .

[0719] 1H NMR(600MHz,Methanol-d4)δ8.00(d,J=9.2Hz,1H),7.90(s,1H),7.67(d,J=2.4Hz,1H),7 .20(dd,J=9.4,2.4Hz,1H),7.16(d,J=2.6Hz,1H),6.94(s,1H),6.56(d,J=2.4Hz,1H),6. 49(s,1H),5.37(d,J=4.3Hz,1H),4.62(d,J=10.2Hz,1H),4.47(dt,J=13.8,5.0Hz,2H),4 .39–4.33(m,2H),3.98(s,3H),3.14(s,3H),2.87(q,J=7.6Hz,2H),1.40(t,J=7.6Hz,3H).

[0720] Example 20: (2R,3S,4R,5S)-2-(((4-amino-2-ethylquinolin-7-yl)oxy)methyl)-5-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)tetrahydrofuran-3,4-diol (Compound 20)

[0721]

[0722] Step a: Preparation of Intermediate 20-1

[0723] Intermediate 20-1 (41.7 mg, yield 7%) was prepared as a yellow oily liquid from Intermediate A1 and Intermediate D3 using the method described in Intermediate A2.

[0724] ESI-MS m / z:658.24[M+H] + .

[0725] Step b: Preparation of intermediate 20-2

[0726] Intermediate 20-2 (10.0 mg, 28% yield) was prepared from Intermediate 20-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a brown oily liquid.

[0727] ESI-MS m / z:557.35[M+H] + .

[0728] Step c: Preparation of compound 20

[0729] The trifluoroacetic acid salt of compound 20 was prepared from intermediate 20-2 using the method described for compound 1 and purified by pre-HPLC as a white solid.

[0730] ESI-MS m / z:517.36[M+H] + .

[0731] 1 H NMR(600MHz,Methanol-d4)δ8.06(d,J=9.2Hz,1H),7.91(s,1H),7.66(d,J=2.3Hz,1H),7 .21(dd,J=9.4,2.4Hz,1H),7.15(d,J=2.4Hz,1H),6.96(s,1H),6.57–6.53(m,1H),6.50( s,1H),5.39(d,J=4.6Hz,1H),4.60(d,J=10.6Hz,1H),4.48(t,J=4.9Hz,1H),4.44(t,J=5 .1Hz,1H),4.41–4.35(m,2H),3.98(s,3H),2.81(q,J=7.9Hz,2H),1.36(t,J=7.7Hz,3H).

[0732] Example 21: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((4-(dimethylamino)-2-ethylquinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 21)

[0733]

[0734] Step a: Preparation of Intermediate 21-1

[0735] Intermediate 21-1 (346.6 mg, yield 54%) was prepared from Intermediate A1 and Intermediate D5 as a yellow oily liquid using the method described in Intermediate A2.

[0736] ESI-MS m / z:686.27[M+H] + .

[0737] Step b: Preparation of Intermediate 21-2

[0738] Intermediate 21-2 (223.3 mg, 76% yield) was prepared from Intermediate 21-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a yellow oily liquid.

[0739] ESI-MS m / z:585.39[M+H] + .

[0740] Step c: Preparation of compound 21

[0741] The trifluoroacetic acid salt of compound 21 was prepared from intermediate 21-2 using the method described for compound 1 and purified by pre-HPLC separation as a white solid.

[0742] ESI-MS m / z:545.39[M+H] + .

[0743] 1 H NMR (600MHz, Methanol-d4) δ8.16(d,J=9.4Hz,1H),7.92(s,1H),7.68(d,J=2.4Hz,1H),7.20( d,J=2.4Hz,1H),7.17(dd,J=9.5,2.6Hz,1H),6.99(s,1H),6.64(s,1H),6.59(d,J=2.3Hz,1H), 5.37(d,J=4.5Hz,1H),4.60(dd,J=11.3,2.0Hz,1H),4.48(t,J=4.8Hz,1H),4.44(t,J=5.3Hz,1 H),4.41–4.35(m,2H),3.98(s,3H),3.43(s,6H),2.86(q,J=7.6Hz,2H),1.38(t,J=7.6Hz,3H).

[0744] Example 22: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((4-(4,4-difluoropiperidin-1-yl)-2-ethylquinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 22)

[0745]

[0746] Step a: Preparation of Intermediate 22-1

[0747] Intermediate 22-1 (329.7 mg, yield 66%) was prepared as a yellow oily liquid from Intermediate A1 and Intermediate D11 using the method described in Intermediate A2.

[0748] ESI-MS m / z:762.33[M+H] + .

[0749] Step b: Preparation of intermediate 22-2

[0750] Intermediate 22-2 (296.9 mg, 100% yield) was prepared from Intermediate 22-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a yellow foamy solid.

[0751] ESI-MS m / z:661.42[M+H] + .

[0752] Step c: Preparation of compound 22

[0753] The trifluoroacetic acid salt of compound 22 was prepared from intermediate 22-2 using the method described for compound 1 and purified by pre-HPLC separation as a white solid.

[0754] ESI-MS m / z:621.36[M+H] + .

[0755] 1 H NMR(600MHz,Methanol-d4)δ7.98(d,J=10.0Hz,1H),7.93(s,1H),7.69(d,J=2.3Hz,1H ),7.33–7.29(m,2H),7.04(s,1H),6.99(s,1H),6.61(d,J=2.4Hz,1H),5.39(d,J=4.6Hz ,1H),4.62(dd,J=11.6,2.5Hz,1H),4.48(t,J=4.9Hz,1H),4.46–4.37(m,3H),3.98(s,3 H),3.88–3.77(m,4H),2.96(q,J=7.7Hz,2H),2.35–2.25(m,4H),1.42(t,J=7.6Hz,3H).

[0756] Example 23: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((4-(azetidin-1-yl)-2-ethylquinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 23)

[0757]

[0758] Step a: Preparation of Intermediate 23-1

[0759] Intermediate 23-1 (365.8 mg, yield 52%) was prepared from Intermediate A1 and Intermediate D7 as a brown oily liquid.

[0760] ESI-MS m / z: 698.39 [M+H]+.

[0761] Step b: Preparation of intermediate 23-2

[0762] Intermediate 23-2 (202.0 mg, 59% yield) was prepared from Intermediate 23-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a brown-yellow solid.

[0763] ESI-MS m / z:597.43[M+H]+.

[0764] Step c: Preparation of compound 23

[0765] The trifluoroacetic acid salt of compound 23 was prepared from intermediate 23-2 using the method described for compound 1 and purified by pre-HPLC separation as a white solid.

[0766] ESI-MS m / z:557.37[M+H]+.

[0767] 1 H NMR (600MHz, Methanol-d4) δ7.88(s,1H),7.85(d,J=9.4Hz,1H),7.71(d,J=2.4Hz,1H),7.10( d,J=2.5Hz,1H),7.05(dd,J=9.4,2.6Hz,1H),6.94(s,1H),6.61(d,J=2.4Hz,1H),6.01(s,1H), 5.31(d,J=3.6Hz,1H),4.63–4.58(m,1H),4.48(q,J=4.9Hz,2H),4.43(s,4H),4.34(dd,J=9.0 ,3.2Hz,2H),3.99(s,3H),2.78(q,J=7.6Hz,2H),2.63(p,J=7.9Hz,2H),1.35(t,J=7.6Hz,3H).

[0768] Example 24: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((4-(cyclopropylamino)-2-ethylquinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 24)

[0769]

[0770] Step a: Preparation of Intermediate 24-1

[0771] Intermediate 24-1 (265.0 mg, 40% yield) was prepared from Intermediate A1 and Intermediate D6 as a light yellow foamy solid.

[0772] ESI-MS m / z: 698.37 [M+H]+.

[0773] Step b: Preparation of intermediate 24-2

[0774] Intermediate 24-2 (120.0 mg, 53% yield) was prepared from Intermediate 24-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a yellow oily liquid.

[0775] ESI-MS m / z:597.46[M+H]+.

[0776] Step c: Preparation of compound 24

[0777] The trifluoroacetic acid salt of compound 24 was prepared from intermediate 24-2 using the method described for compound 1 and purified by pre-HPLC separation as a white solid.

[0778] ESI-MS m / z:557.37[M+H]+.

[0779] 1 H NMR (600MHz, Methanol-d4) δ8.08(d,J=9.1Hz,1H),7.92(s,1H),7.68(d,J=2.4Hz,1H),7.21(dd, J=12.2,2.9Hz,2H),7.01(s,1H),6.88(s,1H),6.59(d,J=2.5Hz,1H),5.38(d,J=4.5Hz,1H),4.60( d,J=10.3Hz,1H),4.46(dt,J=25.3,5.1Hz,2H),4.41–4.33(m,2H),3.98(s,3H),2.92(q,J=7.6Hz, 2H), 2.81 (tt, J=7.2, 3.9Hz, 1H), 1.42 (t, J=7.6Hz, 3H), 1.06 (d, J=7.1Hz, 2H), 0.84–0.75 (m, 2H).

[0780] Example 25: (2S,3R,4S,5R)-2-(4-amino-5-iodopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((4-chloro-2-ethylquinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 25)

[0781]

[0782] Step a: Preparation of Intermediate 25-1

[0783] Intermediate 25-1 (316.0 mg, yield 73%) was prepared from Intermediate A1 and Intermediate D2 as a yellow foamy solid using the method described in Intermediate A2.

[0784] ESI-MS m / z:677.23,679.18[M+H]+.

[0785] Step b: Preparation of compound 25

[0786] The trifluoroacetic acid salt of compound 25 was prepared from intermediate 25-1 using the method described for compound 1 and purified by pre-HPLC as a white solid.

[0787] ESI-MS m / z:582.15,584.11[M+H]+.

[0788] 1 H NMR (600MHz, Methanol-d4) δ8.30(d,J=9.3Hz,1H),7.86(s,1H),7.77(s,1H),7.48(dd,J=9.4,2.3Hz,1H),7.43(d,J=2.3Hz,1H),6.68(s,1H),5.34(d,J =3.5Hz,1H),4.70(d,J=12.0Hz,1H),4.50(t,J=5.7Hz,1H),4.43(dd,J=8.3, 3.4Hz, 2H), 4.35 (d, J = 6.5Hz, 1H), 3.16–3.09 (m, 2H), 1.49 (t, J = 7.7Hz, 3H).

[0789] Example 26: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((4-chloro-2-ethylquinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 26)

[0790]

[0791] Step a: Preparation of Intermediate 26-1

[0792] Intermediate 26-1 (69.2 mg, 28% yield) was prepared from Intermediate 25-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a yellow foamy solid.

[0793] ESI-MS m / z:576.25,578.26[M+H]+.

[0794] Step b: Preparation of compound 26

[0795] The trifluoroacetic acid salt of compound 26 was prepared from intermediate 26-1 using the method described for compound 1 and purified by pre-HPLC separation as a white solid.

[0796] ESI-MS m / z:536.24,538.22[M+H]+.

[0797] 1 H NMR(600MHz, Methanol-d4)δ8.15(d,J=9.2Hz,1H),7.91(s,1H),7.71–7.65(m,2 H),7.49–7.42(m,2H),6.97(s,1H),6.56(d,J=2.3Hz,1H),5.39(d,J=4.4Hz,1H) ,4.71–4.61(m,1H),4.48(dt,J=15.2,5.1Hz,2H),4.44(dd,J=11.5,3.6Hz,1H), 4.40(d,J=5.2Hz,1H),3.98(s,3H),3.03(q,J=7.7Hz,2H),1.41(t,J=7.7Hz,3H).

[0798] Example 27: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(pyrrolidin-1-yl)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 27)

[0799]

[0800] Step a: Preparation of Intermediate 27-1

[0801] Intermediate 27-1 (317.5 mg, 53% yield) was prepared from Intermediate A1 and Intermediate B18 as a yellow foamy solid.

[0802] ESI-MS m / z:684.1[M+H]+.

[0803] Step b: Preparation of intermediate 27-2

[0804] Intermediate 27-2 (125.0 mg, 46% yield) was prepared from Intermediate 27-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a yellow oily liquid.

[0805] ESI-MS m / z:583.36[M+H]+.

[0806] Step c: Preparation of compound 27

[0807] The trifluoroacetic acid salt of compound 27 was prepared from intermediate 27-2 using the method described for compound 1 and purified by pre-HPLC separation as a white solid.

[0808] ESI-MS m / z:543.1[M+H]+.

[0809] 1 H NMR (600MHz, Methanol-d4) δ8.16(d,J=9.4Hz,1H),7.91(s,1H),7.71(d,J=8.8Hz,1H),7.68(d, J=2.4Hz,1H),7.40(d,J=2.4Hz,1H),7.11(dd,J=8.8,2.4Hz,1H),7.02(s,1H),6.94(d,J=9.4Hz, 1H),6.59(d,J=2.4Hz,1H),5.38(d,J=4.7Hz,1H),4.63–4.52(m,1H),4.48(t,J=4.9Hz,1H),4.43 (t,J=5.2Hz,1H),4.40–4.33(m,2H),3.98(s,3H),3.71(d,J=36.6Hz,4H),2.20(d,J=9.1Hz,4H).

[0810] Example 28: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-morpholinoquinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 28)

[0811]

[0812] Step a: Preparation of Intermediate 28-1

[0813] Intermediate 28-1 (424.7 mg, yield 90%) was prepared from Intermediate A1 and Intermediate B19 as a yellow oily liquid using the method described in Intermediate A2.

[0814] ESI-MS m / z:700.22[M+H]+.

[0815] Step b: Preparation of intermediate 28-2

[0816] Intermediate 28-2 (262.3 mg, 72% yield) was prepared from Intermediate 28-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a yellow oily liquid.

[0817] ESI-MS m / z:599.34[M+H]+.

[0818] Step c: Preparation of compound 28

[0819] The trifluoroacetic acid salt of compound 28 was prepared from intermediate 28-2 using the method described for compound 1 and purified by pre-HPLC separation as a white solid.

[0820] ESI-MS m / z:559.2[M+H]+.

[0821] 1 H NMR (600MHz, Methanol-d4) δ8.27(d,J=9.6Hz,1H),7.90(s,1H),7.75(d,J=8.8Hz,1H),7.67(d,J=2.3Hz,1H),7.43(d,J=2.4Hz, 1H),7.23(d,J=9.6Hz,1H),7.16(dd,J=8.8,2.3Hz,1H),7.06(s,1H),6.60(d,J=2.4Hz,1H),5.39(d,J=4.7Hz,1H),4.58–4.52(m, 1H), 4.48 (t, J = 4.9 Hz, 1H), 4.40 (t, J = 5.2 Hz, 1H), 4.38–4.32 (m, 2H), 3.98 (s, 3H), 3.91–3.88 (m, 4H), 3.88–3.84 (m, 4H). Example 29: (2S, 3R, 4S, 5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(dimethylamino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 29)

[0822]

[0823] Step a: Preparation of Intermediate 29-1

[0824] Intermediate 29-1 (351.4 mg, 72% yield) was prepared from Intermediate A1 and Intermediate B16 as a yellow foamy solid.

[0825] ESI-MS m / z: 658.0 [M+H]+.

[0826] Step b: Preparation of intermediate 29-2

[0827] Intermediate 29-2 (180.0 mg, 61% yield) was prepared from Intermediate 29-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a yellow oily liquid.

[0828] ESI-MS m / z:557.1[M+H]+.

[0829] Step c: Preparation of compound 29

[0830] Compound 29 was prepared from intermediate 29-2 by the method described in Compound 1 and purified by silica gel column chromatography as a white solid.

[0831] ESI-MS m / z: 517.0 [M+H]+.

[0832] Example 30: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 30)

[0833]

[0834] Step a: Preparation of intermediate 30-1

[0835] Intermediate 30-1 (258.8 mg, 62% yield) was prepared from Intermediate A1 and 1-methyl-1H-benzo[d]imidazol-5-ol as a white foamy solid using the method described in Intermediate A2.

[0836] ESI-MS m / z: 617.9 [M+H]+.

[0837] Step b: Preparation of intermediate 30-2

[0838] Intermediate 30-2 (136.4 mg, 63% yield) was prepared from Intermediate 30-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a yellow oily liquid.

[0839] ESI-MS m / z:517.1[M+H]+.

[0840] Step c: Preparation of compound 30

[0841] The trifluoroacetic acid salt of compound 30 was prepared from intermediate 30-2 using the method described for compound 1 and purified by pre-HPLC separation as a white solid.

[0842] ESI-MS m / z:477.0[M+H]+.

[0843] 1 H NMR (600MHz, Methanol-d4) δ9.20(s,1H),7.92(s,1H),7.76(d,J=9.1Hz,1H),7.68(d,J=2.3Hz,1H),7.36(s,1H),7.30(d,J=9.1H z,1H),7.12(s,1H),6.62(d,J=2.4Hz,1H),5.38(d,J=4.8Hz,1H),4.53–4.44(m,2H),4.43–4.29(m,3H),4.07(s,3H),3.98(s,3H).

[0844] Example 31: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 31)

[0845]

[0846] Step a: Preparation of Intermediate 31-1

[0847] Intermediate 31-1 (492.2 mg, 100% yield) was prepared from Intermediate A1 and N-BOC-6-hydroxy-3,4-dihydroisoquinoline as a yellow oily liquid using the method described in Intermediate A2.

[0848] ESI-MS m / z:719.1[M+H]+.

[0849] Step b: Preparation of intermediate 31-2

[0850] Intermediate 31-2 (503.5 mg, 100% yield) was prepared as a brown oily liquid from Intermediate 31-1 and 1-methylpyrazole-3-boronic acid pinacol ester using the method described in Intermediate 2-1.

[0851] ESI-MS m / z: 618.2 [M+H]+.

[0852] Step c: Preparation of compound 31

[0853] The intermediate 31-2 was separated and purified by silica gel column chromatography using the method described in Compound 1 to prepare Compound 31 (128.7 mg, yield 33%) as a light yellow solid.

[0854] ESI-MS m / z:478.0[M+H]+.

[0855] Example 32: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-((3-((dimethylamino)methyl)phenoxy)methyl)tetrahydrofuran-3,4-diol (Compound 32)

[0856]

[0857] Step a: Preparation of Intermediate 32-1

[0858] Intermediate 32-1 (218.3 mg, 45% yield) was prepared from Intermediate A1 and 3-((dimethylamino)methyl)phenol as a yellow oily liquid using the method described in Intermediate A2.

[0859] ESI-MS m / z: 621.0 [M+H]+.

[0860] Step b: Preparation of intermediate 32-2

[0861] Intermediate 32-2 (141.7 mg, 78% yield) was prepared from Intermediate 32-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a yellow oily liquid.

[0862] ESI-MS m / z:520.1[M+H]+.

[0863] Step c: Preparation of compound 32

[0864] The intermediate 32-2 was separated and purified by silica gel column chromatography using the method described in Compound 1 to prepare Compound 32 (34.4 mg, yield 26%) as a white solid.

[0865] ESI-MS m / z:480.0[M+H]+.

[0866] Example 33: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((1,2,3,4-tetrahydroisoquinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 33)

[0867]

[0868] Step a: Preparation of Intermediate 33-1

[0869] Intermediate 33-1 (310.4 mg, yield 66%) was prepared as a yellow oily liquid from Intermediate A1 and tert-butyl 7-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate using the method described in Intermediate A2.

[0870] ESI-MS m / z:719.1[M+H]+.

[0871] Step b: Preparation of intermediate 33-2

[0872] Intermediate 33-2 (218.0 mg, 82% yield) was prepared from Intermediate 33-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a brown oily liquid.

[0873] ESI-MS m / z: 618.2 [M+H]+.

[0874] Step c: Preparation of compound 33

[0875] The trifluoroacetic acid salt of compound 33 was prepared from intermediate 33-2 by pre-HPLC separation and purification using the method described for compound 1 as a white solid.

[0876] ESI-MS m / z:478.0[M+H]+.

[0877] 1H NMR (600MHz, Methanol-d4) δ7.93 (s, 1H), 7.70 (d, J = 2.3Hz, 1H), 7.20 (s, 1H), 7.1 7(d,J=8.5Hz,1H),6.95(dd,J=8.5,2.6Hz,1H),6.84(d,J=2.6Hz,1H),6.65(d,J=2 .3Hz,1H),5.39(d,J=4.7Hz,1H),4.45(t,J=4.7Hz,1H),4.34–4.28(m,5H),4.19( dd,J=10.6,3.8Hz,1H),3.97(s,3H),3.46(t,J=6.4Hz,2H),3.04(t,J=6.4Hz,2H).

[0878] Example 34: 7-(((2R,3S,4R,5S)-5-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (Compound 34)

[0879]

[0880] Step a: Preparation of Intermediate 34-1

[0881] Intermediate 34-1 (241.5 mg, 52% yield) was prepared from Intermediate A1 and 7-hydroxy-3,4-dihydroquinolone as a light yellow oily liquid using the method described in Intermediate A2.

[0882] ESI-MS m / z: 633.0 [M+H]+.

[0883] Step b: Preparation of intermediate 34-2

[0884] Intermediate 34-2 (140.6 mg, 69% yield) was prepared from Intermediate 34-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a brown oily liquid.

[0885] ESI-MS m / z: 532.0 [M+H]+.

[0886] Step c: Preparation of compound 34

[0887] The method described in Compound 1 was used to separate and purify the intermediate 34-2 by silica gel column chromatography to prepare Compound 34 (71.9 mg, yield 55%) as an off-white solid.

[0888] ESI-MS m / z:492.1[M+H]+.

[0889] 1 H NMR (600MHz, DMSO-d6) δ10.00(s,1H),9.96(d,J=3.1Hz,1H),7.90(d,J=3.2Hz,1H),7.81(s,1H),7.76(d,J=2.3Hz,1 H),7.05(d,J=8.3Hz,1H),7.03(s,1H),6.61(d,J=2.3Hz,1H),6.54(dd,J=8.2,2.5Hz,1H),6.48(d,J=2.5Hz,1H),5. 21(d,J=5.6Hz,1H),5.18(d,J=6.0Hz,1H),5.13(d,J=5.5Hz,1H),4.32(q,J=5.5Hz,1H),4.13(dd,J=10.3,3.2Hz,1H ),4.11–4.05(m,2H),4.02(dd,J=10.3,5.2Hz,1H),3.88(s,3H),2.78(t,J=7.5Hz,2H),2.41(dd,J=8.5,6.6Hz,2H).

[0890] Example 35: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-((imidazo[1,2-a]pyridin-7-yloxy)methyl)tetrahydrofuran-3,4-diol (Compound 35)

[0891]

[0892] Step a: Preparation of Intermediate 35-1

[0893] Intermediate 35-1 (156.6 mg, 36% yield) was prepared from Intermediate A1 and imidazo[1,2-a]pyridin-7-ol as a yellow oily liquid using the method described in Intermediate A2.

[0894] ESI-MS m / z: 603.9 [M+H]+.

[0895] Step b: Preparation of intermediate 35-2

[0896] Intermediate 35-2 (96.9 mg, 74% yield) was prepared as a colorless oily liquid from Intermediate 35-1 and 1-methylpyrazole-3-boronic acid pinacol ester using the method described in Intermediate 2-1.

[0897] ESI-MS m / z:503.1[M+H]+.

[0898] Step c: Preparation of compound 35

[0899] The trifluoroacetic acid salt of compound 35 was prepared from intermediate 35-2 using the method described for compound 1 and purified by pre-HPLC separation as a white solid.

[0900] ESI-MS m / z:463.0[M+H]+.

[0901] 1 H NMR(600MHz,Methanol-d4)δ8.55(d,J=7.4Hz,1H),7.95(d,J=2.3Hz,1H),7.9 4(s,1H),7.79(d,J=2.2Hz,1H),7.70(d,J=2.3Hz,1H),7.30(d,J=2.5Hz,1H),7 .15(s,1H),7.13(dd,J=7.4,2.4Hz,1H),6.72(d,J=2.4Hz,1H),5.40(d,J=4.5H z,1H),4.60(dd,J=11.1,2.1Hz,1H),4.50–4.44(m,2H),4.37(t,J=3.6Hz,2H).

[0902] Example 36: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((4-((2-methoxyethyl)amino)-2-(methylamino)quinazolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 36)

[0903]

[0904] Step a: Preparation of Intermediate 36-1

[0905] Intermediate 36-1 (205.0 mg, yield 51%) was prepared from Intermediate A1 and Intermediate F1 as a yellow oily liquid using the method described in Intermediate A2.

[0906] ESI-MS m / z:868.3[M+H]+.

[0907] Step b: Preparation of Intermediate 36-2

[0908] Intermediate 36-2 (162.0 mg, 89% yield) was prepared from Intermediate 36-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a yellow foamy solid.

[0909] ESI-MS m / z:767.2[M+H]+.

[0910] Step c: Preparation of compound 36

[0911] The method described in Compound 1 was used to separate and purify the intermediate 36-2 by silica gel column chromatography to prepare Compound 36 (51.7 mg, yield 42%) as a white solid.

[0912] ESI-MS m / z: 577.2 [M+H]+.

[0913] 1 H NMR(600MHz, DMSO-d6)δ9.96(d,J=3.2Hz,1H),7.97–7.84(m,2H),7.80(s,1H),7.75(d,J=2.3Hz,1H),7.07(s,1H),6.73(s,1H),6.66(d d,J=8.9,2.5Hz,1H),6.63(d,J=2.3Hz,1H),6.38(s,1H),5.25(d,J=5.4Hz,1H),5.17(dd,J=13.8,5.7Hz,2H),4.36–4.22(m,2H),4.21– 4.05 (m, 3H), 3.89 (s, 3H), 3.60 (d, J = 6.9 Hz, 2H), 3.53 (t, J = 6.0 Hz, 2H), 3.27 (s, 4H), 2.80 (d, J = 4.8 Hz, 3H). Example 37: (2S, 3R, 4S, 5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(azetidin-1-yl)-4-((2-methoxyethyl)amino)quinazolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 37)

[0914]

[0915] Step a: Preparation of Intermediate 37-1

[0916] Intermediate 37-1 (386.6 mg, yield 76%) was prepared from Intermediate A1 and Intermediate F2 as a brown oily liquid.

[0917] ESI-MS m / z:744.0[M+H]+.

[0918] Step b: Preparation of Intermediate 37-2

[0919] Intermediate 37-2 (203.1 mg, 61% yield) was prepared from Intermediate 37-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a yellow oily liquid using the method described in Intermediate 2-1.

[0920] ESI-MS m / z: 643.1[M+H]+.

[0921] Step c: Preparation of compound 37

[0922] The method described in Compound 1 was used to separate and purify the intermediate 37-2 by silica gel column chromatography to prepare Compound 37 (86.2 mg, yield 45%) as an off-white solid.

[0923] ESI-MS m / z: 603.2 [M+H]+.

[0924] Example 38: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(azetidin-1-yl)-4-((2-methoxyethyl)amino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 38)

[0925]

[0926] Step a: Preparation of Intermediate 38-1

[0927] Intermediate 38-1 (118.4 mg, yield 23%) was prepared from Intermediate A1 and Intermediate E2 as a pale yellow oily liquid.

[0928] ESI-MS m / z:743.2[M+H]+.

[0929] Step b: Preparation of Intermediate 38-2

[0930] Intermediate 38-2 (41.0 mg, 40% yield) was prepared from Intermediate 38-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a yellow oily liquid.

[0931] ESI-MS m / z: 642.0 [M+H]+.

[0932] Step c: Preparation of compound 38

[0933] The intermediate 38-2 was separated and purified by silica gel column chromatography using the method described in Compound 1 to prepare Compound 38 (3.0 mg, yield 8%) as a pale yellow solid.

[0934] ESI-MS m / z: 602.1[M+H]+.

[0935] Example 39: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((6-aminopyridin-3-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 39)

[0936]

[0937] Step a: Preparation of Intermediate 39-1

[0938] 2-(Boc-amino)pyrrolidine-5-boronic acid pinacol ester (85.8 mg, 267.96 μmol) was dissolved in THF (4 mL), hydrogen peroxide (30% w / w) was added at 0°C, the temperature was slowly raised to room temperature, and stirred overnight. TLC detected that the raw material reaction was complete. Sodium sulfite solution was added to quench, extracted with ethyl acetate (20 mL*3), washed with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. It was separated and purified by silica gel column chromatography (PE / EA=3 / 1) to obtain a white solid (55.0 mg, yield 98%).

[0939] 1 H NMR (400MHz, Chloroform-d) δ7.88(d,J=3.0Hz,1H),7.81(d,J=9.0Hz,1H),7.21(dd,J=9.0,3.0Hz,1H),1.52(s,9H).

[0940] Step b: Preparation of Intermediate 39-2

[0941] Intermediate 39-2 (350.7 mg, 75% yield) was prepared from Intermediate A1 and Intermediate 39-1 as a yellow foamy solid.

[0942] ESI-MS m / z: 680.1 [M+H]+.

[0943] Step c: Preparation of Intermediate 39-3

[0944] Intermediate 39-3 (284.1 mg, 63% yield) was prepared from Intermediate 39-2 and 1-methylpyrazole-3-boronic acid pinacol ester as a yellow foamy solid.

[0945] ESI-MS m / z:579.1[M+H]+.

[0946] Step d: Preparation of compound 39

[0947] The method described in Compound 1 was used to separate and purify the intermediate 39-3 by silica gel column chromatography to prepare Compound 39 (101.7 mg, yield 47%) as an off-white solid.

[0948] ESI-MS m / z:438.9[M+H]+.

[0949] Example 40: (2R,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-3,4-dihydroxy-5-(((2-(methylamino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-2-carbonitrile (Compound 40)

[0950]

[0951] Step a: Preparation of Intermediate 40-1

[0952] Intermediate 40-1 (382.7 mg, 86% yield) was prepared from Intermediate H and Intermediate B2 as a light yellow foamy solid using the method described in Intermediate A2.

[0953] ESI-MS m / z:819.1[M+H]+.

[0954] Step b: Preparation of Intermediate 40-2

[0955] Intermediate 40-2 (340.0 mg, 100% yield) was prepared from Intermediate 40-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a brown-yellow foamy solid.

[0956] ESI-MS m / z:718.2[M+H]+.

[0957] Step c: Preparation of compound 40

[0958] The intermediate 40-2 was separated and purified by silica gel column chromatography using the method described in Compound 1 to prepare Compound 40 (119.2 mg, yield 48%) as a yellow solid.

[0959] ESI-MS m / z:528.1[M+H]+.

[0960] 1 H NMR(400MHz, Methanol-d4)δ7.79(s,1H),7.69(d,J=8.9Hz,1H),7.50(d,J=2.3Hz,1H),7 .42(d,J=8.7Hz,1H),7.15(d,J=2.4Hz,1H),7.07(s,1H),6.80(dd,J=8.7,2.5Hz,1H),6.5 5(d,J=8.9Hz,1H),6.35(d,J=2.3Hz,1H),4.55(dq,J=9.0,3.1Hz,2H),4.51(d,J=2.9Hz, 1H), 4.37 (dd, J=6.5, 5.1Hz, 1H), 4.31 (dd, J=11.2, 3.9Hz, 1H), 3.90 (s, 3H), 2.98 (s, 3H).

[0961] Example 41: (2R,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(azetidin-1-yl)quinolin-7-yl)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-carbonitrile (Compound 41)

[0962]

[0963] Step a: Preparation of Intermediate 41-1

[0964] Intermediate 41-1 (304.7 mg, 72% yield) was prepared from Intermediate H and Intermediate B4 as a yellow foamy solid using the method described in Intermediate A2.

[0965] ESI-MS m / z: 695.0 [M+H]+.

[0966] Step b: Preparation of Intermediate 41-2

[0967] Intermediate 41-2 (236.2 mg, 91% yield) was prepared from Intermediate 41-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a yellow foamy solid.

[0968] ESI-MS m / z:594.2[M+H]+.

[0969] Step c: Preparation of compound 41

[0970] The intermediate 41-2 was separated and purified by silica gel column chromatography using the method described in Compound 1 to prepare Compound 41 (120.8 mg, yield 55%) as a yellow solid.

[0971] ESI-MS m / z:554.1[M+H]+.

[0972] Example 42: (2R,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(cyclobutylamino)quinolin-7-yl)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-carbonitrile (Compound 42)

[0973]

[0974] Step a: Preparation of Intermediate 42-1

[0975] Intermediate 42-1 (295.6 mg, 69% yield) was prepared from Intermediate H and Intermediate B3 as a light yellow foamy solid using the method described in Intermediate A2.

[0976] ESI-MS m / z:708.9[M+H]+.

[0977] Step b: Preparation of intermediate 42-2

[0978] Intermediate 42-2 (214.1 mg, 85% yield) was prepared from Intermediate 42-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a brown-red foamy solid.

[0979] ESI-MS m / z: 608.0 [M+H]+.

[0980] Step c: Preparation of compound 42

[0981] The method described in Compound 1 was used to separate and purify the intermediate 42-2 by silica gel column chromatography to prepare Compound 42 (119.9 mg, yield 59%) as a light yellow solid.

[0982] ESI-MS m / z:568.0[M+H]+.

[0983] Example 43: (2S,3R,4R,5R)-2-(4-amino-5-iodopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3-methyl-5-(((2-(methylamino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 43)

[0984]

[0985] Step a: Preparation of Intermediate 43-1

[0986] Intermediate 43-1 (127.9 mg, yield 99%) was prepared from Intermediate G and Intermediate B2 as a brown oily liquid.

[0987] ESI-MS m / z:808.2[M+H]+.

[0988] Step b: Preparation of compound 43

[0989] The intermediate 43-1 was separated and purified by silica gel column chromatography using the method described in Compound 1 to prepare Compound 43 (57.0 mg, yield 64%) as a white solid.

[0990] ESI-MS m / z:562.8[M+H]+.

[0991] Example 44: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(isopropylamino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 44)

[0992]

[0993] Step a: Preparation of Intermediate 44-1

[0994] Intermediate 44-1 (273.6 mg, yield 62%) was prepared from Intermediate A1 and Intermediate B7 as a brown oily liquid.

[0995] ESI-MS m / z: 672.0 [M+H]+.

[0996] Step b: Preparation of Intermediate 44-2

[0997] Intermediate 44-2 (193.7 mg, 83% yield) was prepared from Intermediate 44-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a brown oily liquid.

[0998] ESI-MS m / z:571.2[M+H]+.

[0999] Step c: Preparation of compound 44

[1000] The method described in Compound 1 was used to separate and purify the intermediate 44-2 by silica gel column chromatography to prepare Compound 44 (97.5 mg, yield 54%) as a pale yellow solid.

[1001] ESI-MS m / z: 531.0 [M+H]+.

[1002] Example 45: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(tert-butylamino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 45)

[1003]

[1004] Step a: Preparation of Intermediate 45-1

[1005] Intermediate 45-1 (191.8 mg, yield 62%) was prepared from Intermediate A1 and Intermediate B8 as a brown oily liquid.

[1006] ESI-MS m / z: 686.2 [M+H]+.

[1007] Step b: Preparation of Intermediate 45-2

[1008] Intermediate 45-2 (162.7 mg, 99% yield) was prepared as a brown oily liquid from Intermediate 45-1 and 1-methylpyrazole-3-boronic acid pinacol ester using the method described in Intermediate 2-1.

[1009] ESI-MS m / z:585.1[M+H]+.

[1010] Step c: Preparation of compound 45

[1011] The trifluoroacetic acid salt of compound 45 was prepared from intermediate 45-2 using the method described for compound 1 and purified by pre-HPLC separation as a white solid.

[1012] ESI-MS m / z: 545.2 [M+H]+.

[1013] 1H NMR(600MHz, Methanol-d4)δ8.19(d,J=9.4Hz,1H),7.91(s,1H),7.74(d,J=8.8H z,1H),7.66(d,J=2.3Hz,1H),7.36(s,1H),7.15(dd,J=8.8,2.3Hz,1H),7.09(d, J=9.4Hz,1H),7.05(s,1H),6.58(d,J=2.3Hz,1H),5.40(d,J=4.9Hz,1H),4.60–4 .52(m,1H),4.48(t,J=4.9Hz,1H),4.43–4.32(m,3H),3.97(s,3H),1.57(s,9H).

[1014] Example 46: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(cyclopentylamino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 46)

[1015]

[1016] Step a: Preparation of Intermediate 46-1

[1017] Intermediate 46-1 (199.4 mg, 65% yield) was prepared from Intermediate A1 and Intermediate B12 as a yellow oily liquid using the method described in Intermediate A2.

[1018] ESI-MS m / z: 698.0 [M+H]+.

[1019] Step b: Preparation of Intermediate 46-2

[1020] Intermediate 46-2 (130.0 mg, 76% yield) was prepared as a brown oily liquid from Intermediate 46-1 and 1-methylpyrazole-3-boronic acid pinacol ester using the method described in Intermediate 2-1.

[1021] ESI-MS m / z:597.0[M+H]+.

[1022] Step c: Preparation of compound 46

[1023] The method described in Compound 1 was used to separate and purify the intermediate 46-2 by silica gel column chromatography to prepare Compound 46 (72.0 mg, yield 59%) as a yellow solid.

[1024] ESI-MS m / z: 557.0 [M+H]+.

[1025] Example 47: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(cyclohexylamino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 47)

[1026]

[1027] Step a: Preparation of Intermediate 47-1

[1028] Intermediate 47-1 (216.3 mg, 43% yield) was prepared from Intermediate A1 and Intermediate B13 as a brown oily liquid.

[1029] ESI-MS m / z:712.0[M+H]+.

[1030] Step b: Preparation of Intermediate 47-2

[1031] Intermediate 47-2 (100.9 mg, 54% yield) was prepared from Intermediate 47-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a brown-red oily liquid.

[1032] ESI-MS m / z: 611.0 [M+H]+.

[1033] Step c: Preparation of compound 47

[1034] The method described in Compound 1 was used to separate and purify the intermediate 47-2 by silica gel column chromatography to prepare Compound 47 (40.7 mg, yield 43%) as an off-white solid.

[1035] ESI-MS m / z:571.1[M+H]+.

[1036] Example 48: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-((4,4-difluorocyclohexyl)amino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 48)

[1037]

[1038] Step a: Preparation of Intermediate 48-1

[1039] Intermediate 48-1 (294.0 mg, 55% yield) was prepared from Intermediate A1 and Intermediate B14 as a brown oily liquid.

[1040] ESI-MS m / z:748.2[M+H]+.

[1041] Step b: Preparation of Intermediate 48-2

[1042] Intermediate 48-2 (147.6 mg, 58% yield) was prepared from Intermediate 48-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a brown-yellow foamy solid.

[1043] ESI-MS m / z: 647.1[M+H]+.

[1044] Step c: Preparation of compound 48

[1045] The method described in Compound 1 was used to separate and purify the intermediate 48-2 by silica gel column chromatography to prepare Compound 48 (78.1 mg, yield 56%) as a yellow solid.

[1046] ESI-MS m / z: 607.2 [M+H]+.

[1047] 1 H NMR (600MHz, Methanol-d4) δ7.72(d,J=8.0Hz,2H),7.51(d,J=2.3Hz,1H),7.48(d,J=8.7Hz,1H),7.17(d,J=2. 5Hz,1H),6.97(s,1H),6.90(dd,J=8.7,2.5Hz,1H),6.58(d,J=8.9Hz,1H),6.39(d,J=2.3Hz,1H),5.43(d,J=5. 1Hz,1H),4.49(t,J=5.1Hz,1H),4.44(dd,J=10.7,3.0Hz,1H),4.39(t,J=5.3Hz,1H),4.35(q,J=4.9,4.3Hz,1H ),4.29(dd,J=10.7,4.3Hz,1H),4.09(s,1H),3.91(s,3H),2.08(s,4H),2.03–1.92(m,2H),1.66–1.58(m,2H).

[1048] Example 49: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-((tetrahydro-2H-pyran-4-yl)amino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 49)

[1049]

[1050] Step a: Preparation of Intermediate 49-1

[1051] Intermediate 49-1 (94.0 mg, yield 16%) was prepared from Intermediate A1 and Intermediate B15 as a brown oily liquid.

[1052] ESI-MS m / z:714.1[M+H]+.

[1053] Step b: Preparation of Intermediate 49-2

[1054] Intermediate 49-2 (68.8 mg, 85% yield) was prepared from Intermediate 49-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a brown oily liquid.

[1055] ESI-MS m / z: 613.1 [M+H]+.

[1056] Step c: Preparation of compound 49

[1057] The trifluoroacetic acid salt of compound 49 was prepared from intermediate 49-2 using the method described for compound 1 and purified by pre-HPLC separation as a white solid.

[1058] ESI-MS m / z:573.1[M+H]+.

[1059] 1H NMR (600MHz, Methanol-d4) δ8.12(s,1H),7.90(s,1H),7.73(dd,J=9.0,7.0Hz,1H),7.66(d,J=2.3Hz,1H ),7.39(s,1H),7.15(dd,J=8.8,2.3Hz,1H),7.01(s,1H),6.55(d,J=2.3Hz,1H),5.40(d,J=4.9Hz,1H),4 .58–4.51(m,1H),4.47(t,J=4.9Hz,1H),4.40(t,J=5.1Hz,1H),4.37(dd,J=8.9,4.4Hz,2H),4.04(d,J=1 2.3Hz,2H),3.97(s,3H),3.88(s,1H),3.60–3.54(m,2H),2.01(d,J=13.2Hz,2H),1.71(t,J=12.0Hz,2H).

[1060] Example 50: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-aminoquinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 50)

[1061]

[1062] Step a: Preparation of Intermediate 50-1

[1063] Intermediate 50-1 (192.6 mg, yield 38%) was prepared from Intermediate A1 and Intermediate B5 as a yellow oily liquid.

[1064] ESI-MS m / z:780.1[M+H]+.

[1065] Step b: Preparation of Intermediate 50-2

[1066] Intermediate 50-2 (100.0 mg, 60% yield) was prepared from Intermediate 50-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a brown-red oily liquid.

[1067] ESI-MS m / z: 679.1 [M+H]+.

[1068] Step c: Preparation of compound 50

[1069] The method described in Compound 1 was used to separate and purify the intermediate 50-2 by silica gel column chromatography to prepare Compound 50 (146.7 mg, yield 100%) as a white solid.

[1070] ESI-MS m / z:489.0[M+H]+.

[1071] Example 51: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-((3,3-difluorocyclobutyl)amino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 51)

[1072]

[1073] Step a: Preparation of Intermediate 51-1

[1074] Intermediate 51-1 (374.1 mg, yield 79%) was prepared from Intermediate A1 and Intermediate B10 as a yellow oily liquid using the method described in Intermediate A2.

[1075] ESI-MS m / z:720.0[M+H]+.

[1076] Step b: Preparation of Intermediate 51-2

[1077] Intermediate 51-2 (289.2 mg, 90% yield) was prepared from Intermediate 51-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a brown-red oily liquid.

[1078] ESI-MS m / z: 619.2 [M+H]+.

[1079] Step c: Preparation of compound 51

[1080] The intermediate 51-2 was separated and purified by silica gel column chromatography using the method described in Compound 1 to prepare Compound 51 (104.5 mg, yield 39%) as a yellow solid.

[1081] ESI-MS m / z:579.0[M+H]+.

[1082] Example 52: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(ethylamino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 52)

[1083]

[1084] Step a: Preparation of Intermediate 52-1

[1085] Intermediate 52-1 (226.5 mg, 52% yield) was prepared from Intermediate A1 and Intermediate B6 as a yellow oily liquid using the method described in Intermediate A2.

[1086] ESI-MS m / z: 657.9 [M+H]+.

[1087] Step b: Preparation of Intermediate 52-2

[1088] Intermediate 52-2 (210.5 mg, 100% yield) was prepared from Intermediate 52-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a brown oily liquid.

[1089] ESI-MS m / z:557.1[M+H]+.

[1090] Step c: Preparation of compound 52

[1091] The intermediate 52-2 was separated and purified by silica gel column chromatography using the method described in Compound 1 to prepare Compound 52 (122.0 mg, yield 62%) as a pale yellow solid.

[1092] ESI-MS m / z: 517.0 [M+H]+.

[1093] Example 53: (2S,3R,4R,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-3-methyl-5-(((2-(methylamino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 53)

[1094]

[1095] Step a: Preparation of Intermediate 53-1

[1096] Intermediate 53-1 (455.8 mg, 90% yield) was prepared from Intermediate G and Intermediate B2 as a yellow foamy solid using the method described in Intermediate A2.

[1097] ESI-MS m / z:808.1[M+H]+.

[1098] Step b: Preparation of Intermediate 53-2

[1099] Intermediate 53-2 (437.0 mg, 100% yield) was prepared from Intermediate 53-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a dark brown oily liquid.

[1100] ESI-MS m / z:707.3[M+H]+.

[1101] Step c: Preparation of compound 53

[1102] The method described in Compound 1 was used to separate and purify the intermediate 53-2 by silica gel column chromatography to prepare Compound 53 (135.0 mg, yield 42%) as a white solid.

[1103] ESI-MS m / z:517.1[M+H]+.

[1104] Example 54: (2S,3R,4R,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(cyclobutylamino)quinolin-7-yl)oxy)methyl)-3-methyltetrahydrofuran-3,4-diol (Compound 54)

[1105]

[1106] Step a: Preparation of Intermediate 54-1

[1107] Intermediate 54-1 (362.0 mg, 84% yield) was prepared from Intermediate G and Intermediate B3 as a brown oily liquid using the method described in Intermediate A2.

[1108] ESI-MS m / z: 698.0 [M+H]+.

[1109] Step b: Preparation of Intermediate 54-2

[1110] Intermediate 54-2 (300.9 mg, 97% yield) was prepared as a dark brown oily liquid from Intermediate 54-1 and 1-methylpyrazole-3-boronic acid pinacol ester using the method described in Intermediate 2-1.

[1111] ESI-MS m / z:597.0[M+H]+.

[1112] Step c: Preparation of compound 54

[1113] The trifluoroacetic acid salt of compound 54 was prepared from intermediate 54-2 using the method described for compound 1 and purified by pre-HPLC separation as a white solid.

[1114] ESI-MS m / z:556.9[M+H]+.

[1115] 1 H NMR (600MHz, Methanol-d4) δ8.17(s,1H),7.96(s,1H),7.81(d,J=8.8Hz,1H),7.67(d,J=2.4Hz,1H),7. 52(s,1H),7.26(dd,J=8.8,2.4Hz,1H),7.10(s,1H),6.85(s,1H),6.59(s,1H),5.59(s,1H),4.65(dd,J =11.2,2.1Hz,1H),4.47(dd,J=11.1,4.6Hz,2H),4.34(ddd,J=8.9,4.7,2.1Hz,1H),4.06(d,J=8.8Hz,1 H),3.97(s,3H),2.57(s,2H),2.18(q,J=9.3Hz,2H),1.92(ddd,J=18.2,10.3,7.7Hz,2H),1.08(s,3H).

[1116] Example 55: (2S,3R,4R,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(azetidin-1-yl)quinolin-7-yl)oxy)methyl)-3-methyltetrahydrofuran-3,4-diol (Compound 55)

[1117]

[1118] Step a: Preparation of Intermediate 55-1

[1119] Intermediate 55-1 (310.3 mg, yield 75%) was prepared as a brown oily liquid from Intermediate G and Intermediate B4 using the method described in Intermediate A2.

[1120] ESI-MS m / z:684.1[M+H]+.

[1121] Step b: Preparation of Intermediate 55-2

[1122] Intermediate 55-2 (300.0 mg, 92% yield) was prepared from Intermediate 55-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a dark brown foamy solid.

[1123] ESI-MS m / z:583.2[M+H]+.

[1124] Step c: Preparation of compound 55

[1125] The method described in Compound 1 was used to separate and purify the intermediate 55-2 by silica gel column chromatography to prepare Compound 55 (106.7 mg, yield 47%) as an off-white solid.

[1126] ESI-MS m / z:543.1[M+H]+.

[1127] Example 56: (2S,3R,4S,5R)-2-(4-aminoimidazo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(methylamino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 56)

[1128]

[1129] Step a: Preparation of Intermediate 56-1

[1130] Intermediate 56-1 (349.0 mg, 53% yield) was prepared from Intermediate I and Intermediate B2 as a light yellow foamy solid using the method described in Intermediate A2.

[1131] ESI-MS m / z: 669.1 [M+H]+.

[1132] Step b: Preparation of compound 56

[1133] The method described in Compound 1 was used to separate and purify the intermediate 56-1 by silica gel column chromatography to prepare Compound 56 (238.6 mg, yield 100%) as a yellow solid.

[1134] ESI-MS m / z:424.0[M+H]+.

[1135] Example 57: (2S,3R,4S,5R)-2-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(methylamino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 57)

[1136]

[1137] Step a: Preparation of Intermediate 57-1

[1138] Intermediate 57-1 (466.8 mg, 100% yield) was prepared from Intermediate A5 and Intermediate B2 as a yellow oily liquid using the method described in Intermediate A2.

[1139] ESI-MS m / z:746.1,,748.1[M+H]+.

[1140] Step b: Preparation of compound 57

[1141] The method described in Compound 1 was used to separate and purify the intermediate 57-1 by silica gel column chromatography to prepare Compound 57 (104.2 mg, yield 33%) as a white solid.

[1142] ESI-MS m / z:500.9,502.9[M+H]+.

[1143] Example 58: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(cyclopropylamino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 58)

[1144]

[1145] Step a: Preparation of Intermediate 58-1

[1146] Intermediate 58-1 (269.7 mg, 60% yield) was prepared from Intermediate A1 and Intermediate B9 as a yellow foamy solid using the method described in Intermediate A2.

[1147] ESI-MS m / z: 670.1 [M+H]+.

[1148] Step b: Preparation of Intermediate 58-2

[1149] Intermediate 58-2 (266.1 mg, 100% yield) was prepared from Intermediate 58-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a brown-red foamy solid.

[1150] ESI-MS m / z: 569.0 [M+H]+.

[1151] Step c: Preparation of compound 58

[1152] The trifluoroacetic acid salt of compound 58 was prepared from intermediate 58-2 using the method described for compound 1 and purified by pre-HPLC separation as a white solid.

[1153] ESI-MS m / z: 529.0 [M+H]+.

[1154] 1H NMR(600MHz, Methanol-d4)δ8.11(s,1H),7.90(s,1H),7.71(d,J=8.8Hz,1H),7.66( d,J=2.4Hz,1H),7.51(s,1H),7.13(d,J=8.9Hz,1H),7.05(s,1H),6.77(s,1H),6.58( d,J=2.4Hz,1H),5.36(d,J=4.7Hz,1H),4.58–4.52(m,1H),4.48(t,J=4.8Hz,1H),4. 42–4.31(m,3H),3.96(s,3H),2.84(s,1H),1.19–1.00(m,2H),0.78(p,J=4.6Hz,2H).

[1155] Example 59: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(bicyclo[1.1.1]pentan-1-ylamino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 59)

[1156]

[1157] Step a: Preparation of Intermediate 59-1

[1158] Intermediate 59-1 (327.8 mg, yield 68%) was prepared from Intermediate A1 and Intermediate B11 as a yellow oily liquid using the method described in Intermediate A2.

[1159] ESI-MS m / z: 696.0 [M+H]+.

[1160] Step b: Preparation of Intermediate 59-2

[1161] Intermediate 59-2 (253.2 mg, 90% yield) was prepared from intermediate 59-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a brown-red foamy solid.

[1162] ESI-MS m / z:595.1[M+H]+.

[1163] Step c: Preparation of compound 59

[1164] The trifluoroacetic acid salt of compound 59 was prepared from intermediate 59-2 using the method described for compound 1 and purified by pre-HPLC separation as a white solid.

[1165] ESI-MS m / z: 555.0 [M+H]+.

[1166] 1 H NMR(600MHz,Methanol-d4)δ8.26(d,J=9.3Hz,1H),7.92(s,1H),7.77(d,J=8.9Hz, 1H),7.66(d,J=2.4Hz,1H),7.30(s,1H),7.17(dd,J=8.9,2.3Hz,1H),7.12(d,J=8.9 Hz,1H),7.06(s,1H),6.60(d,J=2.4Hz,1H),5.39(d,J=4.8Hz,1H),4.59–4.54(m,1H ),4.48(t,J=4.9Hz,1H),4.42–4.35(m,3H),3.98(s,3H),2.64(s,1H),2.35(s,6H).

[1167] Example 60: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(cyclobutyl(methyl)amino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 60)

[1168]

[1169] Step a: Preparation of Intermediate 60-1

[1170] Intermediate 60-1 (393.5 mg, yield 89%) was prepared from Intermediate A1 and Intermediate B17 as a yellow oily liquid using the method described in Intermediate A2.

[1171] ESI-MS m / z: 698.1 [M+H]+.

[1172] Step b: Preparation of Intermediate 60-2

[1173] Intermediate 60-2 (331.8 mg, 99% yield) was prepared from Intermediate 60-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a red-brown oily liquid.

[1174] ESI-MS m / z:597.0[M+H]+.

[1175] Step c: Preparation of compound 60

[1176] The trifluoroacetic acid salt of compound 60 was prepared from intermediate 60-2 using the method described for compound 1 and purified by pre-HPLC separation as a white solid.

[1177] ESI-MS m / z: 557.0 [M+H]+.

[1178] 1 H NMR (600MHz, Methanol-d4) δ8.21(d,J=9.6Hz,1H),7.91(s,1H),7.74(d,J=8.8Hz,1H),7.67(d,J=2.4Hz,1H),7.47(d,J=2.3Hz,1H) ,7.15–7.10(m,2H),7.08(s,1H),6.60(d,J=2.4Hz,1H),5.37(d,J=4.7Hz,1H),4.68(ddd,J=16.8,9.3,7.3Hz,1H),4.56–4.49(m,1H ), 4.48 (t, J = 4.8 Hz, 1H), 4.37 (ddt, J = 13.5, 8.8, 4.7 Hz, 3H), 3.97 (s, 3H), 3.32 (s, 3H), 2.53–2.34 (m, 4H), 1.92–1.78 (m, 2H). Example 61: (2S, 3R, 4S, 5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(methylamino)quinazolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 61)

[1179]

[1180] Step a: Preparation of Intermediate 61-1

[1181] Intermediate 61-1 (363.1 mg, yield 96%) was prepared from Intermediate A1 and Intermediate C1 as a brown oily liquid.

[1182] ESI-MS m / z:795.0[M+H]+.

[1183] Step b: Preparation of Intermediate 61-2

[1184] Intermediate 61-2 (331.8 mg, 97% yield) was prepared as a yellow foamy solid from Intermediate 61-1 and 1-methylpyrazole-3-boronic acid pinacol ester using the method described in Intermediate 2-1.

[1185] ESI-MS m / z: 694.1 [M+H]+.

[1186] Step c: Preparation of compound 61

[1187] The intermediate 61-2 was separated and purified by silica gel column chromatography using the method described in Compound 1 to prepare Compound 61 (120.0 mg, yield 50%) as a yellow solid.

[1188] ESI-MS m / z: 504.0 [M+H]+.

[1189] Example 62: (2S,3R,4S,5R)-2-(4-amino-5-chloropyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(methylamino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 62)

[1190]

[1191] Step a: Preparation of Step 62-1

[1192] Intermediate 62-1 (203.0 mg, yield 51%) was prepared as a yellow oily liquid from Intermediate A6 and Intermediate B2 using the method described in Intermediate A2.

[1193] ESI-MS m / z:702.0,704.2[M+H]+.

[1194] Step b: Preparation of compound 62

[1195] The intermediate 62-1 was separated and purified by silica gel column chromatography using the method described in Compound 1 to prepare Compound 62 (110.4 mg, yield 84%) as a yellow solid.

[1196] ESI-MS m / z:456.9,459.0[M+H]+.

[1197] 1 H NMR (400MHz, Methanol-d4) δ7.85(d,J=9.1Hz,1H),7.76(s,1H),7.57(d,J=8.7Hz,1H),7.21(d,J=2.4Hz,1H),6.95(dd,J=8.7,2.4Hz,1 H),6.68(s,1H),6.65(d,J=9.1Hz,1H),5.39(d,J=4.7Hz,1H),4.47–4.40(m,2H),4.37(t,J=5.2Hz,1H),4.34–4.24(m,2H),3.05(s,3H).

[1198] Example 63: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((4-((2-methoxyethyl)amino)-2-(methylamino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 63)

[1199]

[1200] Step a: Preparation of Intermediate 63-1

[1201] Intermediate 63-1 (217.4 mg, 57% yield) was prepared from Intermediate A1 and Intermediate E1 as a yellow oily liquid.

[1202] ESI-MS m / z:867.1[M+H]+.

[1203] Step b: Preparation of Intermediate 63-2

[1204] Intermediate 63-2 (126.0 mg, 66% yield) was prepared from Intermediate 63-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a yellow foamy solid.

[1205] ESI-MS m / z:766.2[M+H]+.

[1206] Step c: Preparation of compound 63

[1207] The trifluoroacetic acid salt of compound 63 was prepared from intermediate 63-2 using the method described for compound 1 and purified by pre-HPLC separation as a white solid.

[1208] ESI-MS m / z:576.1[M+H]+.

[1209] 1H NMR (600MHz, Methanol-d4) δ7.90(s,1H),7.86(d,J=9.1Hz,1H),7.65(d,J=2.3Hz,1H),7.07(s ,1H),6.98(s,1H),6.97(dd,J=9.2,2.5Hz,1H),6.56(d,J=2.3Hz,1H),5.66(s,1H),5.36(d,J=4 .4Hz,1H),4.54(dd,J=11.4,2.4Hz,1H),4.47(t,J=4.8Hz,1H),4.43(t,J=5.4Hz,1H),4.37–4. 27(m,2H),3.97(s,3H),3.70(t,J=5.4Hz,2H),3.56(t,J=5.4Hz,2H),3.42(s,3H),3.01(s,3H).

[1210] Example 64: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(azetidin-1-yl)quinazolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 64)

[1211]

[1212] Step a: Preparation of Intermediate 64-1

[1213] Intermediate 64-1 (272.2 mg, yield 95%) was prepared from Intermediate A1 and Intermediate C2 as a yellow oily liquid using the method described in Intermediate A2.

[1214] ESI-MS m / z: 670.9 [M+H]+.

[1215] Step b: Preparation of Intermediate 64-2

[1216] Intermediate 64-2 (178.0 mg, 77% yield) was prepared as a brown-red solid from Intermediate 64-1 and 1-methylpyrazole-3-boronic acid pinacol ester using the method described in Intermediate 2-1.

[1217] ESI-MS m / z: 570.0 [M+H]+.

[1218] Step c: Preparation of compound 64

[1219] The method described in Compound 1 was used to separate and purify the intermediate 64-2 by silica gel column chromatography to prepare Compound 64 (110.1 mg, yield 60%) as a dark yellow solid.

[1220] ESI-MS m / z: 530.0 [M+H]+.

[1221] Example 65: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(cyclobutylamino)quinazolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 65)

[1222]

[1223] Step a: Preparation of Intermediate 65-1

[1224] Intermediate 65-1 (274.3 mg, 83% yield) was prepared from Intermediate A1 and Intermediate C3 as a yellow oily liquid using the method described in Intermediate A2.

[1225] ESI-MS m / z: 684.9 [M+H]+.

[1226] Step b: Preparation of Intermediate 65-2

[1227] Intermediate 65-2 (180.0 mg, 77% yield) was prepared from Intermediate 65-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a brown-red foamy solid.

[1228] ESI-MS m / z:584.0[M+H]+.

[1229] Step c: Preparation of compound 65

[1230] The method described in Compound 1 was used to separate and purify the intermediate 65-2 by silica gel column chromatography to prepare Compound 65 (92.3 mg, yield 55%) as a yellow solid.

[1231] ESI-MS m / z:544.0[M+H]+.

[1232] Example 66: (2S,3R,4S,5R)-2-(4-amino-5-(pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(methylamino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 66)

[1233]

[1234] Step a: Preparation of Intermediate 66-1

[1235] Intermediate 66-1 (114.7 mg, 61% yield) was prepared from Intermediate A2 and 3-pyridineboronic acid pinacol ester as a yellow oily liquid using the method described in Intermediate 2-1.

[1236] ESI-MS m / z:745.2[M+H]+.

[1237] Step b: Preparation of compound 66

[1238] The trifluoroacetic acid salt of compound 66 was prepared from intermediate 66-1 using the method described for compound 1 and purified by pre-HPLC separation as a white solid.

[1239] ESI-MS m / z: 500.0 [M+H]+.

[1240] Example 67: (2S,3R,4S,5R)-2-(4-amino-5-(5-methylthiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(methylamino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 67)

[1241]

[1242] Step a: Preparation of Intermediate 67-1

[1243] Intermediate 67-1 (185.9 mg, 97% yield) was prepared as a brown oily liquid from Intermediate A2 and 2-methylthiophene-5-boronic acid pinacol ester using the method described in Intermediate 2-1.

[1244] ESI-MS m / z:764.2[M+H]+.

[1245] Step b: Preparation of compound 67

[1246] The trifluoroacetic acid salt of compound 67 was prepared from intermediate 67-1 by pre-HPLC separation and purification using the method described for compound 1 as a white solid.

[1247] ESI-MS m / z: 518.9 [M+H]+.

[1248] Example 68: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(methylamino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 68)

[1249]

[1250] Step a: Preparation of Intermediate 68-1

[1251] Intermediate 68-1 (95.7 mg, 51% yield) was prepared from Intermediate A2 and 1-methylpyrazole-4-boronic acid pinacol ester as a brown-red oily liquid using the method described in Intermediate 2-1.

[1252] ESI-MS m / z:748.3[M+H]+.

[1253] Step b: Preparation of compound 68

[1254] The intermediate 68-1 was separated and purified by silica gel column chromatography using the method described in Compound 1 to prepare Compound 68 (32.6 mg, yield 51%) as a yellow solid.

[1255] ESI-MS m / z: 503.0 [M+H]+.

[1256] Example 69: (2S,3R,4S,5R)-2-(4-amino-5-(1-isopropyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(methylamino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 69)

[1257]

[1258] Step a: Preparation of Intermediate 69-1

[1259] Intermediate 69-1 (148.6 mg, 82% yield) was prepared from Intermediate A2 and 1-isopropylpyrazole-3-boronic acid pinacol ester as a brown-red oily liquid.

[1260] ESI-MS m / z:721.1[M+H]+.

[1261] Step b: Preparation of compound 69

[1262] The method described in Compound 1 was used to prepare Compound 69 (53.7 mg, yield 49%) from Intermediate 69-1 by separation and purification by silica gel column chromatography.

[1263] ESI-MS m / z:531.1[M+H]+.

[1264] Example 70: (2S,3R,4S,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-5-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(methylamino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 70)

[1265]

[1266] Step a: Preparation of Intermediate 70-1

[1267] Intermediate 70-1 (198.4 mg, 70% yield) was prepared from Intermediate A2 and 1-methyl-1H-pyrazole-5-boronic acid pinacol ester as a brown-red oily liquid using the method described in Intermediate 2-1.

[1268] ESI-MS m / z:748.1[M+H]+.

[1269] Step b: Preparation of compound 70

[1270] The intermediate 70-1 was separated and purified by silica gel column chromatography using the method described in Compound 1 to prepare Compound 70 (74.4 mg, yield 56%) as a yellow solid.

[1271] ESI-MS m / z: 503.0 [M+H]+.

[1272] Example 71: (2S,3R,4S,5R)-2-(4-amino-5-(1-phenyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(methylamino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 71)

[1273]

[1274] Step a: Preparation of Intermediate 71-1

[1275] Intermediate 71-1 (235.7 mg, 83% yield) was prepared from Intermediate A2 and 1-phenylpyrazole-3-boronic acid pinacol ester as a brown-red oily liquid using the method described in Intermediate 2-1.

[1276] ESI-MS m / z:755.1[M+H]+.

[1277] Step b: Preparation of compound 71

[1278] The intermediate 71-1 was separated and purified by silica gel column chromatography using the method described in Compound 1 to prepare Compound 71 (46.7 mg, yield 26%) as a white solid.

[1279] ESI-MS m / z:565.1[M+H]+.

[1280] Example 72: (2S,3R,4S,5R)-2-(4-amino-5-(1-(oxetane-3-yl)-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(methylamino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 72)

[1281]

[1282] Step a: Preparation of Intermediate 72-1

[1283] Intermediate 72-1 (187.3 mg, 67% yield) was prepared from Intermediate A2 and 1-(3-oxetanyl)pyrazole-3-boronic acid pinacol ester as a brown-red oily liquid.

[1284] ESI-MS m / z:735.1[M+H]+.

[1285] Step b: Preparation of compound 72

[1286] The trifluoroacetic acid salt of compound 72 was prepared from intermediate 72-1 using the method described for compound 1 and purified by pre-HPLC as a white solid.

[1287] ESI-MS m / z:545.1[M+H]+.

[1288] 1H NMR (600MHz, Methanol-d4) δ8.08(s,1H),7.97(s,1H),7.86(d,J=2.4Hz,1H),7.71(d,J=8.7Hz,1H), 7.40(s,1H),7.16(s,1H),7.13(dd,J=8.8,2.4Hz,1H),6.80(s,1H),6.70(d,J=2.4Hz,1H),5.61(tt, J=7.4,5.5Hz,1H),5.41(d,J=4.7Hz,1H),5.16(td,J=7.3,4.0Hz,2H),4.96(ddd,J=7.7,5.5,2.6Hz, 2H),4.58–4.53(m,1H),4.50(t,J=4.9Hz,1H),4.41(t,J=5.2Hz,1H),4.39–4.34(m,2H),3.15(s,3H).

[1289] Example 73: (2S,3R,4S,5R)-2-(4-amino-5-(cyclohex-1-en-1-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(methylamino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 73)

[1290]

[1291] Step a: Preparation of Intermediate 73-1

[1292] Intermediate 73-1 (161.8 mg, 57% yield) was prepared from Intermediate A2 and cyclohexene-1-boronic acid pinacol ester as a yellow oily liquid using the method described in Intermediate 2-1.

[1293] ESI-MS m / z:748.1[M+H]+.

[1294] Step b: Preparation of compound 73

[1295] The trifluoroacetic acid salt of compound 73 was prepared from intermediate 73-1 by pre-HPLC separation and purification using the method described for compound 1 as a white solid.

[1296] ESI-MS m / z:503.1[M+H]+.

[1297] Example 74: (2S,3R,4S,5R)-2-(4-amino-5-(4,4-difluorocyclohex-1-en-1-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(methylamino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 74)

[1298]

[1299] Step a: Preparation of Intermediate 74-1

[1300] Intermediate 74-1 (230.3 mg, 78% yield) was prepared as a yellow oily liquid from Intermediate A2 and 2-(4,4-difluorocyclohex-1-en-1-yl)boronic acid pinacol ester using the method described in Intermediate 2-1.

[1301] ESI-MS m / z:784.2[M+H]+.

[1302] Step b: Preparation of compound 74

[1303] The method described in Compound 1 was used to separate and purify the intermediate 74-1 by silica gel column chromatography to prepare Compound 74 (51.7 mg, yield 33%) as a white solid.

[1304] ESI-MS m / z:539.1[M+H]+.

[1305] Example 75: (2S,3R,4S,5R)-2-(4-amino-5-(pyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(methylamino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 75)

[1306]

[1307] Step a: Preparation of Intermediate 75-1

[1308] Intermediate 75-1 (175.9 mg, 62% yield) was prepared from Intermediate A2 and 4-pyridineboronic acid pinacol ester as a brown-red oily liquid using the method described in Intermediate 2-1.

[1309] ESI-MS m / z:745.2[M+H]+.

[1310] Step b: Preparation of compound 75

[1311] The trifluoroacetic acid salt of compound 75 was prepared from intermediate 75-1 by pre-HPLC separation and purification using the method described for compound 1 as a white solid.

[1312] ESI-MS m / z: 500.2 [M+H]+.

[1313] Example 76: (2S,3R,4S,5R)-2-(4-amino-5-(1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(methylamino)quinolin-7-yl)oxy)methyl)tetrahydrofuran-3,4-diol (Compound 76)

[1314]

[1315] Step a: Preparation of Intermediate 76-1

[1316] Intermediate 76-1 (243.3 mg, 79% yield) was prepared as a brown-red oily liquid from Intermediate A2 and 1-(tetrahydro-2H-pyran-2-yl)pyrazole-3-boronic acid pinacol ester using the method described in Intermediate 2-1.

[1317] ESI-MS m / z:818.1[M+H]+.

[1318] Step b: Preparation of compound 76

[1319] The method described in Compound 1 was used to separate and purify the intermediate 76-1 by silica gel column chromatography to prepare Compound 76 (72.2 mg, yield 50%) as a white solid.

[1320] ESI-MS m / z:489.0[M+H]+.

[1321] Example 77: (2S,3R,4R,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((4-((2-methoxyethyl)amino)-2-(methylamino)quinazolin-7-yl)oxy)methyl)-3-methyltetrahydrofuran-3,4-diol (Compound 77)

[1322]

[1323] Step a: Preparation of Intermediate 77-1

[1324] Intermediate 77-1 (121.5 mg, yield 25%) was prepared from Intermediate G and Intermediate F1 as a yellow oily liquid using the method described in Intermediate A2.

[1325] ESI-MS m / z:882.2[M+H]+.

[1326] Step b: Preparation of Intermediate 77-2

[1327] Intermediate 77-2 (89.6 mg, 83% yield) was prepared from Intermediate 77-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a yellow oily liquid.

[1328] ESI-MS m / z:781.2[M+H]+.

[1329] Step c: Preparation of compound 77

[1330] The trifluoroacetic acid salt of compound 77 was prepared from intermediate 77-2 using the method described for compound 1 and purified by pre-HPLC as a white solid.

[1331] ESI-MS m / z:591.0[M+H]+.

[1332] 1 H NMR(600MHz,Methanol-d4)δ8.05(d,J=9.1Hz,1H),7.96(s,1H),7.67(d,J=2.3Hz,1H), 7.12(s,1H),7.05(s,1H),6.58(d,J=2.4Hz,1H),5.59(s,1H),4.64(dd,J=11.3,2.1Hz,1 H),4.45(dd,J=11.3,4.6Hz,1H),4.31(ddd,J=8.9,4.7,2.0Hz,1H),4.05(d,J=8.8Hz,1 H),3.98(s,3H),3.91–3.82(m,2H),3.70(s,2H),3.40(s,3H),3.07(s,3H),1.08(s,3H).

[1333] Example 78: (2S,3R,4R,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(azetidin-1-yl)-4-((2-methoxyethyl)amino)quinazolin-7-yl)oxy)methyl)-3-methyltetrahydrofuran-3,4-diol (Compound 78)

[1334]

[1335] Step a: Preparation of Intermediate 78-1

[1336] Intermediate 78-1 (286.0 mg, yield 71%) was prepared from Intermediate G and Intermediate F2 as a yellow oily liquid using the method described in Intermediate A2.

[1337] ESI-MS m / z:758.1[M+H]+.

[1338] 1 H NMR(600MHz,Chloroform-d)δ8.79(s,1H),8.03(s,1H),7.44(d,J=8.9Hz,1H),6.98–6.92(m,1H),6. 88(s,1H),6.73(dd,J=8.9,2.5Hz,1H),5.81(d,J=6.2Hz,1H),5.77(s,1H),4.51(q,J=3.1,2.3Hz,2H ),4.27(qd,J=10.3,3.7Hz,2H),4.18(t,J=7.5Hz,4H),3.78(q,J=5.2Hz,2H),3.62(t,J=5.2Hz,2H), 3.40(s,3H),3.33(s,3H),3.19(s,3H),2.31(p,J=7.4Hz,2H),1.72(s,3H),1.43(s,3H),1.27(s,3H).

[1339] Step b: Preparation of Intermediate 78-2

[1340] Intermediate 78-2 (230.0 mg, 93% yield) was prepared from Intermediate 78-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a yellow oily liquid.

[1341] ESI-MS m / z: 657.1[M+H]+.

[1342] Step c: Preparation of compound 78

[1343] The trifluoroacetic acid salt of compound 78 was prepared from intermediate 78-2 using the method described for compound 1 and purified by pre-HPLC separation as a white solid.

[1344] ESI-MS m / z: 617.2 [M+H]+.

[1345] 1H NMR (600MHz, Methanol-d4) δ8.03(d,J=9.0Hz,1H),7.97(s,1H),7.69(d,J=2.4Hz,1H),7.11(dd,J=9.1,2 .4Hz,1H),7.07(d,J=2.4Hz,1H),7.05(s,1H),6.58(d,J=2.4Hz,1H),5.57(s,1H),4.63(dd,J=11.4,2.1H z,1H),4.44(dd,J=11.3,4.6Hz,1H),4.35(t,J=7.7Hz,4H),4.30(td,J=4.4,2.0Hz,1H),4.04(d,J=8.8Hz ,1H),3.98(s,3H),3.82(t,J=5.5Hz,2H),3.71–3.64(m,2H),3.40(s,3H),2.54–2.46(m,2H),1.08(s,3H).

[1346] Example 79: (2S,3R,4R,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((4-((2-methoxyethyl)amino)-2-(methylamino)quinolin-7-yl)oxy)methyl)-3-methyltetrahydrofuran-3,4-diol (Compound 79)

[1347]

[1348] Step a: Preparation of Intermediate 79-1

[1349] Intermediate 79-1 (186.5 mg, 40% yield) was prepared from Intermediate G and Intermediate E1 as a yellow oily liquid using the method described in Intermediate A2.

[1350] ESI-MS m / z:881.2[M+H]+.

[1351] Step b: Preparation of Intermediate 79-2

[1352] Intermediate 79-2 (142.9 mg, 87% yield) was prepared from Intermediate 79-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a brown-red oily liquid.

[1353] ESI-MS m / z:780.3[M+H]+.

[1354] Step c: Preparation of compound 79

[1355] The trifluoroacetic acid salt of compound 79 was prepared from intermediate 79-2 using the method described for compound 1 and purified by pre-HPLC as a white solid.

[1356] ESI-MS m / z:590.1[M+H]+.

[1357] 1 H NMR (600MHz, Methanol-d4) δ8.01(d,J=9.1Hz,1H),7.93(s,1H),7.65(d,J=2.3Hz,1H),7.23(s,1H),7 .13(dd,J=9.1,2.5Hz,1H),7.04(s,1H),6.54(d,J=2.4Hz,1H),5.73(s,1H),5.57(s,1H),4.63(dd,J= 11.3,2.1Hz,1H),4.43(dd,J=11.3,4.4Hz,1H),4.31(ddd,J=8.9,4.4,2.0Hz,1H),4.06(d,J=8.7Hz,1 H),3.97(s,3H),3.71(t,J=5.4Hz,2H),3.59(t,J=5.4Hz,2H),3.41(s,3H),3.04(s,3H),1.07(s,3H).

[1358] Example 80: (2S,3R,4R,5R)-2-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(((2-(azetidin-1-yl)-4-((2-methoxyethyl)amino)quinolin-7-yl)oxy)methyl)-3-methyltetrahydrofuran-3,4-diol (Compound 80)

[1359]

[1360] Step a: Preparation of Intermediate 80-1

[1361] Intermediate 80-1 (136.7 mg, yield 36%) was prepared from Intermediate G and Intermediate E2 as a yellow oily liquid using the method described in Intermediate A2.

[1362] ESI-MS m / z:757.2[M+H]+.

[1363] Step b: Preparation of Intermediate 80-2

[1364] Intermediate 80-2 (113.5 mg, 96% yield) was prepared from Intermediate 80-1 and 1-methylpyrazole-3-boronic acid pinacol ester as a brown-red oily liquid.

[1365] ESI-MS m / z: 656.1 [M+H]+.

[1366] Step c: Preparation of compound 80

[1367] The trifluoroacetic acid salt of compound 80 was prepared from intermediate 80-2 using the method described for compound 1 and purified by pre-HPLC separation as a white solid.

[1368] ESI-MS m / z: 616.2 [M+H]+.

[1369] 1 H NMR (600MHz, Methanol-d4) δ8.03(d,J=9.1Hz,1H),7.96(s,1H),7.68(d,J=2.3Hz,1H),7.23(d,J=2.5Hz,1H) ,7.14(dd,J=9.1,2.5Hz,1H),7.05(s,1H),6.53(d,J=2.3Hz,1H),5.58(s,1H),5.42(s,1H),4.63(dd,J=11.4 ,2.1Hz,1H),4.42(dd,J=11.4,4.3Hz,1H),4.33(t,J=7.6Hz,4H),4.30(d,J=1.8Hz,1H),4.06(d,J=8.8Hz,1H ),3.98(s,3H),3.70(t,J=5.3Hz,2H),3.60(t,J=5.3Hz,2H),3.41(s,3H),2.55(p,J=7.6Hz,2H),1.08(s,3H).

[1370] Biological evaluation

[1371] The present invention is further described and explained below in conjunction with tests, but these tests are not intended to limit the scope of the present invention.

[1372] Testing METTL3 enzyme activity assay

[1373] In this experiment, we used the HTRF method to detect the activity of the compound. HTRF technology includes two technologies: fluorescence resonance energy transfer and time-resolved fluorescence. 3+The labeled antibody (HTRF donor) recognizes the affinity tag, glutathione S-transferase (GST) recognizes the corresponding labeled protein, and the biotinylated RNA is labeled with biotin-streptavidin, and the corresponding labeled RNA is recognized by the interaction between biotin-streptavidin and XL665-conjugated streptavidin. When the biological molecules interact, fluorescence resonance energy transfer occurs between the acceptor and the donor, and there are two excitation lights of 620nm and 665nm. When there is no interaction, there is only one excitation light of 620nm. In this experiment, the YTHDF2 protein with a GST tag can specifically recognize the methylated single-stranded fragment RNA with biotin, thereby generating a 665nm light signal. The strength of the light signal is related to the degree of RNA methylation; the methyltransferase METTL3 can methylate the substrate fragment RNA, and the inhibitory effect of the compound on the METTL3 enzyme activity can be achieved by detecting the degree of RNA methylation, thereby reflecting the inhibitory effect of the compound on METTL3.

[1374] 1.1 Reagents and Instruments

[1375] Instruments and equipment: Multifunctional microplate reader (Tecan Spark cyto), TopSeal TM -A films (Article No. 6005185), White optiplate TM -384 (Cat. No. 6007299);

[1376] Reagent: HTRF donor Eu 3+ -labeled antibody and HTRF acceptor XL665-conjugatedstreptavidin were purchased from Shanghai PerkinElmer; the enzyme reaction substrate 5′-biotinylated singlestrand (ss) RNA (5′-AAGAACCGGACUAAGCU-3′) was purchased from Guangzhou Ruibo Biotechnology Co., Ltd.; the recombinant METTL3 / METTL14 complex (recombinant METTL3 / METTL14 complex) and recombinant YTHDF2 were purchased from Shanghai Molder Shanghai Biotechnology Center; the methyl donor SAM (catalog number A7007) was purchased from Sigma, USA.

[1377] 1.2 Test methods

[1378] (1) Prepare reaction buffer and dilute METTL3 / METTL14 enzyme, SAM, inhibitors and RNA fragments with reaction buffer;

[1379] (2) Add the following reagents to a 384-well white microplate in sequence: 5 μL of inhibitor (4×) or Assay Buffer, 5 μL of METTL3 / METTL14 enzyme (4×), incubate at room temperature for 20 min, and then add the following reagents in sequence: 5 μL of RNA fragment (4×), 5 μL of SAM (4×).

[1380] (3) Seal the microplate and keep it away from light and place it at room temperature for 60 min;

[1381] (4) Prepare Detection Buffer, and use Detection Buffer to prepare SA-XL665 Beads and YTHDF2 enzyme; add 10 μL (4×) SA-XL665 Beads and 10 μL (4×) YTHDF2 enzyme, seal and incubate in dark for 60 min;

[1382] (6) Read the results using a multifunctional microplate reader Tecan. Two sets of wells were set up for each group of experiments, and a blank control group was set up.

[1383] Inhibition rate (%) = {[(positive control signal value - blank control signal value) - (test compound signal value - blank control signal value)] / (positive control signal value - blank control signal value)}

[1384] With inhibition rate (%) as the ordinate and compound concentration as the abscissa, competitive inhibition curves were drawn using Graphpad prism software, and the IC of the compound was calculated using the obtained regression equation. 50 .

[1385] IC of the compounds of Examples 1-80 for METTL3 enzymatic inhibition 50 See Table 3 for values.

[1386] Table 3

[1387]

[1388]

[1389]

[1390] Note: “+++” means IC 50 ≤100nM; "++" means 100nM <IC 50 ≤1000nM; “+” indicates IC 50 >1000nM.

[1391] Conclusion: As shown in Table 2, the compounds of the present invention have a significant inhibitory effect on the activity of METTL3 enzyme.

[1392] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[1393] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A compound having a structure represented by formula (I), or a pharmaceutically acceptable salt thereof: in, R 0 Selected from H or CN; R 1 , R 2 are independently selected from H, halogen, C 1-6 Alkyl, -OR 3 , cyano or amino; R 3 Selected from H, C 1-6 Alkyl or -C(=O)C 1-6 ; Q is selected from -N- or -CR4; X is selected from -O-, -S- or -CH2-; Y is selected from -O-, -S-, -CR a R b or -NR c ; R a and R b independently selected from H, deuterium, C 1-6 Alkyl or halogen; R c Select from H or C 1-6 alkyl; Z is selected from -(CH2) n -、 Among them, -(CH2) n -、 Each is optionally substituted by 1-3 independently selected halogens; n is an integer from 1 to 6, n1 and n2 are independently integers from 0 to 4, and n1+n2=4; Ring A is selected from benzene, naphthalene, a 4- to 7-membered monocyclic heterocycloalkyl, a 5- to 6-membered monocyclic heteroaromatic ring, or an 8- to 10-membered bicyclic heteroaromatic ring, wherein the benzene, naphthalene, 4- to 7-membered monocyclic heterocycloalkyl, 5- to 6-membered monocyclic heteroaromatic ring, and 8- to 10-membered bicyclic heteroaromatic ring are each optionally substituted by 1-6 independently selected R 7 replace; R 7 Each occurrence is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, halogen, -CN, =O, -OR 7a 、-NR 7a R 7b 、-OC(=O)R 7a 、-NR 7a C(=O)R 7a 、-NR 7a C(=O)NR 7a R 7b 、-C(=O)NR 7a R 7b 、-C(=O)R 7a OR -C(=O)OR 7a , wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4 to 7 membered heterocycloalkyl, phenyl and 5 to 6 membered heteroaryl are each optionally substituted with 0 to 3 substituents independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, halogen, -CN, -OR 7a 、-NR 7a R 7b 、-C(=O)NR 7a R 7b 、-C(=O)R 7a 、-C(=O)OR 7a 、-NR 7a C(=O)R 7a or -OC(=O)R 7a ; R 7a and R 7b Independently selected from H, C 1-6 Alkyl, -(CH2) n OC 1-6 Alkyl, -(CH2) n NC 1-6 Alkyl C 1-6 Alkyl, C 3-8 cycloalkyl, 4 to 6 membered heterocycloalkyl, phenyl or 5 to 6 membered heteroaryl, wherein the C 1-6 Alkyl, -(CH2) m OC 1-6 Alkyl, -(CH2) m NC 1-6 Alkyl C 1-6 Alkyl, C 3-8 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally substituted with 0-3 substituents independently selected from halogen, -OH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl or 4- to 7-membered heterocycloalkyl; or R 7a and R 7b Together with the nitrogen atom to which they are attached, they form a 4- to 6-membered heterocycloalkyl group, or R 7a and R 7b Together with the N atom to which they are attached and a heteroatom additionally selected from O, N or S, they form a 4- to 6-membered heterocycloalkyl group, wherein the 4- to 6-membered heterocycloalkyl group is optionally substituted by 0-3 substituents independently selected from halogen, C 1-4 Alkyl or C 1-4 Haloalkyl; m is an integer of 1 to 6; R 4 Selected from H, deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 5-8 Cycloalkenyl, 4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkenyl, phenyl, 5- to 6-membered heteroaryl, halogen, -CN, -OR 4a 、-NR 4a R 4b 、-C(=O)R 4a 、-NR 4a C(=O)R 4a 、-OC(=O)R 4a 、-C(=O)OR 4a or -C(=O)NR 4a R 4b , wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 5-8 The cycloalkenyl, 4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkenyl, phenyl and 5- to 6-membered heteroaryl are each optionally substituted with 0-3 substituents independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, halogen, -CN, -OR 4a 、-NR 4a R 4b 、-C(=O)R 4a 、-C(=O)NR 4a R 4b NR 4a C(=O)R 4a 、-OC(=O)R 4a OR -C(=O)OR 4a ; R 4a and R 4b Independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl or 4- to 6-membered heterocycloalkyl; or R 4a and R 4b Together with the nitrogen atom to which they are attached, they form a 4- to 6-membered heterocycloalkyl group, or R 4a and R 4b Together with the N atom to which they are attached and a heteroatom additionally selected from O, N or S, they form a 4- to 6-membered heterocycloalkyl group, wherein the 4- to 6-membered heterocycloalkyl group is optionally substituted by 0-3 substituents independently selected from halogen, C 1-4 Alkyl or C 1-4 Haloalkyl; R 5 Selected from H, amino, hydroxy, halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, -NR 5a R 5b 、-NR 5a CR 5b R 5c OR 5a ; R 5a , R 5b and R 5c Independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 5-8 Cycloalkenyl, 4 to 7 membered heterocycloalkyl, 4 to 7 membered heterocycloalkenyl, phenyl, 5 to 6 membered heteroaryl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 5-8 Cycloalkenyl, 4 to 7 membered heterocycloalkyl, 4 to 7 membered heterocycloalkenyl, phenyl and 5 to 6 membered heteroaryl are each optionally substituted with 0-3 substituents independently selected from halogen, C 1-4 Alkyl or C 1-4 haloalkyl; or R 5a and R 5b Together with the nitrogen atom to which they are attached, they form a 4- to 6-membered heterocycloalkyl group, or R 5a and R 5b Together with the N atom to which they are attached and a heteroatom additionally selected from O, N or S, they form a 4- to 6-membered heterocycloalkyl group, wherein the 4- to 6-membered heterocycloalkyl group is optionally substituted by 0-3 substituents independently selected from halogen, C 1-4 Alkyl or C 1-4 Haloalkyl; R 6 Selected from H, halogen, amino or C 1-6 alkyl.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein The R 1 is H or CH3, the R 2 For OH.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein The R 3 For H.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein The Q is -CR 4 .

5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein The R 4 Selected from H, halogen or one of the following groups:

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein The X is -O-.

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Said Y is -O-.

8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Said Z is -CH2-.

9. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein The ring A is selected from quinoline, quinazoline, 2,3-naphthyridine, quinoxaline, cinnoline, 1,5-naphthyridine, pyridopyrimidine, pyridopyrazine, pteridine, indole, isoindole, indolizine, indazole, benzimidazole, benzotriazole, benzoxazole, benzisoxazole, benzothiazole, benzofuran, isobenzofuran, benzothiophene, benzothiadiazole, azaindole, purine, imidazopyridine, pyrrolopyrimidine, imidazopyridazine, imidazopyrazine, pyrazolopyrimidine, pyrazolopyridine, pyrazolotriazine, oxazolopyridine, isoxazolopyridine, thiazolopyridine, isothiazolopyridine, thienopyridine, pyridine, piperidine or benzene, wherein the quinoline , quinazoline, 2,3-naphthyridine, quinoxaline, cinnoline, 1,5-naphthyridine, pyridopyrimidine, pyridopyrazine, pteridine, indole, isoindole, indolizine, indazole, benzimidazole, benzotriazole, benzoxazole, benzisoxazole, benzothiazole, benzofuran, isobenzofuran, benzothiophene, benzothiadiazole, azaindole, purine, imidazopyridine, pyrrolopyrimidine, imidazopyridazine, imidazopyrazine, pyrazolopyrimidine, pyrazolopyridine, pyrazolotriazine, oxazolopyridine, isoxazolopyridine, thiazolopyridine, isothiazolopyridine, thienopyridine, pyridine, piperidine and and benzene are each optionally replaced by 1-6 independently selected R 7 replace.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, characterized in that: The compound has a structure shown in any one of formula (II)-1 to formula (II)-10: Here, p is an integer from 0 to 3.

11. The compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein The R 7 Each occurrence is independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl, halogen, =O, OR 7a or -NR 7a R 7b .

12. The compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein The R 7a and R 7b Independently selected from H, C 1-6 Alkyl, -(CH2) m OC 1-6 Alkyl, -(CH2) m NC 1-6 Alkyl C 1-6 Alkyl or C 3-8 Cycloalkyl, or R 7a and R 7b Together with the nitrogen atom to which they are attached, they form a 4- to 6-membered heterocycloalkyl group, wherein The 4- to 6-membered heterocycloalkyl is substituted by 0-3 substituents independently selected from halogen or C 1-6 alkyl.

13. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein The R 7a and R 7b The 4- to 6-membered heterocycloalkyl group substituted with 0-3 substituents formed together with the N atom to which they are attached is selected from one of the following groups:

14. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein The R 5 is -NH2.

15. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein The R 6 is -H.

16. The compound according to any one of claims 1 to 9, 11 to 15, or a pharmaceutically acceptable salt thereof, characterized in that: The compound has a structure represented by any one of formulas (III)-1 to (III)-12:

17. The compound according to claim 16, or a pharmaceutically acceptable salt thereof, wherein The compound is selected from one of the following structures:

18. A method for preparing a compound having a structure represented by formula (I), or a pharmaceutically acceptable salt thereof, characterized in that: The following steps are involved: Under acidic conditions, removing the protecting group from the compound having the structure represented by formula (I-1) to obtain a compound having the structure represented by formula (I-2), and obtaining a compound having the structure represented by formula (I) through the compound having the structure represented by formula (I-2); Among them, the R 0 , R 1 , R 2 , R 3 , Q, X, Y, Z, Ring A, R 5 and R 6 As described in any one of claims 1 to 17.

19. A pharmaceutical composition, characterized in that The invention comprises a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, diluent or excipient.

20. Use of the compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19 in the preparation of a medicament for treating and / or preventing a disease associated with or mediated by METTL3 activity.

21. The use according to claim 20, characterized in that The disease is selected from cancer, autoimmune disease, inflammatory disease or autosomal dominant polycystic kidney disease.

22. Use of the compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19 in combination with one or more other anti-tumor drugs in the preparation of a drug for treating and / or preventing cancer associated with or mediated by METTL3 activity.

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