WO2023103898A1 - Compound having clk and dyrk inhibitory activities, preparation method therefor and use thereof - Google Patents

Abstract

Provided is a novel compound having a macrocyclic structure. Specifically, provided are a compound having a macrocyclic structure of formula (I), or a pharmaceutically acceptable salt or a deuterated form thereof, and a method for preparing such compounds. This type of compounds has inhibitory effects on DYRK and/or CLK.

Description

Compound with CLK and DYRK inhibitory activity, its preparation method and use technical field

The invention belongs to the field of medicine and relates to a class of macrocyclic compounds with inhibitory effects on CLK and/or DYRK. More specifically, the present invention relates to compounds represented by general formula (I), their preparation methods and their use as CLK and/or DYRK inhibitors, and their preparation for the prevention and/or treatment of tumors, bone or cartilage-related diseases , fibrotic diseases and other drugs.

Background technique

CLK family kinases are an evolutionarily conserved group of specific kinases capable of phosphorylating serine, threonine and tyrosine residues (Prasad, J et.al Mol. Cell. Biol. 2003, 23, 4139-4149), Contains four family members (CLK1, CLK2, CLK3 and CLK4). CLK can catalyze the phosphorylation of a class of proteins with molecular mechanisms for regulating the spliceosome, namely, serine- and arginine-rich splicing factors 1-12 (SRSF1-12) (Aubol, B.E.et.al Mol.Cell 2016, 63, 218-228). Through this mechanism, CLK regulates the splicing of pre-mRNA, thereby affecting the translation process (Muraki, M. et. al J. Biol. Chem. 2004, 279, 24246-24254). CLK is expressed in most tissues and cells (eg, prostate, leukocytes, testis, muscle, brain, liver, lung, kidney, and thyroid), but different isoforms are expressed at varying levels in each tissue (Paula Martín Moyano et. al Int. J. Mol. Sci. 2020, 21, 7549).

CLK2 acts as an inhibitor of peroxisome proliferator-activated receptor coactivator (PGC-1α), which regulates fatty acid oxidation and ketogenesis (Tabata, M et. al Diabetes 2014, 63, 1519-1532). In addition, CLK2 phosphorylates protein phosphatase 2A (PP2A), which dephosphorylates (protein kinase B) AKT, resulting in attenuation of AKT activity (Hatting, M et. al Cell Metab. 2017, 25, 428-437). CLK2 can also phosphorylate protein tyrosine phosphatase (PTP-1B), thereby increasing its activity (Moeslein, F. M et. al J. Biol. Chem. 1999, 274, 26697-26704). Recent findings indicate that CLK2 hyperphosphorylates prostate-associated gene 4 (PAGE4) at multiple serine and tyrosine residues. Interestingly, it has been shown that (homeodomain-interacting protein kinase 1) phosphorylation of PAGE4 by HIPK1 enhances the proto-oncogene c-JUN, whereas phosphorylation of PAGE4 by CLK2 attenuates the activity of c-JUN (Kulkarni, P et.al Proc. Natl. Acad. Sci. USA 2017, 114, E2644-E2653).

The DYRK (dual specificity tyrosine phosphorylation-regulated kinase) family of kinases comprises five members (DYRK1A, DYRK1B, DYRK2, DYRK3 and DYRK4). DYRK acts by directly phosphorylating serine and threonine residues. DYRK kinases phosphorylate a wide range of substrates that are involved in a variety of cellular processes and are essential for development and homeostasis. Therefore, the abnormal regulation or expression of DYRK kinase is related to various human pathological processes such as cancer (Jacopo Boni et.al Cancers 2020, 12, 2106).

The DYRK1A gene, located on chromosome 21, plays a key role in neurogenesis and the etiology of some pathological features associated with Down syndrome and is the most extensively studied member of this family (Arbones, M.L et.al Pharmacol.Ther. 2019, 194, 199-221). DYRK1A is a dose-sensitive gene, and slight changes in its protein expression will produce obvious clinical phenotypes. The expression of DYRK1A is up-regulated by about 1.5 times in individuals with Down syndrome (Guimera, J et.al Genomics 1999, 57, 407-418), overexpression of DYRK1A in animal models also produces Down syndrome-related morphological and cognitive deficits (Arbones, M.L et.al Pharmacol. Ther. 2019, 194, 199-221).

Contents of the invention

In one or more embodiments of the present application, the compound of the present application has high CLK and/or DYRK kinase inhibitory activity and cell proliferation inhibitory activity in vitro.

One or more embodiments of the present application provide compounds represented by general formula (I):

Or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereoisomers or mixtures thereof, or pharmaceutically acceptable salts and deuteriums thereof ,

in:

X ¹ and X ² are each independently CH ₂ , CH, O, NH, or S; when X ¹ and X ² are CH at the same time, X ¹ and X ² are linked by a double bond;

X ⁶ is CR ⁶ , N, O, or S;

R ⁶ is H, halogen, hydroxyl, amino, -C(O)NH ₂ , CN, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy, halogenated C ₁ ~C ₆ alkyl, hydroxyl substitution C ₁ ~ C ₆ alkyl;

Ring A is a substituted or unsubstituted five-membered or six-membered aryl or heteroaryl group, wherein the heteroatoms are selected from N, O, and S; the substituents of the A ring are selected from halogen, hydroxyl, amino, -C (O) NH ₂ , CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogenated C ₁ -C ₆ alkyl, and hydroxy substituted C ₁ -C ₆ alkyl;

X ⁷ is CR ⁶ or N;

^X8 is O or NH;

R ¹ is H, C ₁ to C ₆ alkyl, C ₃ to C ₆ cycloalkyl, C ₂ to C ₆ heterocycloalkyl, -(CH ₂ ) _p C(O)R ⁷ , C ₅ to C ₁₀ Aryl, C ₂ -C ₉ heteroaryl, C ₄ -C ₁₅ fused cycloalkyl, C ₄ -C ₁₅ fused heterocycloalkyl, wherein the C ₁ -C ₆ alkyl, C ₃ -C ₆ Cycloalkyl, C ₂ ~C ₆ heterocycloalkyl, C ₅ ~C ₁₀ aryl, C ₂ ~C ₉ heteroaryl, C ₄ ~C ₁₅ fused cycloalkyl, C ₄ ~C ₁₅ fused heterocycloalkane Each group is independently and optionally substituted by one or more selected from halogen, -CF ₃ , C ₁ to C ₆ alkyl, C ₃ to C ₆ cycloalkyl, and C ₁ to C ₆ alkoxy;

R ⁷ is H, amino, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogenated C ₁ -C ₆ alkyl, halogenated C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ Alkoxy, C ₂ -C ₆ heterocycloalkyl; wherein the heteroatom is selected from N, O, and S; p is 0, 1, 2, or 3;

R ² , R ³ , R ⁴ , and R ⁵ are each independently H, halogen, hydroxyl, amino, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogenated C ₁ -C ₆ alkane Group, C ₁ ~ C ₆ alkyl substituted by hydroxyl, -C(O)NR ⁸ R ⁹ , or -NR ⁸ C(O)R ¹⁰ ;

R ⁸ and R ⁹ are each independently hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, or halogenated C ₁ -C ₃ alkyl;

R ¹⁰ is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogenated C ₁ -C ₆ alkyl, or hydroxy substituted C ₁ -C ₆ alkyl;

-W ¹(CR ^aR ^b) _m3CR ^a＝CR ^a(CR ^aR ^b) _n2W ²-、或-W ¹(CR ^aR ^b) _m4W ³(CR ^aR ^b) _n3W ²-； L is -W ¹ (CR ^a R ^b ) _m1 W ² -,

-W ¹ (CR ^a R ^b ) _m3 CR ^a =CR ^a (CR ^a R ^b ) _n2 W ² -, or -W ¹ (CR ^a R ^b ) _m4 W ³ (CR ^a R ^b ) _n3 W ² -;

W ¹ and W ² are each independently CR ¹² R ¹³ , O, S;

R ¹² and R ¹³ are each independently H, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogenated C _{1 -C 3} alkyl, or -C(O)NH ₂ ;

R ^a and R ^b are each independently H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, halogenated C ₁ -C ₆ alkyl, halogenated C ₃ -C ₆ cycloalkyl, or -C(O)NH ₂ or R ^a and R ^b form a three- to six-membered ring together with the carbon atoms connected to them;

R ¹¹ is H, halogen, hydroxyl, amino, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogenated C ₁ -C ₆ alkyl, hydroxyl substituted C ₁ -C ₆ alkyl, or -C(O)NH ₂ ;

W ³ is O, or S;

m1, m2, m3, m4, n1, n2, and n3 are each independently 0, 1, 2, 3, or 4.

In one or more embodiments, the compound of the present application is a compound shown in general formula (II):

in:

X ¹ and X ² are each independently CH ₂ , O, NH, or S;

X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ are each independently CR ⁶ or N;

R ⁶ is H, halogen, hydroxyl, amino, -C(O)NH ₂ , CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogenated C ₁ -C ₆ alkyl, or hydroxyl Substitute C ₁ ~ C ₆ alkyl;

^X8 is O or NH;

R ¹ is H, C ₁ to C ₆ alkyl, C ₃ to C ₆ cycloalkyl, or -(CH ₂ ) _p C(O)R ⁷ , wherein the C ₁ to C ₆ alkyl, C ₃ Each of ~C ₆ cycloalkyl is independently and optionally selected from one of halogen, -CF ₃ , C ₁ ~C ₆ alkyl, C ₃ ~C ₆ cycloalkyl, and C ₁ ~C ₆ alkoxy, or multiple replaced;

R ⁷ is H, amino, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogenated C ₁ -C ₆ alkyl, halogenated C ₃ -C ₆ cycloalkyl, or C _{1 -C 6} alkoxy;

p is 0, 1, 2, or 3;

R ² , R ³ , R ⁴ , and R ⁵ are each independently H, halogen, hydroxyl, amino, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogenated C ₁ -C ₆ alkane group, hydroxyl substituted C ₁ ~ C ₆ alkyl, -C(O)NR ⁸ R ⁹ , or -NR ⁸ C(O)R ¹⁰ ;

R ⁸ and R ⁹ are each independently hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, or halogenated C ₁ -C ₃ alkyl;

R ¹⁰ is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogenated C ₁ -C ₆ alkyl, or hydroxy substituted C ₁ -C ₆ alkyl;

-W ¹(CR ^aR ^b) _m3CR ^a＝CR ^a(CR ^aR ^b) _n2W ²-、或-W ¹(CR ^aR ^b) _m4W ³(CR ^aR ^b) _n3W ²-； L is -W ¹ (CR ^a R ^b ) _m1 W ² -,

-W ¹ (CR ^a R ^b ) _m3 CR ^a =CR ^a (CR ^a R ^b ) _n2 W ² -, or -W ¹ (CR ^a R ^b ) _m4 W ³ (CR ^a R ^b ) _n3 W ² -;

W ¹ and W ² are each independently CR ¹² R ¹³ , O, or S;

R ¹² and R ¹³ are each independently H, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogenated C _{1 -C 3} alkyl, or -C(O)NH ₂ ;

R ^a and R ^b are each independently H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, halogenated C ₁ -C ₆ alkyl, halogenated C ₃ -C ₆ cycloalkyl, or -C(O)NH ₂ or R ^a and R ^b together form a three- to six-membered ring with the carbon atoms connected to them;

R ¹¹ is H, halogen, hydroxyl, amino, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogenated C ₁ -C ₆ alkyl, hydroxyl substituted C ₁ -C ₆ alkyl, or -C(O)NH ₂ ;

W ³ is O, or S;

m1, m2, m3, m4, n1, n2, and n3 are each independently 0, 1, 2, 3, or 4.

In one or more embodiments, R ² , R ³ , R ⁴ , and R ⁵ are each independently H, halogen, amino, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogenated C ₁ -C ₃ alkyl, -C(O)NH ₂ , or -NHC(O)R ¹⁰ , R ¹⁰ is C ₁ -C ₃ alkyl, or halogenated C ₁ -C ₃ alkyl.

In one or more embodiments, X ³ , X ⁴ , X ⁵ , and X ⁶ are each independently CR ⁶ or N; R ⁶ is H, halogen, amino, -C(O)NH ₂ , C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, or halogenated C ₁ -C ₃ alkyl.

In one or more embodiments, X ⁶ is CR ⁶ , N, S; R ⁶ is selected from H, halogen, amino, -C(O)NH ₂ , C ₁ ~C ₃ alkyl, C ₁ ~C ₃ Alkoxy, or halogenated C ₁ -C ₃ alkyl.

In one or more embodiments, ^X7 is CH or N.

In one or more embodiments, R ¹ is H, C ₁ to C ₃ alkyl, or -(CH ₂ ) _p C(O)R ⁷ , wherein the C ₁ to C ₃ alkyl is optionally Substituted by one or more substituents selected from halogen, -CF ₃ , C ₁ ~C ₆ alkyl, C ₃ ~C ₆ cycloalkyl, and C ₁ ~C ₆ alkoxy; R ⁷ is C ₁ -C ₃ alkyl, or C ₃ -C ₆ cycloalkyl; _p is 0 or 1.

In one or more embodiments, R ¹ is H, C ₁ -C ₃ alkyl, -(CH ₂ ) _p C(O)R ⁷ , C ₅ -C ₁₀ aryl, C ₂ -C ₉ heteroaryl C ₄ -C ₁₀ fused cycloalkyl, or C ₄ -C ₁₀ fused heterocycloalkyl, wherein the C ₁ -C ₃ alkyl, C ₅ -C ₁₀ aryl, C ₂ -C ₉ hetero Aryl, C ₄ -C ₁₀ fused cycloalkyl, C ₄ -C ₁₀ fused heterocycloalkyl are optionally selected from halogen, -CF ₃ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkane substituted by one or more substituents in C ₁ -C ₆ alkoxy; R ⁷ is C ₁ -C ₃ alkyl, halogenated C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkane group, halogenated C ₃ -C ₆ cycloalkyl, or C ₂ -C ₆ heterocycloalkyl; the heteroatom is selected from N, O, and S; p is 0 to 1.

In one or more embodiments, R ¹ is -CH ₃ ,

In one or more embodiments, R ¹ is -CH ₃ ,

In one or more embodiments, X ¹ is O, NH, or S; X ² is CH ₂ , O, or CH.

In one or more embodiments, L is -W ¹ (CR ^a R ^b ) _m1 W ² -;

W ¹ and W ² are each independently CR ¹² R ¹³ , O, S;

R ¹² and R ¹³ are each independently H, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogenated C _{1 -C 3} alkyl, or -C(O)NH ₂ ;

R ^a and R ^b are each independently H, C ₁ to C ₃ alkyl, C ₁ to C ₃ alkoxy, or halogenated C ₁ to C ₃ alkyl, or R ^a and R ^b are jointly form three- to six-membered rings;

m1 is 0, 1, 2 or 3.

In one or more embodiments, W ¹ , W ² are CH ₂ or O.

-W ¹(CR ^aR ^b) _m3CR ^a＝CR ^a(CR ^aR ^b) _n2W ²-、或-W ¹(CR ^aR ^b) _m4W ³(CR ^aR ^b) _n3W ²-；优选地，L为

In one or more embodiments, L is

-W ¹ (CR ^a R ^b ) _m3 CR ^a =CR ^a (CR ^a R ^b ) _n2 W ² -, or -W ¹ (CR ^a R ^b ) _m4 W ³ (CR ^a R ^b ) _n3 W ² -; Preferably, L is

CR ¹² R ¹³ , O, S, R ¹² and R ¹³ are each independently H, C ₁ to C ₃ alkyl, C ₁ to C ₃ alkoxy, halogenated C ₁ to C ₃ alkyl, or -C (O) _NH2 ;

R ^a and R ^b are each independently H, C ₁ to C ₃ alkyl, C ₁ to C ₃ alkoxy, a halogenated C ₁ to C ₃ alkyl, or the carbon atom to which R ^a and R ^b are connected form three- to six-membered rings;

m2, m3, m4, n1, n2, n3 are 0, 1, 2, or 3.

In one or more embodiments, W ¹ , W ² are CH ₂ or O.

In one or more embodiments, L is

m is 2, 3, or 4;

n is 1, 2, or 3.

In one or more embodiments, L is

m is 2, 3, or 4;

n is 1, 2, or 3.

In one or more embodiments, the compound of the present application is a compound shown in general formula (III):

Wherein, X ¹ , X ² , X ⁶ , X ⁸ , R ¹ , L are as defined above;

X ³ , X ⁴ , X ⁵ are as defined above.

In one or more embodiments, the compound of the present application is a compound shown in general formula (IV):

Wherein, X ¹ , X ⁶ , X ⁷ , X ⁸ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and L are as defined above;

X ³ , X ⁴ , X ⁵ are as defined above.

In one or more embodiments, the compound of the present application is a compound shown in general formula (V):

Wherein, X ¹ , X ⁶ , X ⁸ , R ¹ , L are as defined above;

X ³ , X ⁴ , X ⁵ are as defined above.

In one or more embodiments, the compound of the present application is a compound shown in general formula (VI):

Wherein, X ¹ , X ⁶ , X ⁸ , R ¹ , L are as defined above;

X ³ , X ⁴ , X ⁵ are as defined above.

In one or more embodiments, the compound of the present application is a compound shown in general formula (VII):

Wherein, X ¹ , X ² , X ⁶ , X ⁷ , X ⁸ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and L are as defined above;

X ⁹ and X ¹⁰ are each independently CR ¹⁴ , N, O, or S; preferably, X ⁶ is S, X ⁹ is N, and X ¹⁰ is CH;

R ¹⁴ is H, halogen, hydroxyl, amino, -C(O)NH ₂ , CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogenated C ₁ -C ₆ alkyl, or hydroxyl Substitute C ₁ -C ₆ alkyl.

In one or more embodiments, the compound of the present application has the following structure:

One or more embodiments of the present application provide a pharmaceutical composition, which comprises the compound of the present application, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, Diastereomers or their mixtures, or their pharmaceutically acceptable salts, deuterated substances, and pharmaceutically acceptable diluents or carriers.

One or more embodiments of the present application provide the compound of the present application, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereoisomers Or a mixture thereof, or a pharmaceutically acceptable salt, deuterated substance thereof, or the application of the pharmaceutical composition of the present application in the preparation of DYRK1a and/or CLK inhibitor drugs.

In one or more embodiments, the CLK inhibitor is selected from one or more of CLK1, CLK2 and CLK4 inhibitors.

One or more embodiments of the present application provide the compound of the present application, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereoisomers or a mixture thereof, or a pharmaceutically acceptable salt, a deuterated product thereof, or a use of the pharmaceutical composition of the present application in the preparation of a medicament for preventing and/or treating DYRK1a and/or CLK-related cancers.

In one or more embodiments, the cancer is selected from liver cancer, colorectal cancer, breast cancer, pancreatic cancer, leukemia, lymphoma, sarcoma, ovarian cancer, lung cancer, melanoma, squamous cell carcinoma, multiple myeloma One or more of , prostate cancer, gastrointestinal tumor, malignant glioma, squamous cell carcinoma of the head and neck, and pancreatic ductal carcinoma.

One or more embodiments of the present application provide the compound of the present application, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereoisomers or a mixture thereof, or a pharmaceutically acceptable salt, a deuterated product thereof, or a pharmaceutical composition of the present application in the preparation of a medicine for preventing and/or treating DYRK1a and/or CLK-related bone or cartilage-related diseases.

In one or more embodiments, the bone or cartilage-related disease is selected from osteoarthritis, osteochondral dysplasia, axial spondylitis, costochondritis, degenerative disc disease, degenerative spondylolisthesis, elbow joint development Unfavorable, juvenile idiopathic arthritis, osteoarthritis, osteochondritis dissecans, Panner disease, reactive arthritis, relapsing polychondritis, rheumatoid arthritis, sacroiliac joint dysfunction, and septic arthritis one or more of.

One or more embodiments of the present application provide the compound of the present application, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereoisomers Or a mixture thereof, or a pharmaceutically acceptable salt, a deuterated product thereof, or the use of the pharmaceutical composition of the present application in the medicine for preventing and/or treating DYRK1a and/or CLK-related fibrotic diseases.

In one or more embodiments, the fibrotic disease is selected from pulmonary fibrosis, cutaneous fibrosis, scleroderma, progressive systemic fibrosis, glomerulosclerosis, glomerulonephritis, hypertrophic scarring, uterine Fibrosis, renal fibrosis, cirrhosis, hepatic fibrosis, abdominal adhesions, pelvic adhesions, spinal adhesions, tendon adhesions, chronic obstructive pulmonary disease, fibrosis after myocardial infarction, fibrosis associated with diffuse or interstitial lung disease, and Scarring, central nervous system fibrosis, post-stroke fibrosis, fibrosis associated with neurodegenerative diseases such as Alzheimer's or multiple sclerosis, fibrosis associated with proliferative vitreoretinopathy, restenosis, intrauterine Membranous disease, ischemic disease, and radiation fibrosis.

One or more embodiments of the present application provide the compound of the present application or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereoisomers or Its mixture, or its pharmaceutically acceptable salt, deuterium, or the pharmaceutical composition of the present application is used for preventing and/or treating DYRK1a and/or CLK-related inflammatory diseases or autoimmune diseases, neurodegenerative diseases , hereditary diseases, metabolic diseases, infectious diseases or other diseases.

In one or more embodiments, the inflammatory disease or autoimmune disease is selected from psoriasis, systemic lupus erythematosus, hepatitis, inflammatory bowel disease, neuroinflammation, Hashimoto's thyroiditis, allergic purpura, One or more of Sjogren's syndrome and Wegener's granulomatosis.

In one or more embodiments, the neurodegenerative disease is selected from one or more of Alzheimer's disease, dementia, tauopathy, and Parkinson's disease.

In one or more embodiments, the genetic disease is selected from Ehlers-Danlos syndrome, hemochromatosis, hyperimmunoglobulin D syndrome, familial Mediterranean fever, tumor necrosis factor receptor-associated periodic fever syndrome, and one or more of CDKL5 deficiency.

In one or more embodiments, the metabolic disease is selected from one or more of type I and type II diabetes, abnormal metabolism of folic acid and methionine, Duchenne muscular dystrophy, and gout.

In one or more embodiments, the infectious disease is selected from one or more of viral infection, Lyme disease, Whipple's disease, and anemia and infection caused by unicellular parasites.

In one or more embodiments, the other disease is selected from the group consisting of celiac disease, non-celiac gluten sensitivity, sarcoidosis, Down syndrome, Phelan-McDermid syndrome, and autism one or more.

One or more embodiments of the present application provide a preparation method of a compound of formula (II), comprising the following steps:

The compound represented by formula (VIII) is placed in an organic solvent, and a ring-closing reaction occurs under alkaline conditions to generate the target product;

Among them, X ¹ , X ² , X ^{3 ,} X ⁴ , X 5 , X ⁶ , X ⁷ , X ⁸ , R ¹ , R 2 , R ³ , R ⁴ , ^{R 5 ,} R ^a , R ^b , W ¹ , m1 is as defined above;

W ² is O;

^Y is H, 2-(trimethylsilyl)ethoxymethyl, or 4-methylbenzenesulfonyl;

Wherein, when Y ¹ is 2-(trimethylsilyl)ethoxymethyl or 4-methylbenzenesulfonyl, the step of deprotection is also included after ring closure; when Y ¹ is 2-(trimethylsilane For ethoxymethyl groups, the deprotection conditions are: dioxane hydrochloride solution followed by ammonia methanol solution, trifluoroacetic acid followed by ammonia methanol solution, tetrabutylammonium fluoride tetrahydrofuran solution followed by ammonia Methanol solution; when ^Y1 is 4-methylbenzenesulfonyl, the deprotection conditions are: lithium hydroxide/methanol/water, sodium hydroxide/methanol/water, potassium hydroxide/methanol/water, potassium carbonate/methanol / water, tetrahydrofuran solution of tetrabutylammonium fluoride, dioxane hydrochloride solution;

Y ² is H, 4-methoxybenzyl, tetrahydropyranyl, or benzyl;

^Y3 is H, halogen, methylsulfonyloxy, 4-methylbenzenesulfonyloxy, or trifluoromethanesulfonyloxy;

The organic solvent is selected from N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, N-methylpyrrolidone, and acetonitrile;

The base is selected from cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, potassium tert-butoxide, and sodium tert-butoxide.

One or more embodiments of the present application provide a preparation method of a compound of formula (II), comprising the following steps:

The compound shown in the formula (IX) is placed in an organic solvent, and a ring-closing reaction occurs under alkaline conditions to generate the target product;

Among them, X ¹ , X ² , X ^{3 ,} X ⁴ , X 5 , X ⁶ , X ⁷ , X ⁸ , R 1 , R ² , R ³ , R ⁴ , ^{R 5 ,} R ^a , R ^b , W ² , m1 is as defined above;

W ¹ is O;

^Y is H, 2-(trimethylsilyl)ethoxymethyl, or 4-methylbenzenesulfonyl;

Wherein, when Y ¹ is 2-(trimethylsilyl)ethoxymethyl or 4-methylbenzenesulfonyl, the step of deprotection is also included after ring closure; when Y ¹ is 2-(trimethylsilane For ethoxymethyl groups, the deprotection conditions are: dioxane hydrochloride solution followed by ammonia methanol solution, trifluoroacetic acid followed by ammonia methanol solution, tetrabutylammonium fluoride tetrahydrofuran solution followed by ammonia Methanol solution; when ^Y1 is 4-methylbenzenesulfonyl, the deprotection conditions are: lithium hydroxide/methanol/water, sodium hydroxide/methanol/water, potassium hydroxide/methanol/water, potassium carbonate/methanol / water, tetrahydrofuran solution of tetrabutylammonium fluoride, dioxane hydrochloride solution;

Y ² is H, 4-methoxybenzyl, tetrahydropyranyl, or benzyl;

^Y3 is H, halogen, methylsulfonyloxy, 4-methylbenzenesulfonyloxy, or trifluoromethanesulfonyloxy;

The organic solvent is N, N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, N-methylpyrrolidone, or acetonitrile;

The base is cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, potassium tert-butoxide, or sodium tert-butoxide.

One or more embodiments of the present application provide a preparation method of a compound of formula (II), comprising the following steps:

The compound of formula (X) is placed in an organic solvent, and a ring-closing reaction occurs under alkaline conditions to generate the target product;

Wherein, X ² , X ³ , X ⁴ , X ⁷ , X ⁸ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^a , R ^b , W ¹ , W ² , m1 are as defined above;

^X1 is NH or O;

Wherein, X ⁵ or X ⁶ is N, and m1 is not 0;

^Y is H, 2-(trimethylsilyl)ethoxymethyl, or 4-methylbenzenesulfonyl;

Wherein, when Y ¹ is 2-(trimethylsilyl)ethoxymethyl or 4-methylbenzenesulfonyl, the step of deprotection is also included after ring closure; when Y ¹ is 2-(trimethylsilane In the case of ethoxymethyl groups, the deprotection conditions are: dioxane hydrochloride solution followed by ammonia methanol solution, trifluoroacetic acid followed by ammonia methanol solution, tetrabutylammonium fluoride tetrahydrofuran solution followed by ammonia Methanol solution; when ^Y1 is 4-methylbenzenesulfonyl, the deprotection conditions are: lithium hydroxide/methanol/water, sodium hydroxide/methanol/water, potassium hydroxide/methanol/water, potassium carbonate/methanol / water, tetrahydrofuran solution of tetrabutylammonium fluoride, dioxane hydrochloride solution;

^Y3 is H, halogen, methylsulfonyloxy, 4-methylbenzenesulfonyloxy, trifluoromethanesulfonyloxy, 4-nitrobenzenesulfonyloxy, trifluoroethoxy, or methyl Sulfone group;

When ^X is NH, the organic solvent is selected from N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, or methyltetrahydrofuran; the base is selected from N , N-diisopropylethylamine, triethylamine, and N-methylmorpholine; when ^X is O, the organic solvent is selected from tetrahydrofuran, dichloromethane, and methyltetrahydrofuran; the base is selected from From sodium hydride, potassium tert-butoxide, and sodium tert-butoxide.

One or more embodiments of the present application provide the compound shown in formula (VIII):

Among them, X ¹ , X ² , X ^{3 ,} X ⁴ , X 5 , X ⁶ , X ⁷ , X ⁸ , R ¹ , R 2 , R ³ , R ⁴ , ^{R 5 ,} R ^a , R ^b , W ¹ , W ² , m1 are as defined above;

Y ^is H, 2-(trimethylsilyl)ethoxymethyl, 4-methylbenzenesulfonyl, benzoyl, pivaloyl, tert-butoxycarbonyl, or benzyloxycarbonyl;

^Y is H, 4-methoxybenzyl, tetrahydropyranyl, benzyl, tert-butyldimethylsilyl, or benzoyl;

Y ³ is H, halogen, methylsulfonyloxy, 4-methylbenzenesulfonyloxy, trifluoromethanesulfonyloxy, or 4-nitrobenzenesulfonyloxy.

One or more embodiments of the present application provide compounds shown in formula (IX):

Among them, X ¹ , X ² , X ^{3 ,} X ⁴ , X 5 , X ⁶ , X ⁷ , X ⁸ , R ¹ , R 2 , R ³ , R ⁴ , ^{R 5 ,} R ^a , R ^b , W ¹ , W ² , m1 are as defined above;

Y ^is H, 2-(trimethylsilyl)ethoxymethyl, 4-methylbenzenesulfonyl, benzoyl, pivaloyl, tert-butoxycarbonyl, or benzyloxycarbonyl;

^Y is H, 4-methoxybenzyl, tetrahydropyranyl, benzyl, tert-butyldimethylsilyl, or benzoyl;

Y ³ is H, halogen, methylsulfonyloxy, 4-methylbenzenesulfonyloxy, trifluoromethanesulfonyloxy, or 4-nitrobenzenesulfonyloxy.

One or more embodiments of the present application provide compounds represented by formula (X):

Among them, X ¹ , X ² , X ^{3 ,} X ⁴ , X 5 , X ⁶ , X ⁷ , X ⁸ , R ¹ , R 2 , R ³ , R ⁴ , ^{R 5 ,} R ^a , R ^b , W ¹ , W ² , m1 are as defined above;

Y ^is H, 2-(trimethylsilyl)ethoxymethyl, 4-methylbenzenesulfonyl, benzoyl, pivaloyl, tert-butoxycarbonyl, or benzyloxycarbonyl;

^Y3 is H, halogen, methylsulfonyloxy, 4-methylbenzenesulfonyloxy, trifluoromethanesulfonyloxy, 4-nitrobenzenesulfonyloxy, trifluoroethoxy, or methyl sulfone.

One or more embodiments of the present application provide the compound represented by formula (I'), or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, Diastereomers or their mixtures, or their pharmaceutically acceptable salts, deuterated substances:

in:

X ¹ and X ² are each independently selected from CH ₂ , O, NH, S;

X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ are each independently selected from CR ⁶ or N; R ⁶ is selected from H, halogen, hydroxyl, amino, -C(O)NH ₂ , CN, C ₁ ~C ₆ alkyl, C ₁ ~ C ₆ alkoxy, halogenated C ₁ ~ C ₆ alkyl, hydroxyl substituted C ₁ ~ C ₆ alkyl;

^X is selected from O or NH;

R ¹ is selected from H, C ₁ to C ₆ alkyl, C ₃ to C ₆ cycloalkyl, -(CH2) _p C(O)R ⁷ , wherein the C ₁ to C ₆ alkyl, C ₃ to Each C ₆ cycloalkyl is independently and optionally selected from one or more of halogen, -CF ₃ , C ₁ to C ₆ alkyl, C ₃ to C ₆ cycloalkyl, and C ₁ to C ₆ alkoxy Substituted; R ⁷ is selected from H, amino, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogenated C ₁ -C ₆ alkyl, halogenated C ₃ -C ₆ cycloalkyl, C ₁ ~ C ₆ alkoxy; _p is selected from 0,1,2,3;

R ² , R ³ , R ⁴ , and R ⁵ are each independently selected from H, halogen, hydroxyl, amino, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogenated C ₁ -C ₆ Alkyl, hydroxyl substituted C ₁ to C ₆ alkyl, -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ¹⁰ ; R ⁸ and R ⁹ are each independently selected from hydrogen, C ₁ to C ₃ Alkyl, C ₁ -C ₃ alkoxy, halogenated C ₁ -C ₃ alkyl; R ¹⁰ is selected from C ₁ -C ₆ alkyl, C _{1 -C 6} alkoxy, halogenated C ₁ -C ₆ Alkyl, hydroxyl substituted C ₁ ~ C ₆ alkyl;

-W ¹(CR ^aR ^b) _m3CR ^a＝CR ^a(CR ^aR ^b) _n2W ²-、-W ¹(CR ^aR ^b) _m4W ³(CR ^aR ^b) _n3W ²-；其中W ¹、W ²各自独立地选自CR ¹²R ¹³、O、S；R ¹²、R ¹³各自独立地选自H、C ₁～C ₃烷基、C ₁～C ₃烷氧基、卤代C ₁～C ₃烷基、-C(O)NH ₂；R ^a、R ^b各自独立地选自H、C ₁～C ₆烷基、C ₃～C ₆环烷基、C ₁～C ₆烷氧基、卤代C ₁～C ₆烷基、卤代C ₃～C ₆环烷基、-C(O)NH ₂或R ^a和R ^b与其相连的碳原子共同形成三到六元环；R ¹¹选自H、卤素、羟基、氨基、CN、C ₁～C ₆烷基、C ₁～C ₆烷氧基、卤代C ₁～C ₆烷基、羟基取代C ₁～C ₆烷基、-C(O)NH ₂；W ³选自O、S；m1、m2、m3、m4、n1、n2、n3各自独立地选自0，1，2，3，4。 L is selected from -W ¹ (CR ^a R ^b ) _m1 W ² -,

-W ¹ (CR ^a R ^b ) _m3 CR ^a =CR ^a (CR ^a R ^b ) _n2 W ² -, -W ¹ (CR ^a R ^b ) _m4 W ³ (CR ^a R ^b ) _n3 W ² -; where W ¹ and W ² are each independently selected from CR ¹² R ¹³ , O, S; R ¹² and R ¹³ are each independently selected from H, C ₁ to C ₃ alkyl, C ₁ to C ₃ alkoxy, halogenated C ₁ ~C ₃ alkyl, -C(O)NH ₂ ; R ^a , R ^b are each independently selected from H, C ₁ ~C ₆ alkyl, C ₃ ~C ₆ cycloalkyl, C ₁ ~C ₆ Alkoxy, halogenated C ₁ -C ₆ alkyl, halogenated C ₃ -C ₆ cycloalkyl, -C(O)NH ₂ or R ^a and R ^b together form a three- to six-membered ring ; R ¹¹ is selected from H, halogen, hydroxyl, amino, CN, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy, halogenated C ₁ ~C ₆ alkyl, hydroxyl substituted C ₁ ~C ₆ alkane Group, -C(O)NH ₂ ; W ³ is selected from O, S; m1, m2, m3, m4, n1, n2, n3 are each independently selected from 0, 1, 2, 3, 4.

Further, wherein R ² , R ³ , R ⁴ , and R ⁵ are each independently selected from H, halogen, amino, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogenated C ₁ -C ₃ Alkyl, -C(O)NH ₂ , -NHC(O)R ¹⁰ , R ¹⁰ is selected from C ₁ -C ₃ alkyl, halogenated C ₁ -C ₃ alkyl.

X ³ , X ⁴ , X ⁵ , X ⁶ are each independently selected from CR ⁶ or N; R ⁶ is selected from H, halogen, amino, -C(O)NH ₂ , C ₁ ~C ₃ alkyl, C ₁ ~ C ₃ alkoxy, halogenated C ₁ -C ₃ alkyl.

^X7 is selected from CH or N.

R ¹ is selected from H, C ₁ to C ₃ alkyl, -(CH2) _p C(O)R ⁷ , wherein said C ₁ to C ₃ alkyl is optionally selected from halogen, -CF ₃ , C ₁ ~ C ₆ alkyl, C ₃ ~ C ₆ cycloalkyl, C ₁ ~ C ₆ alkoxy one or more substituents; R ⁷ is selected from C ₁ ~ C ₃ alkyl, C ₃ ~ C _Cycloalkyl ; p is selected from 0,1. Furthermore, R ¹ is selected from -CH ₃ ,

^X1 is selected from O, NH, S.

L is selected from -W ¹ (CR ^a R ^b ) _m1 W ² -; wherein W ¹ and W ² are each independently selected from CR ¹² R ¹³ , O, S, R ¹² and R ¹³ are each independently selected from H, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogenated C ₁ -C ₃ alkyl, -C(O)NH ₂ ; R ^a and R ^b are each independently selected from H, C ₁ -C ₃ alkyl, C ₁ ~C ₃ alkoxy, halogenated C ₁ ~C ₃ alkyl or R ^a and R ^b together form a three to six-membered ring with the carbon atoms connected to them; m1 is selected from 0, 1, 2, 3; Further, W ¹ and W ² are preferably CH ₂ or O.

-W ¹(CR ^aR ^b) _m3CR ^a＝CR ^a(CR ^aR ^b) _n2W ²-、-W ¹(CR ^aR ^b) _m4W ³(CR ^aR ^b) _n3W ²-；CR ¹²R ¹³、O、S，R ¹²、R ¹³各自独立地选自H、C ₁～C ₃烷基、C ₁～C ₃烷氧基、卤代C ₁～C ₃烷基、-C(O)NH ₂；R ^a、R ^b各自独立地选自H、C ₁～C ₃烷基、C ₁～C ₃烷氧基、卤代C ₁～C ₃烷基或R ^a和R ^b与其相连的碳原子共同形成三到六元环；m2、m3、m4、n1、n2、n3选自0，1，2，3；进一步地，W ¹、W ²优选为CH ₂或O。 or L from

-W ¹ (CR ^a R ^b ) _m3 CR ^a =CR ^a (CR ^a R ^b ) _n2 W ² -, -W ¹ (CR ^a R ^b ) _m4 W ³ (CR ^a R ^b ) _n3 W ² -; CR ¹² R ¹³ , O, S, R ¹² and R ¹³ are each independently selected from H, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogenated C ₁ -C ₃ alkyl, -C( O) NH ₂ ; R ^a and R ^b are each independently selected from H, C ₁ to C ₃ alkyl, C ₁ to C ₃ alkoxy, halogenated C ₁ to C ₃ alkyl or R ^a and R ^b with The connected carbon atoms together form a three- to six-membered ring; m2, m3, m4, n1, n2, and n3 are selected from 0, 1, 2, and 3; further, W ¹ and W ² are preferably CH ₂ or O.

m选自2，3，4；n选自1，2，3。 Furthermore, L is selected from

m is selected from 2,3,4; n is selected from 1,2,3.

In one or more embodiments, R ² , R ³ , R ⁴ , and R ⁵ are each independently selected from H, halogen, amino, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halo C ₁ -C ₃ alkyl, -C(O)NH ₂ , -NHC(O)R ¹⁰ , R ¹⁰ is selected from C ₁ -C ₃ alkyl, halogenated C ₁ -C ₃ alkyl.

In one or more embodiments, X ³ , X ⁴ , X ⁵ , and X ⁶ are each independently selected from CR ⁶ or N; R ⁶ is selected from H, halogen, amino, -C(O)NH ₂ , C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogenated C ₁ -C ₃ alkyl.

In one or more embodiments, ^X7 is selected from CH or N.

In one or more embodiments, R ¹ is selected from H, C ₁ to C ₃ alkyl, -(CH ₂ ) _p C(O)R ⁷ , wherein the C ₁ to C ₃ alkyl is optionally Substituted by one or more substituents selected from halogen, -CF ₃ , C ₁ ~C ₆ alkyl, C ₃ ~C ₆ cycloalkyl, C ₁ ~C ₆ alkoxy; R ⁷ is selected from C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl; p is selected from 0,1.

In one or more embodiments, R ¹ is selected from -CH ₃ ,

In one or more embodiments, X ^is selected from O, NH, S.

In one or more embodiments, L is selected from -W ¹ (CR ^a R ^b ) _m1 W ² -; wherein W ¹ and W ² are each independently selected from CR ¹² R ¹³ , O, S, R ¹² , R ¹³ are each independently selected from H, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogenated C ₁ -C ₃ alkyl, -C(O)NH ₂ ; R ^a , R ^b are each independently is selected from H, C ₁ to C ₃ alkyl, C ₁ to C ₃ alkoxy, halogenated C ₁ to C ₃ alkyl, or R ^a and R ^b together form a three to six membered ring with the carbon atoms to which they are attached; m1 is selected from 0, 1, 2, 3; further, W ¹ and W ² are preferably CH ₂ or O.

-W ¹(CR ^aR ^b) _m3CR ^a＝CR ^a(CR ^aR ^b) _n2W ²-、-W ¹(CR ^aR ^b) _m4W ³(CR ^aR ^b) _n3W ²-；CR ¹²R ¹³、O、S，R ¹²、R ¹³各自独立地选自H、C ₁～C ₃烷基、C ₁～C ₃烷氧基、卤代C ₁～C ₃烷基、-C(O)NH ₂；R ^a、R ^b各自独立地选自H、C ₁～C ₃烷基、C ₁～C ₃烷氧基、卤代C ₁～C ₃烷基或R ^a和R ^b与其相连的碳原子共同形成三到六元环；m2、m3、m4、n1、n2、n3选自0，1，2，3；进一步地，W ¹、W ²优选为CH ₂或O。 In one or more embodiments, L is selected from

-W ¹ (CR ^a R ^b ) _m3 CR ^a =CR ^a (CR ^a R ^b ) _n2 W ² -, -W ¹ (CR ^a R ^b ) _m4 W ³ (CR ^a R ^b ) _n3 W ² -; CR ¹² R ¹³ , O, S, R ¹² and R ¹³ are each independently selected from H, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogenated C ₁ -C ₃ alkyl, -C( O) NH ₂ ; R ^a and R ^b are each independently selected from H, C ₁ to C ₃ alkyl, C ₁ to C ₃ alkoxy, halogenated C ₁ to C ₃ alkyl or R ^a and R ^b with The connected carbon atoms together form a three- to six-membered ring; m2, m3, m4, n1, n2, and n3 are selected from 0, 1, 2, and 3; further, W ¹ and W ² are preferably CH ₂ or O.

m选自2，3，4；n选自1，2，3。 In one or more embodiments, L is selected from

m is selected from 2,3,4; n is selected from 1,2,3.

One or more embodiments of the present application also provide compounds represented by formula (II'), or tautomers, cis-trans isomers, mesoforms, racemates, enantiomers thereof , diastereoisomers or mixtures thereof, or pharmaceutically acceptable salts and deuterated substances thereof:

Wherein, X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁸ , R ¹ , and L are as defined above.

One or more embodiments of the present application also provide compounds represented by formula (III'), or tautomers, cis-trans isomers, mesoforms, racemates, enantiomers thereof , diastereoisomers or mixtures thereof, or pharmaceutically acceptable salts and deuterated substances thereof:

Wherein, X ¹ , X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and L are as defined above.

One or more embodiments of the present application also provide compounds represented by formula (IV'), or tautomers, cis-trans isomers, mesoforms, racemates, enantiomers thereof , diastereoisomers or mixtures thereof, or pharmaceutically acceptable salts and deuterated substances thereof:

Wherein, X ¹ , X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁸ , R ¹ , and L are as defined above.

One or more embodiments of the present application also provide compounds represented by formula (V'), or tautomers, cis-trans isomers, mesoforms, racemates, enantiomers thereof , diastereoisomers or mixtures thereof, or pharmaceutically acceptable salts and deuterated substances thereof:

Wherein, X ¹ , X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁸ , R ¹ , W ¹ , W ² , R ^a , R ^b , and m1 are as defined above.

One or more embodiments of the present application provide the compound of the following structure, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereoisomers body or its mixture, or its pharmaceutically acceptable salt, deuterated substance:

One or more embodiments of the present application provide the use of the compound of the present application in the preparation of DYRK1a and/or CLK inhibitor drugs.

In one or more embodiments, the CLK inhibitor may be selected from CLK1 and/or CLK2 and/or CLK4 inhibitors.

One or more embodiments of the present application provide the use of the compound of the present application in the preparation of a medicament for preventing and/or treating DYRK1a and/or CLK-related cancers.

In one or more embodiments, the cancer may be selected from liver cancer, colorectal cancer, breast cancer, pancreatic cancer, leukemia, lymphoma, sarcoma, ovarian cancer, lung cancer, melanoma, squamous cell carcinoma, multiple myeloid tumor, prostate cancer, gastrointestinal tumor, malignant glioma, head and neck squamous cell carcinoma, pancreatic ductal carcinoma.

One or more embodiments of the present application provide the use of the compound of the present application in the preparation of a medicament for preventing and/or treating DYRK1a and/or CLK-related bone or cartilage-related diseases.

In one or more embodiments, the bone or cartilage-related disease may be selected from osteoarthritis, osteochondral dysplasia, axial spondylitis, costochondritis, degenerative disc disease, degenerative spondylolisthesis, elbow joint Dysplasia, juvenile idiopathic arthritis, osteoarthritis, osteochondritis dissecans, Panner disease, reactive arthritis, relapsing polychondritis, rheumatoid arthritis, sacroiliac joint dysfunction, septic arthritis .

One or more embodiments of the present application provide the use of the compound of the present application in the preparation of a medicament for preventing and/or treating DYRK1a and/or CLK-related fibrotic diseases.

In one or more embodiments, the fibrotic disease is selected from pulmonary fibrosis, cutaneous fibrosis, scleroderma, progressive systemic fibrosis, glomerulosclerosis, glomerulonephritis, hypertrophic scarring, uterine Fibrosis, renal fibrosis, cirrhosis, hepatic fibrosis, abdominal adhesions, pelvic adhesions, spinal adhesions, tendon adhesions, chronic obstructive pulmonary disease, fibrosis after myocardial infarction, fibrosis associated with diffuse or interstitial lung disease, and Scarring, central nervous system fibrosis, post-stroke fibrosis, fibrosis associated with neurodegenerative diseases such as Alzheimer's or multiple sclerosis, fibrosis associated with proliferative vitreoretinopathy, restenosis, intrauterine Membranous disease, ischemic disease, radiation fibrosis.

One or more embodiments of the present application provide that the compound of the present application is used for the prevention and/or treatment of DYRK1a and/or CLK-related inflammatory diseases or autoimmune diseases, neurodegenerative diseases, genetic diseases, metabolic diseases , infectious diseases or other diseases in medicine.

In one or more embodiments, the inflammatory disease or autoimmune disease includes such as psoriasis, systemic lupus erythematosus, hepatitis, inflammatory bowel disease, neuroinflammation, Hashimoto's thyroiditis, allergic purpura, Sjogren's syndrome, Wegener's granulomatosis.

In one or more embodiments, the neurodegenerative disease includes Alzheimer's disease, dementia, tau protein disease, Parkinson's disease; the genetic disease includes Ehlers-Danlos syndrome, hemochromatosis, hyperimmune Globulin D syndrome, familial Mediterranean fever, tumor necrosis factor receptor-associated periodic fever syndrome, CDKL5 deficiency; the metabolic diseases include type I and type II diabetes, abnormal folic acid and methionine metabolism, Du Xing Muscular Dystrophy, Gout.

In one or more embodiments, the infectious diseases include viral infections, Lyme disease, Whipple's disease, anemia and infections caused by unicellular parasites; the other diseases include celiac disease, non-celiac gluten Texture sensitivity, sarcoidosis, Down syndrome, Phelan-McDermid syndrome, autism.

One or more embodiments of the present application provide a synthetic method of the compound of the present application, comprising the following steps:

The compound shown in the formula (VI') is in an organic solvent, and the ring-closing reaction under alkaline conditions generates the target product;

Among them, X ¹ , X ² , X ^{3 ,} X ⁴ , X 5 , X ⁶ , X ⁷ , X ⁸ , R ¹ , R 2 , R ³ , R ⁴ , ^{R 5 ,} R ^a , R ^b , W ¹ , m1 is as defined above;

W ² is O;

Y ^is selected from H, 2-(trimethylsilyl)ethoxymethyl, 4-methylbenzenesulfonyl;

Wherein, when Y ¹ is 2-(trimethylsilyl)ethoxymethyl or 4-methylbenzenesulfonyl, the step of deprotection is also included after ring closure; when Y ¹ is 2-(trimethylsilane When Y) ethoxymethyl group, the condition of deprotection can be: hydrochloric acid dioxane solution then ammonia methanol solution, trifluoroacetic acid then ammonia methanol solution, tetrahydrofuran solution of tetrabutylammonium fluoride then ammonia methanol solution; When Y When ¹ is 4-methylbenzenesulfonyl, the deprotection conditions can be: lithium hydroxide/methanol/water, sodium hydroxide/methanol/water, potassium hydroxide/methanol/water, potassium carbonate/methanol/water, four Tetrahydrofuran solution of butylammonium fluoride, dioxane hydrochloride solution;

^Y2 is selected from H, 4-methoxybenzyl, tetrahydropyranyl, benzyl;

Y ^is selected from H, halogen, methylsulfonyloxy, 4-methylbenzenesulfonyloxy, trifluoromethanesulfonyloxy;

The organic solvent is selected from N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile;

The base is selected from cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, potassium tert-butoxide, sodium tert-butoxide.

One or more embodiments of the present application provide a synthetic method of the compound of the present application, comprising the following steps:

The compound shown in the formula (VII') is in an organic solvent, and the ring-closing reaction under alkaline conditions generates the target product;

Among them, X ¹ , X ² , X ^{3 ,} X ⁴ , X 5 , X ⁶ , X ⁷ , X ⁸ , R 1 , R ² , R ³ , R ⁴ , ^{R 5 ,} R ^a , R ^b , W ² , m1 is as defined above;

W ¹ is O;

Y ^is selected from H, 2-(trimethylsilyl)ethoxymethyl, 4-methylbenzenesulfonyl;

Wherein, when Y ¹ is 2-(trimethylsilyl)ethoxymethyl or 4-methylbenzenesulfonyl, the step of deprotection is also included after ring closure; when Y ¹ is 2-(trimethylsilane When Y) ethoxymethyl group, the condition of deprotection can be: hydrochloric acid dioxane solution then ammonia methanol solution, trifluoroacetic acid then ammonia methanol solution, tetrahydrofuran solution of tetrabutylammonium fluoride then ammonia methanol solution; When Y When ¹ is 4-methylbenzenesulfonyl, the deprotection conditions can be: lithium hydroxide/methanol/water, sodium hydroxide/methanol/water, potassium hydroxide/methanol/water, potassium carbonate/methanol/water, four Tetrahydrofuran solution of butylammonium fluoride, dioxane hydrochloride solution;

^Y2 is selected from H, 4-methoxybenzyl, tetrahydropyranyl, benzyl;

Y ^is selected from H, halogen, methylsulfonyloxy, 4-methylbenzenesulfonyloxy, trifluoromethanesulfonyloxy;

The organic solvent is selected from N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile;

The base is selected from cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, potassium tert-butoxide, sodium tert-butoxide.

One or more embodiments of the present application provide a synthetic method of the compound of the present application, comprising the following steps:

With the compound of formula (VIII') in an organic solvent, ring-closing reaction under basic conditions generates the target product;

Wherein, X ² , X ³ , X ⁴ , X ⁷ , X ⁸ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^a , R ^b , W ¹ , W ² , m1 are as defined above;

^X1 is NH or O;

Wherein, X ⁵ or X ⁶ is N, and m1 is not 0;

Y ^is selected from H, 2-(trimethylsilyl)ethoxymethyl, 4-methylbenzenesulfonyl;

Wherein, when Y ¹ is 2-(trimethylsilyl)ethoxymethyl or 4-methylbenzenesulfonyl, the step of deprotection is also included after ring closure; when Y ¹ is 2-(trimethylsilane When Y) ethoxymethyl group, the condition of deprotection can be: hydrochloric acid dioxane solution then ammonia methanol solution, trifluoroacetic acid then ammonia methanol solution, tetrahydrofuran solution of tetrabutylammonium fluoride then ammonia methanol solution; When Y When ¹ is 4-methylbenzenesulfonyl, the deprotection conditions can be: lithium hydroxide/methanol/water, sodium hydroxide/methanol/water, potassium hydroxide/methanol/water, potassium carbonate/methanol/water, four Tetrahydrofuran solution of butylammonium fluoride, dioxane hydrochloride solution;

Y ^is selected from H, halogen, methylsulfonyloxy, 4-methylbenzenesulfonyloxy, trifluoromethanesulfonyloxy, 4-nitrobenzenesulfonyloxy, trifluoroethoxy, methyl Sulfone group;

When ^X is NH, the organic solvent is selected from N, N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, methyl tetrahydrofuran; the base is selected from N, N-diisopropylethylamine, triethylamine, N-methylmorpholine; when ^X is O, the organic solvent is selected from tetrahydrofuran, dichloromethane, methyltetrahydrofuran; the base is selected from sodium hydride , potassium tert-butoxide, sodium tert-butoxide.

One or more embodiments of the present application provide the compound shown in formula (VI'):

Among them, X ¹ , X ² , X ^{3 ,} X ⁴ , X 5 , X ⁶ , X ⁷ , X ⁸ , R ¹ , R 2 , R ³ , R ⁴ , ^{R 5 ,} R ^a , R ^b , W ¹ , W ² , m1 are as defined above;

Y ^is selected from H, 2-(trimethylsilyl)ethoxymethyl, 4-methylbenzenesulfonyl, benzoyl, pivaloyl, tert-butoxycarbonyl, benzyloxycarbonyl;

^Y2 is selected from H, 4-methoxybenzyl, tetrahydropyranyl, benzyl, tert-butyldimethylsilyl, benzoyl;

^Y3 is selected from H, halogen, methylsulfonyloxy, 4-methylbenzenesulfonyloxy, trifluoromethanesulfonyloxy, 4-nitrobenzenesulfonyloxy.

One or more embodiments of the present application provide the compound shown in formula (VII'):

Among them, X ¹ , X ² , X ^{3 ,} X ⁴ , X 5 , X ⁶ , X ⁷ , X ⁸ , R ¹ , R 2 , R ³ , R ⁴ , ^{R 5 ,} R ^a , R ^b , W ¹ , W ² , m1 are as defined above;

Y ^is selected from H, 2-(trimethylsilyl)ethoxymethyl, 4-methylbenzenesulfonyl, benzoyl, pivaloyl, tert-butoxycarbonyl, benzyloxycarbonyl;

^Y2 is selected from H, 4-methoxybenzyl, tetrahydropyranyl, benzyl, tert-butyldimethylsilyl, benzoyl;

^Y3 is selected from H, halogen, methylsulfonyloxy, 4-methylbenzenesulfonyloxy, trifluoromethanesulfonyloxy, 4-nitrobenzenesulfonyloxy.

One or more embodiments of the present application provide the compound shown in formula (VIII'):

Among them, X ¹ , X ² , X ^{3 ,} X ⁴ , X 5 , X ⁶ , X ⁷ , X ⁸ , R ¹ , R 2 , R ³ , R ⁴ , ^{R 5 ,} R ^a , R ^b , W ¹ , W ² , m1 are as defined above;

Y ^is selected from H, 2-(trimethylsilyl)ethoxymethyl, 4-methylbenzenesulfonyl, benzoyl, pivaloyl, tert-butoxycarbonyl, benzyloxycarbonyl;

Y ^is selected from H, halogen, methylsulfonyloxy, 4-methylbenzenesulfonyloxy, trifluoromethanesulfonyloxy, 4-nitrobenzenesulfonyloxy, trifluoroethoxy, methyl Sulfone group.

One or more embodiments of the present application also provide a pharmaceutical composition comprising the compound of the present application, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers isomers, diastereoisomers or their mixtures, or their pharmaceutically acceptable salts, deuterated substances, and pharmaceutically acceptable diluents or carriers.

In one or more embodiments, in the pharmaceutical composition described in the present application, the compound of the present application, or its tautomer, cis-trans isomer, mesoform, racemate, enantiomer The isomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts, deuterated species thereof, are present in amounts effective for the treatment of a disease or condition.

One or more embodiments of the present application provide the compound of the present application, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereoisomers The use of a conformer or a mixture thereof, or a pharmaceutically acceptable salt, deuterated product thereof, or a pharmaceutical composition comprising the compound of the present application in the preparation of a medicament as a DYRK1a and/or CLK inhibitor.

In one or more embodiments, the CLK inhibitor may be selected from CLK1 and/or CLK2 and/or CLK4 inhibitors.

One or more embodiments of the present application provide the compound of the present application, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereoisomers Conforms or mixtures thereof, or pharmaceutically acceptable salts, deuteriums thereof, or pharmaceutical compositions comprising the compounds of the present application are used in the preparation of inhibiting DYRK1a and/or CLK activity.

The embodiment of the present application provides the compound of the present application, or its tautomer, cis-trans isomer, mesoform, racemate, enantiomer, diastereoisomer or its The mixture, or its pharmaceutically acceptable salt, deuterated substance, or pharmaceutical composition comprising the compound of the present application is used for preventing and/or treating DYRK1a and/or CLK-related diseases or conditions. The disease or condition is selected from cancer, such as liver cancer, colorectal cancer, breast cancer, pancreatic cancer, leukemia, lymphoma, sarcoma, ovarian cancer, lung cancer, melanoma, squamous cell carcinoma, multiple myeloma, prostate cancer , gastrointestinal tumors, malignant glioma, head and neck squamous cell carcinoma, pancreatic ductal carcinoma; bone or cartilage related diseases, such as osteoarthritis, osteochondral dysplasia, axial spondylitis, costochondritis, degenerative Disc disease, degenerative spondylolisthesis, elbow dysplasia, juvenile idiopathic arthritis, osteoarthritis, osteochondritis dissecans, Panner disease, reactive arthritis, relapsing polychondritis, rheumatoid arthritis , sacroiliac joint dysfunction, septic arthritis; fibrotic diseases such as pulmonary fibrosis, cutaneous fibrosis, scleroderma, progressive systemic fibrosis, glomerulosclerosis, glomerulonephritis, hypertrophic scarring, Uterine fibrosis, renal fibrosis, cirrhosis, hepatic fibrosis, abdominal adhesions, pelvic adhesions, spinal adhesions, tendon adhesions, chronic obstructive pulmonary disease, fibrosis after myocardial infarction, fibrosis associated with diffuse or interstitial lung disease and scarring, central nervous system fibrosis, post-stroke fibrosis, fibrosis associated with neurodegenerative diseases such as Alzheimer's or multiple sclerosis, fibrosis associated with proliferative vitreoretinopathy, restenosis, uterine Endometriosis, ischemic disease, radiation fibrosis; inflammatory or autoimmune disease such as psoriasis, systemic lupus erythematosus, hepatitis, inflammatory bowel disease, neuroinflammation, Hashimoto's thyroiditis, Henoch-Schonlein purpura, Sjögren's syndrome, Wegener's granulomatosis; neurodegenerative diseases, such as Alzheimer's disease, dementia, tauopathy, Parkinson's disease; genetic diseases, such as Ehlers-Danlos syndrome, hemochromatosis , hyperimmunoglobulin D syndrome, familial Mediterranean fever, tumor necrosis factor receptor-associated periodic fever syndrome, CDKL5 deficiency; metabolic disorders such as type 1 and type 2 diabetes mellitus, abnormal folic acid and methionine metabolism , Duchenne muscular dystrophy, gout; infectious diseases such as viral infections, Lyme disease, Whipple's disease, anemia and infections caused by unicellular parasites; other diseases such as celiac disease, non-celiac gluten Texture sensitivity, sarcoidosis, Down syndrome, Phelan-McDermid syndrome, autism.

One or more embodiments of the present application provide the compound of the present application, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereoisomers Constructs or mixtures thereof, or pharmaceutically acceptable salts, deuterated products thereof, and compositions of the present application, which are used as medicines.

One or more embodiments of the present application provide the compound of the present application, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereoisomers Conforms or mixtures thereof, or pharmaceutically acceptable salts, deuterated products, and compositions of the present application, which are DYRK1a and/or CLK inhibitors.

One or more embodiments of the present application provide the compound of the present application, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereoisomers Constructs or mixtures thereof, or pharmaceutically acceptable salts, deuteriums thereof, and compositions of the present application, which are used for treating and/preventing DYRK1a and/or CLK-related cancers.

One or more embodiments of the present application provide the compound of the present application, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereoisomers Constructs or mixtures thereof, or pharmaceutically acceptable salts, deuteriums thereof, and compositions of the present application, which are used for treating and/or preventing DYRK1a and/or CLK-related bone or cartilage-related diseases.

One or more embodiments of the present application provide the compound of the present application, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereoisomers Constructs or mixtures thereof, or pharmaceutically acceptable salts, deuteriums thereof, and compositions of the present application, which are used for treating and/or preventing DYRK1a and/or CLK-related fibrotic diseases.

One or more embodiments of the present application provide the compound of the present application, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereoisomers Conformant or its mixture, or its pharmaceutically acceptable salt, deuterium, and the composition of the present application, it is used for treating and/or preventing DYRK1a and/or CLK related inflammatory disease or autoimmune disease, neurodegenerative disease, hereditary, metabolic, infectious or otherwise.

One or more embodiments of the present application provide methods for treating and/or preventing diseases, comprising administering a therapeutically effective amount of the compound or composition of the present application to a subject in need thereof.

One or more embodiments of the present application provide a method for treating and/or preventing a disease, which comprises treating a therapeutically effective amount of the compound or its tautomer, cis-trans isomer, meso, racemic Isomers, enantiomers, diastereoisomers or mixtures thereof, or pharmaceutically acceptable salts, deuterated products thereof, and the composition of the present application are administered to objects in need.

One or more embodiments of the present application provide a method of inhibiting DYRK1a and/or CLK, which comprises a therapeutically effective amount of the compound or its tautomers, cis-trans isomers, mesoforms, racemic Isomers, enantiomers, diastereoisomers or mixtures thereof, or pharmaceutically acceptable salts, deuterated products thereof, and the composition of the present application are administered to objects in need.

One or more embodiments of the present application provide a method for treating and/or preventing DYRK1a and/or CLK-related cancers, which comprises treating a therapeutically effective amount of the compound or its tautomer, cis-trans isomer, endo The rotamers, racemates, enantiomers, diastereoisomers or mixtures thereof, or their pharmaceutically acceptable salts, deuterated products, and the composition of the present application are administered to objects in need.

One or more embodiments of the present application provide a method for treating and/or preventing DYRK1a and/or CLK-related bone or cartilage-related diseases, which comprises treating a therapeutically effective amount of the compound or its tautomer, cis-trans isomer Body, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or its pharmaceutically acceptable salt, deuterated substance, and the composition of the present application are administered to the need Object.

One or more embodiments of the present application provide a method for treating and/preventing DYRK1a and/or CLK-related fibrotic diseases, which comprises a therapeutically effective amount of the compound or its tautomers, cis-trans isomers, endogenous Racemates, racemates, enantiomers, diastereoisomers or mixtures thereof, or pharmaceutically acceptable salts, deuterated products thereof, and the composition of the present application are administered to subjects in need thereof.

One or more embodiments of the present application provide treatment and/prevention of DYRK1a and/or CLK-related inflammatory diseases or autoimmune diseases, neurodegenerative diseases, genetic diseases, metabolic diseases, infectious diseases or other diseases A method comprising administering a therapeutically effective amount of a compound or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereoisomers or mixtures thereof , or pharmaceutically acceptable salts, deuteriums thereof, and compositions of the present application are administered to objects in need thereof.

Detailed ways

Before further describing the present invention, it should be understood that the present invention is not limited to the specific embodiments described, the terms used herein are only for the purpose of describing specific embodiments, and are not intended to limit it, and the scope of the present invention is only limited in the appended claims and description. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

chemical definition

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The term "alkyl" refers to an aliphatic hydrocarbon group, which refers to a saturated hydrocarbon group. The alkyl moiety may be straight-chain or branched-chain. For example, C1-6 alkyl, C1-4 alkyl or C1-3 alkyl. C1-6 alkyl refers to an alkyl group having 1 to 6 carbon atoms, such as an alkane having 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms base. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2 -Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1, 3-Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc.

The term "ring" refers to any covalently closed structure, including, for example, carbocycles (such as aryl or cycloalkyl), heterocycles (such as heteroaryl or heterocycloalkyl), aromatic groups (such as aryl or heterocycloalkyl), aryl), non-aromatic (such as cycloalkyl or heterocycloalkyl). Rings may be optionally substituted and may be monocyclic or polycyclic. Typical polycyclic rings generally include bicyclic and tricyclic rings. The ring of the present application usually has 1-20 ring atoms, such as 1 ring atom, 2 ring atoms, 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms ring atoms, 9 ring atoms, 10 ring atoms, 11 ring atoms, 12 ring atoms, 13 ring atoms, 14 ring atoms, 15 ring atoms, 16 ring atoms, 17 ring atoms, 18 ring atoms ring atoms, 19 ring atoms or 20 ring atoms.

"Membrane" in the term means the number of skeleton atoms constituting the ring. Typical 5-membered rings include, for example, cyclopentyl, pyrrole, imidazole, thiazole, furan, and thiophene; typical 6-membered rings include, for example, cyclohexyl, pyridine, pyran, pyrazine, thiopyran, pyridazine, pyrimidine, benzene, etc. . Among them, a ring containing heteroatoms in the skeleton atoms is a heterocycle; an aromatic group containing heteroatoms is a heteroaryl group; a non-aromatic group containing heteroatoms is a heterocycloalkyl group, which includes heterocycloalkyl groups.

The term "heteroatom" refers to an atom other than carbon or hydrogen. One or more heteroatoms in the heterocycle of the present application may be independently selected from O, S, N, Si and P, but are not limited thereto.

"Oxo" in the term refers to the replacement of a hydrogen on a carbon with =O.

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

The term "haloalkyl" refers to an alkyl group in which at least one hydrogen is replaced by a halogen atom, such as CF ₃ .

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the cycloalkyl ring contains 3 to 20 (such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, preferably containing 3 to 12 carbon atoms, more preferably containing 3 to 6 carbon atoms, including monocycloalkyl , bicycloalkyl and tricycloalkyl. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Base, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro ring, fused ring and bridged ring cycloalkyl.

The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 (e.g. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms, wherein one or more (for example, 1, 2, 3, or 4) ring atoms are selected from nitrogen, Oxygen or a heteroatom of S(O)r (where r is an integer, 0 to 2), excluding ring portions of -O-O-, -O-S- or -S-S-, the remaining ring atoms being carbon. Preferably contain 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably contain 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably contain 3 to 6 ring atoms, of which 1 to 2 is a heteroatom. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine Base, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc.

Heterocycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio group, heterocycloalkylthio group, oxo group, carboxyl group and carboxylate, cyano group.

Typical heterocycloalkyl groups include, but are not limited to, monovalent radicals derived from the following rings:

These heterocycloalkyl groups can also be represented by commonly understood structural formulas, for example

It should be understood that when a heterocycloalkyl group is attached to two groups depending on the structure or context, the heterocycloalkyl group is a divalent group, ie, there are two points of attachment. In this case, it may also be called a heterocycloalkylene group. Examples of heterocycloalkylene include, but are not limited to, divalent groups formed from the above groups, such as:

The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxy, nitro, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl and carboxylate, cyano.

The term "hydroxyl" refers to a -OH group.

The term "cyano" refers to -CN.

The term "aryl" refers to a 6 to 14 membered (e.g. 6, 7, 8, 9, 10, 11, 12, 13 or 14 membered) all-carbon monocyclic or fused polycyclic ring (also are ring) groups sharing adjacent pairs of carbon atoms, preferably 6 to 10 membered, such as phenyl and naphthyl. Phenyl is more preferred. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, the aryl may be substituted or unsubstituted, and when substituted by When substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro , amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate, cyano .

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (eg 1 , 2, 3 or 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 or 6 membered, containing 1 to 2 heteroatoms; preferred examples are imidazolyl, furyl, thienyl, thiazolyl, pyryl Azolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, tetrazolyl, pyridyl, thienyl, pyrazolyl or pyrimidyl , Thiazolyl; more preferably pyridyl.

Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl and carboxylate, cyano.

"Substitution" refers to one or more hydrogen atoms in the group, preferably up to 5 (such as 1, 2, 3, 4, 5), more preferably 1 to 3 hydrogen atoms can be independently replaced by the corresponding number replaced by substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.

"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example, a "heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes cases where the heterocycle group is substituted with an alkyl group and cases where the heterocycle group is not substituted with an alkyl group .

The term "substituted or unsubstituted" refers herein to any group being monosubstituted or polysubstituted by the specified substituent to the extent such monosubstitution or polysubstitution (including multiple substitutions on the same moiety) is chemically permissible, each Each substituent can be located at any available position on the group and can be attached via any available atom on said substituent. "Any available position" refers to any position on the group that is chemically accessible by methods known in the art or taught herein that do not result in an unduly unstable molecule. When there are two or more substituents on any group, each substituent is defined independently of any other substituent and thus may be the same or different.

"Pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients. The purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.

"Pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other components making up the formulation and/or with the mammal being treated therewith.

"Pharmaceutically acceptable salt" refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has proper biological activity.

"Treatment" is intended to alleviate or eliminate the disease state or disorder being addressed. If the subject has received a therapeutically effective amount of the compound, its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof according to the method described in this application , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and the subject shows an observable and/or detectable reduction or improvement in one or more of the signs and symptoms, the subject is Successfully "cured". It should also be understood that reference to treatment of a disease state or disorder includes not only complete treatment, but also incomplete treatment while achieving some biologically or medically relevant result.

An "effective amount" refers to an amount sufficient to achieve the desired therapeutic effect, eg, an amount that achieves alleviation of symptoms associated with the disease being treated.

表示该化学键可以为单键或双键。

Indicates that the chemical bond can be a single bond or a double bond.

表示其所在的环具有芳香性。

Indicates that the ring it is in is aromatic.

表示其所在的手性碳原子为消旋体。

Indicates that the chiral carbon atom where it is located is a racemate.

In addition, it should be pointed out that the dose and method of use of the compound of the present application depend on many factors, including the patient's age, body weight, sex, natural health status, nutritional status, activity intensity of the compound, time of administration, metabolic rate, severity of the disease, and The subjective judgment of the treating physician. The preferred dosage is 0.001-1000 mg/kg body weight/day.

For the compounds described in this application, for the same compound, if the name is inconsistent with the structural formula, the structural formula of the compound shall prevail.

For L in this application, there is no limitation on the connection method of W ¹ and W ² , that is, one end of W ¹ can be connected to either a single ring or a parallel ring.

-W ¹(CR ^aR ^b) _mCR ^a＝CR ^a(CR ^aR ^b) _nW ²-、-W ¹(CR ^aR ^b) _mW ³(CR ^aR ^b) _nW ²-中括号内的重复单元，每个重复单元中的R ^aR ^b可与其他重复单元中相同或不同。例如对于-W ¹(CR ^aR ^b) _mW ²-，非限制性示例包括

For -W ¹ (CR ^a R ^b ) _m W ² -,

-W ¹ (CR ^a R ^b ) _m CR ^a ＝CR ^a (CR ^a R ^b ) _n W ² -, -W ¹ (CR ^a R ^b ) _m W ³ (CR ^a R ^b ) _n W ² -brackets In the repeating unit, R ^a R ^b in each repeating unit may be the same as or different from other repeating units. For example, for -W ¹ (CR ^a R ^b ) _m W ² -, non-limiting examples include

The disclosure also includes isotopically labeled compounds of the disclosure that are identical to those described herein, but with one or more atoms replaced by an atom of an atomic mass or mass number different from that normally found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I, ¹²⁵ I and ³⁶ Cl, etc.

Certain isotopically-labeled compounds of the disclosure (eg, those labeled ^{with3H and14C} ) are useful in compound and/or substrate tissue distribution assays. Tritiated ( ^ie3H ) and carbon-14 ( ^ie14C ) isotopes are especially preferred for their ease of preparation and detectability. Positron-emitting isotopes, such as ¹⁵ O, ¹³ N, ¹¹ C, and ¹⁸ F, can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures similar to those disclosed in the Schemes and/or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

Furthermore, substitution with heavier isotopes such as deuterium (i.e. ² H) may confer certain therapeutic advantages resulting from greater metabolic stability (e.g. increased in vivo half-life or reduced dosage requirements), and thus in some cases The following may be preferred, where deuterium substitution may be partial or complete, partial deuterium substitution meaning at least one hydrogen is replaced by at least one deuterium.

Compounds of the present disclosure may be asymmetric, eg, possess one or more stereoisomers. Unless otherwise stated, all stereoisomers are included, eg, cis-trans isomers, enantiomers and diastereomers. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.

The pharmaceutical compositions of the present invention can be formulated by techniques known to those skilled in the art. The pharmaceutical composition of the present invention can be prepared by mixing the compound of the present invention or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients.

Examples of pharmaceutically acceptable excipients in the present invention are adjuvants, diluents, carriers, pH regulators, buffers, sweeteners, fillers, stabilizers, surfactants, wetting agents, lubricants, Emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, flavoring agents, flavoring agents, diluents, binders and other known additives.

The compounds of the present invention or pharmaceutically acceptable salts thereof can be formulated into solutions, emulsions, suspensions or dispersions in suitable pharmaceutical solvents or carriers according to conventional methods known in the art for preparing various dosage forms, Or formulated together with pharmaceutically acceptable excipients such as tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops formulations, aerosols, dry powder preparations and sterile injectable aqueous or oily solutions or suspensions. The pharmaceutical compositions of this specification can be delivered by suitable means of administration, for example, oral, intravenous, rectal, parenteral, topical, transdermal, ophthalmic, nasal, buccal or pulmonary (inhalation), wherein parenteral infusion includes intramuscular , intravenous, intraarterial, intraperitoneal or subcutaneous administration.

In this disclosure, unless otherwise defined, the meanings of the abbreviations used are as follows:

min means minutes;

h means hour;

d refers to the sky;

°C means degrees Celsius;

V: V refers to the volume ratio;

TsCl represents p-toluenesulfonyl chloride;

TEA means triethylamine;

DMAP means 4-dimethylaminopyridine;

DCM means dichloromethane;

PMBCl represents 4-methoxybenzyl chloride;

K ₂ CO ₃ represents potassium carbonate;

DMF means N,N-dimethylformamide;

B ₂ (pin) ₂ represents pinacol ester of diboronic acid;

Pd(dppf)Cl _represents [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride;

AcOK means potassium acetate or potassium acetate;

1,4-dioxane or dioxane means 1,4-dioxane;

TBSCl represents tert-butyldimethylsilyl chloride;

1-Methylimidazole means N-methylimidazole;

Zn(CN) ₂ represents zinc cyanide;

Pd(PPh ₃ ) ₄ represents tetrakis(triphenylphosphine)palladium;

DMA means N,N-dimethylacetamide;

_H represents hydrogen;

Pd/C means palladium carbon;

MeOH means methanol;

Cs ₂ CO ₃ means cesium carbonate;

LAH or LiAlH ₄ represents lithium aluminum hydride;

NaH means sodium hydride;

SEMCl represents 2-(trimethylsilyl) ethoxymethyl chloride;

THF means tetrahydrofuran;

DHP means 3,4-dihydro-2H-pyran;

TsOH represents p-toluenesulfonic acid;

KSAc represents potassium thioacetate;

HCl/1,4-dioxane means dioxane hydrochloride solution;

KOH means potassium hydroxide;

HATU means 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate;

NaBH ₄ represents sodium borohydride;

MsCl represents methylsulfonyl chloride;

Pd(dppf)Cl ₂ ·DCM means [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex;

H ₂ O means water;

TBAF means tetrabutyl ammonium fluoride;

DPPA means diphenylphosphoryl azide;

DBU means 1,8-diazabicycloundec-7-ene;

PPh ₃ represents triphenylphosphine;

Boc ₂ O represents di-tert-butyl dicarbonate;

BnBr represents benzyl bromide;

Toluene means toluene;

Imidazole means imidazole;

CO stands for carbon monoxide;

EtOH means ethanol;

PPTS means pyridinium 4-methylbenzenesulfonate;

NH ₃ /MeOH means ammonia methanol solution;

MeNH ₂ or CH ₃ NH ₂ represents methylamine;

DIPEA or DIEA means N, N-diisopropylethylamine;

NaSMe means sodium methyl mercaptide;

NH ₃ /1,4-dioxane means ammonia in dioxane;

Py represents pyridine;

Oxone means potassium peroxymonosulfonate;

Pd(OAc) represents _palladium acetate;

BINAP means 1,1'-binaphthyl-2,2'-bisdiphenylphosphine;

Pd ₂ (dba) ₃ represents three (dibenzylidene acetone) dipalladium;

XPhos means 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl;

LiCl means lithium chloride;

DMSO means dimethyl sulfoxide;

Tf ₂ O represents trifluoromethanesulfonic anhydride;

TFA means trifluoroacetic acid;

POBr ₃ represents phosphorus oxybromide;

PhN(Tf) ₂ represents 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide;

Xantphos means 4,5-bisdiphenylphosphine-9,9-dimethylxanthene;

EtONa means sodium ethoxide;

AcOH means acetic acid;

KBr represents potassium bromide;

NaOH means sodium hydroxide;

LCMS refers to liquid chromatography coupled with mass spectrometry;

TLC means thin layer chromatography;

Prep-TLC refers to preparative thin layer chromatography;

Prep-HPLC refers to the preparation of high performance liquid chromatography;

M refers to the molar concentration unit mol/L, for example, 2M refers to 2mol/L;

mM refers to the molar concentration unit millimol/L, for example, 2mM refers to 2mmol/L;

N refers to the equivalent concentration, for example, 1N HCl refers to hydrochloric acid with a concentration of 1mol/L; 2N NaOH refers to sodium hydroxide with a concentration of 2mol/L.

Example

The present invention is further explained below in conjunction with specific examples, but the examples do not limit the present invention in any form.

Preparation of intermediates

Preparation Example 1: Preparation of 2,4-dichloro-5-iodo-7-p-toluenesulfonyl-7H-pyrrole[2,3-d]pyrimidine

Dissolve 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (10.0g) in dichloromethane (100mL), add triethylamine (6.5g), p-toluenesulfonate in sequence Acyl chloride (6.7g) and 4-dimethylaminopyridine (391.0mg) were reacted at room temperature for 1h. TLC showed that the reaction of the raw materials was complete. The reaction system was poured into water (100 mL), extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by column chromatography to obtain 10.0 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 467.8.

Preparation 2: 3-((4-methoxybenzyl)oxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Preparation of quinoline

Step 1: Preparation of 6-bromo-3-((4-methoxybenzyl)oxy)quinoline

Dissolve 6-bromoquinolin-3-ol (4.5g) in N,N-dimethylformamide (50mL), add potassium carbonate (5.5g) and 4-methoxybenzyl chloride (4.7g), and heat up To 50 ° C, the reaction 3h. TLC showed that the reaction was complete. After the system was lowered to room temperature, 100 mL of saturated saline was added, extracted three times with ethyl acetate, the organic phases were combined, backwashed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was separated and purified by column chromatography to obtain 6.5 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 344.0.

Step 2: 3-((4-methoxybenzyl)oxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinone Preparation of morphine

6-bromo-3-((4-methoxybenzyl)oxy)quinoline (6.5g), pinacol diboronate (9.6g), potassium acetate (3.7g) and 1,1-bis (Diphenylphosphine) dioxonium palladium dichloride (1.3g) was dissolved in 1,4-dioxane (70mL), the system was replaced with nitrogen three times, and under a nitrogen atmosphere, the temperature was raised to 90°C and reacted for 2h. TLC showed that the reaction was complete. After the system cooled to room temperature, saturated brine was added, extracted three times with ethyl acetate, the organic phases were combined, backwashed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was separated and purified by column chromatography to obtain 5.5 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 392.1.

Preparation Example 3: Preparation of (4-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)methanamine

Step 1: Preparation of 4-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloropyrimidine

(2-Chloropyrimidin-4-yl)methanol (7.0g) was dissolved in dichloromethane (70mL), and N-methylimidazole (7.97g) and tert-butyldimethylsilyl chloride ( 11.0 g), react at room temperature for 1 hour. After TLC showed that the reaction was complete, a small amount of water was added to the system, extracted three times with dichloromethane, the organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 5.3 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 259.1.

Step 2: Preparation of 4-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidine-2-carbonitrile

Weigh 4-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloropyrimidine (1.8g) and zinc cyanide (1.63g) in a test tube, add N,N-di Methylacetamide (20 mL) was dissolved, and tetrakis(triphenylphosphine)palladium (403 mg) was added after replacing the nitrogen. After the addition, the nitrogen was replaced again, and the temperature was raised to 110° C. for 1 hour. TLC showed that the reaction was complete. After cooling down to room temperature, 5 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 1.2 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 250.1.

Step 3: (4-(((tert-Butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)methanamine

4-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidine-2-carbonitrile (1.2g) was dissolved in methanol (30mL), and palladium carbon (0.24g) was added at room temperature , replaced by hydrogen three times, and reacted at room temperature in a hydrogen atmosphere for 1 hour. After TLC showed that the reaction was complete, the system was directly filtered, and the mother liquor was concentrated under reduced pressure to obtain 1.20 g of the title compound. The crude product was directly used in the next step without purification.

MS (ESI) m/z (M+H) ⁺ = 254.1.

Preparation Example 4: Preparation of (4-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)methanamine

Step 1: Preparation of 4-(((tert-butyldimethylsilyl)oxy)methyl)pyridinecarbonitrile

4-Hydroxymethylpyridine-2-carbonitrile (8.3g) was dissolved in dichloromethane (70mL), and N-methylimidazole (7.97g) and tert-butyldimethylsilyl chloride (11.0g) were added successively, at room temperature React for half an hour. After TLC showed that the reaction was complete, a small amount of water was added to the system, extracted three times with dichloromethane, the organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 9.1 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 249.1.

Step 2: Preparation of (4-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)methanamine

4-(((tert-butyldimethylsilyl)oxy)methyl)pyridinecarbonitrile (3.0g) was dissolved in methanol (100mL), palladium carbon (0.24g) was added, hydrogen was replaced three times, and in The reaction was carried out at room temperature in a hydrogen atmosphere for 2 hours. After TLC showed that the reaction was complete, the system was directly filtered, and the mother liquor was concentrated under reduced pressure to obtain 3.0 g of the title compound. The crude product was directly used in the next step without purification.

MS (ESI) m/z (M+H) ⁺ = 253.1.

Preparation Example 5: Preparation of 5-(aminomethyl)pyridin-3-ol

5-Hydroxynicotinonitrile (500.0 mg) was dissolved in methanol (50 mL), palladium carbon (100.0 mg) and dilute hydrochloric acid (4M, 2 mL) were added to replace the hydrogen, and the reaction was carried out at room temperature under a hydrogen atmosphere for 2 hours. After TLC showed that the reaction was complete, the palladium carbon was removed by filtration, and the filtrate was collected and concentrated under reduced pressure to obtain 450.0 mg of the title compound, which was directly used in the next step without purification.

MS (ESI) m/z (M+H) ⁺ = 125.0.

Preparation Example 6: Preparation of (5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methanol

Step 1: Preparation of methyl 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)nicotinate

Methyl 5-hydroxynicotinate (2.0 g) was dissolved in N, N-dimethylformamide (10 mL), and (2-bromoethoxy) (tert-butyl) dimethylsilane (3.4 g) and Cesium carbonate (8.5g) was heated to 80°C for 4 hours. TLC showed that the reaction of the raw materials was complete. After cooling down to room temperature, the system was poured into water (50mL), extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. . The resulting crude product was separated by chromatography to obtain 2.8 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 312.2.

Step 2: Preparation of (5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methanol

In an ice-water bath, dissolve methyl 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)nicotinate (1.3 g) in tetrahydrofuran (16 mL), and add lithium aluminum hydride in batches (238mg), reacted for half an hour. TLC showed that the reaction of the raw material was complete, adding water (238uL) to quench the reaction, continued to add 15% aqueous sodium hydroxide solution (238uL), then added water (714uL), filtered through diatomaceous earth, collected the filtrate, dried over anhydrous sodium sulfate, filtered, Concentrate under reduced pressure. The obtained crude product was separated and purified by column chromatography to obtain 850 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 284.2.

Preparation 7: 2,4-dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine preparation

2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (10.0g) was dissolved in N,N-dimethylformamide (100mL), and the system was cooled to -40°C. Sodium hydride (1.91g) was added in batches, and the reaction temperature was maintained at this temperature for 5 minutes after the addition was completed, then 2-(trimethylsilyl)ethoxymethyl chloride (6.37g) was added, and the reaction was naturally returned to room temperature for 1 hour. After TLC showed that the reaction was complete, the system was quenched by dropping it into saturated aqueous ammonium chloride solution, extracted three times with ethyl acetate, combined the organic phases, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 14.0 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 444.1.

Preparation 8: 6-(2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5 Preparation of -yl)-3-((tetrahydro-2H-pyran-2-yl)oxy)quinoline

Step 1: Preparation of 6-bromo-3-((tetrahydro-2H-pyran-2-yl)oxy)quinoline

Dissolve 6-bromoquinolin-3-ol (5.0 g) in 1,4-dioxane (100 mL), add p-toluenesulfonic acid (378 mg) and 3,4-dihydro-2H-pyran (9.37 g), the system was refluxed overnight. TLC showed that the reaction was complete. After cooling down to room temperature, the system was quenched with water, adjusted to pH 8 with saturated sodium bicarbonate solution, extracted three times with ethyl acetate, combined organic phases, backwashed once with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The obtained crude product was purified by column chromatography to obtain 6.5 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 308.1.

Step 2: 3-((Tetrahydro-2H-pyran-2-yl)oxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborinane- 2-yl) quinoline preparation

6-Bromo-3-((tetrahydro-2H-pyran-2-yl)oxy)quinoline (6.5g), pinacol diboronate (6.97g) and potassium acetate (4.14g) were dissolved in 1,4-dioxane (80mL), add [1,1′-bis(diphenylphosphino)ferrocene]dichloride (1.54g) after nitrogen replacement, replace nitrogen again, and heat up to 90°C React for 3 hours. TLC showed the reaction was complete. After cooling down to room temperature, 100 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 7.1 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 356.1.

Step 3: 6-(2,4-Dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5- Preparation of base)-3-((tetrahydro-2H-pyran-2-yl)oxy)quinoline

3-((tetrahydro-2H-pyran-2-yl)oxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- base) quinoline (7.1g), 2,4-dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3 -d] Pyrimidine (8.86g) and potassium carbonate (5.52g) were dissolved in 1,4-dioxane (150mL) and water (20mL), and [1,1'-bis(diphenylphosphine) was added after nitrogen replacement base) ferrocene] palladium dichloride (1.46g), after the addition, the nitrogen was replaced again, and the temperature was raised to 90° C. for 3 hours. TLC showed that the reaction was complete. After cooling down to room temperature, 100 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 6.8 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 545.2.

Preparation Example 9: Preparation of (4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-2-yl)methanamine

Step 1: Preparation of 4-((2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridinecarbonitrile

In an ice-water bath, tert-butyldimethylhydroxyethoxysilane (6.4g) was dissolved in N,N-dimethylformamide (10mL), sodium hydride (1.8g) was added in batches, and after 1 hour of reaction, 4-Chloro-2-cyanopyridine (5.0 g) was added, and the reaction was carried out at room temperature for 1 hour. TLC showed that the reaction of the raw materials was complete. Pour the system into water (50 mL), extract three times with ethyl acetate, combine the organic phases, backwash once with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting crude product was separated by chromatography to obtain 3.0 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 279.2.

Step 2: Preparation of (4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-2-yl)methanamine

Dissolve 4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridinecarbonitrile (1.5g) in methanol (50mL), add palladium carbon (300mg), and replace hydrogen 3 times , and reacted at room temperature under hydrogen atmosphere for 1 hour. TLC showed that the raw material was completely consumed, and the palladium carbon was removed by filtration, and the filtrate was collected and concentrated under reduced pressure. 1.5 g of the crude product of the title compound were obtained.

MS (ESI) m/z (M+H) ⁺ = 283.2.

Preparation Example 10: Preparation of (2-(2-(6-bromoquinolin-3-yl)ethoxy)pyridin-4-yl)methanol

Step 1: Preparation of 6-bromo-3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)quinoline

Dissolve 6-bromoquinolin-3-ol (1.2g) in N,N-dimethylformamide (20mL), add cesium carbonate (3.5g) and (2-bromoethoxy)(tert-butyl) Dimethylsilane (1.54 g) was reacted at room temperature for 2 hours. TLC showed that the reaction was complete, quenched with water, extracted three times with ethyl acetate, combined the organic phases, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4.0 g of crude oil.

MS (ESI) m/z (M+H) ⁺ = 382.1.

Step 2: Preparation of 2-((6-bromoquinolin-3-yl)oxy)ethan-1-ol

6-Bromo-3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)quinoline (4.0 g) was dissolved in hydrochloric acid/1,4-dioxane (4M, 20 mL), react at room temperature for 1 hour. After TLC showed that the reaction was complete, it was concentrated under reduced pressure. The obtained crude product was adjusted to pH about 8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 3.7 g of the crude product.

MS (ESI) m/z (M+H) ⁺ = 268.1.

Step 3: Preparation of 2-(2-((6-bromoquinolin-3-yl)oxy)ethoxy)isonicotinonitrile

2-((6-Bromoquinolin-3-yl)oxy)ethan-1-ol (3.7 g) was dissolved in tetrahydrofuran (40 mL), sodium hydride (552 mg) was added in portions, and reacted at room temperature for 5 minutes. 2-Chloroisonicotinonitrile (1.93 g) was added and reacted at room temperature for half an hour. After TLC showed that the reaction was complete, the system was quenched with water, extracted three times with dichloromethane, the organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 1.15 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 370.1.

Step 4: Preparation of 2-(2-((6-bromoquinolin-3-yl)oxy)ethoxy)isonicotinic acid

Dissolve 2-(2-((6-bromoquinolin-3-yl)oxy)ethoxy)isonicotinonitrile (0.8g) in ethanol (10mL)/water (10mL), add potassium hydroxide (0.56 g), react overnight at 90°C. After LCMS showed that the reaction was complete, the system was concentrated under reduced pressure to remove ethanol, the pH was adjusted to about 5 with dilute hydrochloric acid (4M), extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 0.97 g of the title compound , the crude product was directly used in the next step without purification.

MS (ESI) m/z (M+H) ⁺ = 389.1.

Step 5: Preparation of methyl 2-(2-((6-bromoquinolin-3-yl)oxy)ethoxy)isonicotinate

Dissolve 2-(2-((6-bromoquinolin-3-yl)oxy)ethoxy)isonicotinic acid (0.97g) in tetrahydrofuran (20mL), add O-(7-azobenzotri Azolazole-1-oxo)-N,N",N"-tetramethyluronium hexafluorophosphate (1.85g), triethylamine (0.82g) and methanol (1mL) were reacted at room temperature for 1 hour. After TLC showed that the reaction was complete, it was quenched by adding water, extracted three times with ethyl acetate, combined the organic phases, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 0.74 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 403.0.

Step 6: Preparation of (2-(2-(6-bromoquinolin-3-yl)ethoxy)pyridin-4-yl)methanol

Methyl 2-(2-((6-bromoquinolin-3-yl)oxy)ethoxy)isonicotinate (0.74 g) was dissolved in tetrahydrofuran (10 mL)/methanol (10 mL), and boron was added in portions Sodium hydride (140mg), react at room temperature for 1 hour. After TLC showed that the reaction was complete, it was quenched by adding water, extracted three times with ethyl acetate, combined the organic phases, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 200 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 375.0.

Preparation Example 11: Preparation of (4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-2-yl)methanol

Using corresponding commercial reagents as raw materials, the title compound was prepared by using the preparation method similar to the above Preparation Example 6.

MS (ESI) m/z (M+H) ⁺ = 284.1.

Preparation 12: 6-(2,4-Dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7Hpyrrolo[2,3-d]pyrimidine-5- base)-3-((4-methoxybenzyl)oxy)quinoline

Dissolve 2,4-dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (600mg) In a mixed solution of dioxane (12mL) and water (3mL), add 3-((4-methoxybenzyl)oxy)-6-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborolan-2-yl)quinoline (896mg, 2.29mmol), potassium carbonate (527mg) and [1,1'-bis(diphenylphosphino)ferrocene]dichloride The palladium dichloromethane complex (139 mg) was replaced with nitrogen three times, and under a nitrogen atmosphere, the temperature was raised to 90° C. and reacted for 2 h. LCMS monitoring showed that the reaction was complete. After cooling the system, water was added to quench the reaction, extracted three times with ethyl acetate, combined the organic phases, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was separated and purified by column chromatography to obtain 713 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 581.1.

Preparation Example 13: Preparation of (5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methanthiol

Step 1: Preparation of methyl (5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methylsulfonate

Dissolve (5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methanol (2.2g) in dichloromethane (50mL) and add N,N -Diisopropylethylamine (2.0g) and methanesulfonyl chloride (1.33g) were reacted at room temperature for 1 hour. After TLC showed that the reaction was complete, 10 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3.4 g of crude product.

MS (ESI) m/z (M+H) ⁺ = 362.1.

Step 2: Preparation of S-((5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methyl)ethylsulfate

Methyl (5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methanesulfonate (3.4 g) was dissolved in N,N-dimethyl Dimethyl formamide (30 mL), was added potassium thioacetate (2.17 g), and reacted at room temperature for 1 hour. After TLC showed that the reaction was complete, it was quenched by adding water, extracted three times with ethyl acetate, combined the organic phases, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 1.5 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 342.0.

Step 3: Preparation of (5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methylthiol

Dissolve S-((5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methyl)ethsulfate (3.4g) in methanol (25mL )/water (5mL), add potassium carbonate (2.75g), and react at room temperature for 1 hour. After TLC showed that the reaction was complete, it was quenched by adding water, extracted three times with ethyl acetate, combined the organic phases, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 1.3 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 300.1.

Preparation 14: Preparation of (3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)phenyl)methanamine

Step 1: Preparation of 3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)benzonitrile

3-Hydroxybenzonitrile (500mg) was dissolved in N,N-dimethylformamide (10mL), cesium carbonate (2.7g) and (2-bromoethoxy)(tert-butyl)dimethylsilane ( 1.2g), react at room temperature for 5 hours. TLC showed that the reaction of the raw materials was complete. Pour the system into water (50 mL), extract three times with ethyl acetate, combine the organic phases, backwash once with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting crude product was separated by chromatography to obtain 1.0 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 278.2.

Step 2: Preparation of (3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)phenyl)methanamine

In a hydrogen atmosphere, 3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)benzonitrile (1.3 g) was dissolved in methanol (100 mL), and palladium on carbon (130.0 mg ), reacted at room temperature for 4 hours. TLC showed that the raw material was completely consumed, and the palladium carbon was removed by filtration, and the filtrate was collected and concentrated under reduced pressure to obtain 1.1 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 282.2.

Preparation Example 15: Preparation of tert-butyl ((2-(2-((6-bromoquinolin-3-yl)oxy)ethoxy)pyridin-4-yl)methylcarbamate

Step 1: Preparation of 4-(((tert-butyldimethylsilyl)oxy)methyl)-2-fluoropyridine

Dissolve (2-fluoropyridin-4-yl)methanol (200mg) in dichloromethane (10mL), add N-methylimidazole (200mg) and tert-butyldimethylchlorosilane (275mg) successively, and react at room temperature for half Hour. After TLC showed that the reaction was complete, a small amount of water was added to the system, extracted three times with dichloromethane, the organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 400 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 242.1.

Step 2: 6-Bromo-3-(2-((4-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)oxy)ethoxy)quinoline preparation of

Dissolve 2-((6-bromoquinolin-3-yl)oxy)ethan-1-ol (445 mg) in tetrahydrofuran (20 mL), add sodium hydride (133 mg) in batches, react at room temperature for 5 minutes, add 4 -(((tert-butyldimethylsilyl)oxy)methyl)-2-fluoropyridine (400mg), react at room temperature for half an hour. After TLC showed that the reaction was complete, the system was quenched by adding water, extracted three times with dichloromethane, combined the organic phases, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 0.5 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 489.1.

Step 3: Preparation of (2-(2-(6-bromoquinolin-3-yl)ethoxy)pyridin-4-yl)methanol

6-bromo-3-(2-((4-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)oxy)ethoxy)quinoline (0.5 g) Dissolve in tetrabutylammonium fluoride/tetrahydrofuran solution (1M, 10mL) and react at room temperature for 1 hour. After TLC showed that the reaction was complete, it was concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 350 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 375.1.

Step 4: Preparation of 3-(2-((4-(azidomethyl)pyridin-2-yl)oxy)ethoxy)-6-bromoquinoline

Dissolve (2-(2-(6-bromoquinolin-3-yl)ethoxy)pyridin-4-yl)methanol (350 mg) in toluene (10 mL), add diphenylphosphoryl azide (517 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (286mg), react at 100°C for 1 hour. TLC showed that the reaction was complete. After the system cooled to room temperature, it was quenched with water, extracted three times with ethyl acetate, combined the organic phases, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 350 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 400.0.

Step 5: Preparation of (2-(2-(6-bromoquinoline-3-oxy)ethoxy)pyridin-4-yl)methanamine

3-(2-((4-(Azidomethyl)pyridin-2-yl)oxy)ethoxy)-6-bromoquinoline (350 mg) was dissolved in tetrahydrofuran (10 mL) and water (1 mL), Triphenylphosphine (460mg) was added and reacted overnight at room temperature. TLC showed that the reaction was complete, and concentrated under reduced pressure to obtain 600 mg of crude oil.

MS (ESI) m/z (M+H) ⁺ = 374.0.

Step 6: Preparation of tert-butyl ((2-(2-((6-bromoquinolin-3-yl)oxy)ethoxy)pyridin-4-yl)methylcarbamate

Dissolve (2-(2-(6-bromoquinoline-3-oxy)ethoxy)pyridin-4-yl)methanamine (600 mg) in dichloromethane (10 mL), add triethylamine (177 mg) and Di-tert-butyl dicarbonate (382 mg) was reacted at room temperature for 1 hour. After TLC showed that the reaction was complete, it was quenched by adding water, extracted three times with ethyl acetate, combined the organic phases, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 350 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 474.0.

Preparation Example 16: Preparation of (5-(3-((tert-butyldimethylsilyl)oxy)propoxy)pyridin-3-yl)methanol

Using corresponding commercial reagents as raw materials, the title compound was prepared by using the preparation method similar to the above Preparation Example 6.

MS (ESI) m/z (M+H) ⁺ = 298.0.

Preparation 17: Preparation of (6-(2-((6-bromoquinolin-3-yl)oxy)ethoxy)pyridin-2-yl)methanol

Using corresponding commercial reagents as raw materials, the title compound was prepared by using the preparation method similar to the above Preparation Example 10.

MS (ESI) m/z (M+H) ⁺ = 375.0.

Preparation 18: Preparation of (3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)phenyl)methanol

Using corresponding commercial reagents as raw materials, the title compound was prepared by using the preparation method similar to the above Preparation Example 6.

MS (ESI) m/z (M+H) ⁺ = 283.1.

Preparation 19: 3-(Benzyloxy)-6-(2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2 , 3-d] the preparation of pyrimidin-5-yl) quinoline

Step 1: Preparation of 3-(benzyloxy)-6-bromoquinoline

Dissolve 6-bromoquinolin-3-ol (1.00g) in N,N-dimethylformamide (10mL), add potassium carbonate (1.86g) and benzyl bromide (0.92g), and react at 70°C for 1.5 hours . TLC showed that the reaction was complete, the system was cooled to room temperature, quenched with water, extracted three times with ethyl acetate, combined the organic phases, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain the title compound 1.2g.

MS (ESI) m/z (M+H) ⁺ = 314.0, 316.0.

Step 2: 3-(Benzyloxy)-6-(2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2, Preparation of 3-d]pyrimidin-5-yl)quinoline

3-(benzyloxy)-6-bromoquinoline (0.31g), bispinacolate diboron (0.31g), [1,1'-bis(diphenylphosphino)ferrocene]di Palladium chloride (73 mg) and potassium acetate (0.3 g) were dissolved in 1,4-dioxane (10 mL), replaced with nitrogen three times, and heated to 90° C. for 2 hours. TLC showed that the reaction was complete. Add 2,4-dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine to the system ( 0.49g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (73mg), potassium carbonate (0.28g) and water (1mL), nitrogen replacement three times, heated to 100°C React for 2 hours. TLC showed that the reaction was complete, the system was cooled to room temperature, quenched with water, extracted three times with ethyl acetate, combined the organic phases, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain the title compound 0.24g.

MS (ESI) m/z (M+H) ⁺ = 551.1.

Preparation Example 20: Preparation of tert-butyl ((6-(2-((6-bromoquinolin-3-yl)oxy)ethoxy)pyridin-2-yl)methyl)carbamate

Step 1: Preparation of 2-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoropyridine

Dissolve 6-fluoro-2-pyridinemethanol (1.0g) in dichloromethane (10mL), add N-methylimidazole (1.3g) and tert-butyldimethylchlorosilane (1.8g) successively, and react at room temperature for 1 Hour. After TLC showed that the reaction was complete, 10 mL of water was added to the system, extracted three times with dichloromethane, the organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 1.8 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 242.1.

Step 2: 6-Bromo-3-(2-((6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)oxy)ethoxy)quinoline preparation of

Weigh sodium hydride (300.0mg), add anhydrous tetrahydrofuran (20mL) to suspend, add 2-((6-bromoquinolin-3-yl)oxy)ethan-1-ol (1.0g), and react at room temperature for 10 minute. 2-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoropyridine (992.9 mg) was added to the system, and the temperature was raised to 60° C. for 4 hours. After TLC showed that the reaction was complete, the system was slowly added to a saturated aqueous ammonium chloride solution (30 mL) under ice-bath conditions, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The obtained crude product was purified by column chromatography to obtain 0.7 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 489.1.

Step 3: Preparation of (6-(2-((6-bromoquinolin-3-yl)oxy)ethoxy)pyridin-2-yl)methanol

6-bromo-3-(2-((6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)oxy)ethoxy)quinoline (0.7 g) Dissolve in tetrahydrofuran (20 mL), add tetrabutylammonium fluoride (1M, 1.43 mL), and react at room temperature for 10 minutes. After TLC showed that the reaction was complete, 20 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 525.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 375.0.

Step 4: Preparation of 3-(2-((6-(azidomethyl)pyridin-2-yl)oxy)ethoxy)-6-bromoquinoline

Dissolve (6-(2-((6-bromoquinolin-3-yl)oxy)ethoxy)pyridin-2-yl)methanol (350.0 mg) in toluene (10 mL), and add 1,8- Diazabispiro[5.4.0]undec-7-ene (426.7 mg) and diphenylphosphoryl azide (413.6 mg) were heated to 90° C. for 1 hour. TLC showed that the reaction was complete. After cooling down to room temperature, 20 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 360.0 mg of the title compound as a crude product It was directly used in the next step without purification.

MS (ESI) m/z (M+H) ⁺ = 400.0.

Step 5: Preparation of tert-butyl ((6-(2-((6-bromoquinolin-3-yl)oxy)ethoxy)pyridin-2-yl)methyl)carbamate

Crude 3-(2-((6-(azidomethyl)pyridin-2-yl)oxy)ethoxy)-6-bromoquinoline (360.0 mg) was dissolved in THF (5 mL) and water (0.5 mL), added triphenylphosphine (472.8mg, 1.80mmol), and reacted at room temperature for 2 hours. Triethylamine (272.7 mg) and di-tert-butyl dicarbonate (294.3 mg) were added to the system and reacted at room temperature for 30 minutes. After TLC showed that the reaction was complete, 20 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 260.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 474.1.

Preparation 21: Preparation of (5-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)methanol

Step 1: Preparation of pyridine-3,5-dimethyldimethanol

Dimethyl pyridine-3,5-dicarboxylate (20.0 g) was dissolved in tetrahydrofuran (200 mL), and lithium aluminum hydride (7.79 g) was added in batches, and reacted at room temperature for 1 hour. After TLC showed that the reaction was complete, it was quenched by adding water, extracted three times with ethyl acetate, combined the organic phases, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 8.0 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 140.0.

Step 2: Preparation of (5-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)methanol

Dissolve pyridine-3,5-dimethyldimethanol (8.0g) in dichloromethane (400mL), add imidazole (5.87g), cool the system to 0°C and add tert-butyldimethylsilyl chloride (9.1g ), transferred to room temperature for 2 hours. After TLC showed that the reaction was complete, a small amount of water was added to the system, extracted three times with dichloromethane, the organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 4.0 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 254.1.

Preparation 22: Preparation of (5-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)methanamine

Step 1: Preparation of 3-(azidomethyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)pyridine

Dissolve (5-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)methanol (1.0g) in toluene (20mL), add diphenylphosphoryl azide (2.07 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.14 g) were reacted at 100° C. for 1 hour. TLC showed that the reaction was complete. After the system was cooled to room temperature, it was quenched with water, extracted three times with ethyl acetate, combined the organic phases, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 0.8 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 279.0.

Step 2: Preparation of (5-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)methanamine

Dissolve 3-(azidomethyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)pyridine (300 mg) in methanol (100 mL), add palladium on carbon (100 mg), hydrogen After three replacements, the system was reacted at room temperature for 2 hours in a hydrogen atmosphere. After TLC showed that the reaction was complete, palladium carbon was removed by filtration, and the filtrate was collected and concentrated under reduced pressure to obtain 320 mg of the title compound. The crude product was directly used in the next step without purification.

MS (ESI) m/z (M+H) ⁺ = 253.1.

Preparation 23: Preparation of (6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyrazin-2-yl)methanol

Step 1: Preparation of 2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-chloropyrazine

In an ice-water bath, 2-((tert-butyldimethylsilyl)oxy)1-ol (3.9 g) was dissolved in tetrahydrofuran (40 mL), sodium hydride (0.847 g) was added in portions, and reacted for 20 minutes. 2,6-Dichloropyrazine (3 g) and tetrahydrofuran (5 mL) were added, and the reaction was carried out at room temperature for 1.5 hours. After TLC showed that the reaction was complete, it was quenched by adding water, extracted three times with ethyl acetate, combined the organic phases, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain 5.2 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 289.1.

Step 2: Preparation of ethyl 6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyrazine-2-carboxylate

Put 2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-chloropyrazine (1.0g) in a 100mL autoclave, add ethanol (60mL) to dissolve, add tris Ethylamine (0.5mL) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.283g) were filled with carbon monoxide gas, and reacted overnight at 100°C. After LCMS showed that the reaction was complete, the system was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was collected and concentrated. The crude product was purified by column chromatography to obtain 1.1 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 327.2.

Step 3: Preparation of (6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyrazin-2-yl)methanol

In an ice-water bath, dissolve ethyl 6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyrazine-2-carboxylate (0.5 g) in tetrahydrofuran (30 mL), drop A tetrahydrofuran solution (2M, 0.88 mL) of lithium aluminum tetrahydride was added, and the reaction was carried out for half an hour. After TLC showed that the reaction was complete, the system was quenched by adding a small amount of water and 15% sodium hydroxide solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain 120 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 285.1.

Preparation 24: Preparation of (5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridazin-3-yl)methanol

Using corresponding commercial reagents as raw materials, the title compound was prepared by using the preparation method similar to the above Preparation Example 23.

MS (ESI) m/z (M+H) ⁺ = 285.1.

Preparation 25: Preparation of (5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-3-yl)methanol

Step 1: Preparation of methyl 5-((tetrahydro-2H-pyran-2-yl)oxy)nicotinate

Dissolve methyl 5-hydroxynicotinate (1.53g) in toluene (20mL), add 3,4-dihydro-2H-pyran (1.68g) and pyridine 4-methylbenzenesulfonate (1.68g) in sequence, React overnight at 100°C under airtight conditions. After the reaction was completed, the system was cooled down to room temperature, and the system was concentrated. The crude product was purified by column chromatography to obtain 0.9 g of the product.

MS (ESI) m/z (M+H) ⁺ = 238.1.

Step 2: Preparation of (5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-3-yl)methanol

In an ice-water bath, dissolve methyl 5-((tetrahydro-2H-pyran-2-yl)oxy)nicotinate (0.9 g) in methanol (12 mL), add sodium borohydride (0.58 g), and move to React at room temperature for 1 hour. After TLC showed that the reaction was complete, it was quenched with water, extracted three times with ethyl acetate, combined the organic phases, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain 0.65 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 210.1.

Preparation 26: Preparation of (5-(3-((tert-butyldimethylsilyl)oxy)propoxy)pyridin-3-yl)methanamine

Step 1: Preparation of 5-(3-((tert-butyldimethylsilyl)oxy)propoxy)nicotinonitrile

Dissolve 5-hydroxynicotinonitrile (2.0 g) in N,N-dimethylformamide (10 mL), add (2-bromoethoxy)(tert-butyl)dimethylsilane (5.4 g) and cesium carbonate (1.6g), heated to 90°C and reacted for 16 hours. After TLC showed that the reaction was complete, the system was cooled to room temperature, quenched with water, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was separated and purified by column chromatography to obtain 2.4 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 293.1.

Step 2: Preparation of (5-(3-((tert-butyldimethylsilyl)oxy)propoxy)pyridin-3-yl)methanamine

Dissolve 5-(3-((tert-butyldimethylsilyl)oxy)propoxy)nicotinonitrile (1.2g) in methanol (20mL), add palladium on carbon (300mg) and ammonia methanol solution (2mL , 7M), replaced the system with hydrogen three times, reacted at room temperature under hydrogen atmosphere for 1 hour, filtered to remove palladium carbon, collected the filtrate, and concentrated under reduced pressure. The obtained crude product was separated and purified by column chromatography to obtain 415 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 297.1.

Preparation 27: Preparation of (5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methanamine

Using the corresponding commercially available reagents as raw materials, the title compound was prepared using a preparation method similar to that of Preparation Example 26 above.

MS (ESI) m/z (M+H) ⁺ = 283.1.

Preparation 28: N ⁴ -((4-((tert-butyldimethylsilyloxy)methyl)pyrimidin-2-yl)methyl)-5-(3-((4-methoxybenzyl) )Oxy)quinolin-6-yl)-N ² -methyl-7-p-tolyl-7H-pyrrole[2,3-d]pyrimidine-2,4-diamine preparation

Step 1: N-((4-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)methyl)-2-chloro-5-iodo-7-toluenesulfonate Preparation of Acyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Dissolve 2,4-dichloro-5-iodo-7-p-tolyl-7H-pyrrole[2,3-d]pyrimidine (1.79g) in dichloromethane (30mL), and add triethylamine (0.97g ) and (4-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)methanamine (1.2 g), the system was reacted at 40° C. for 1 hour. After TLC showed that the reaction was complete, 30 mL of water was added to the system, extracted three times with dichloromethane, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1.3 g of the title compound. Purification was used directly in the next step.

MS (ESI) m/z (M+H) ⁺ = 685.1.

Step 2: N ⁴ -((4-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)methyl)-5-iodo-N ² -methyl-7 -Preparation of tosyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

Weigh N-((4-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)methyl)-2-chloro-5-iodo-7-toluenesulfonyl -7H-Pyrrolo[2,3-d]pyrimidin-4-amine (1.3g) crude product was placed in a microwave tube, a solution of methylamine in tetrahydrofuran (1M, 20mL) was added, and reacted under microwave at 100°C for 1 hour. After TLC showed that the reaction was complete, the system was cooled to room temperature, 25 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by reverse phase to obtain 700 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 680.1.

Step 3: N ⁴ -((4-((tert-butyldimethylsilyloxy)methyl)pyrimidin-2-yl)methyl)-5-(3-((4-methoxybenzyl) Preparation of oxy)quinolin-6-yl)-N ² -methyl-7-p-tolyl-7H-pyrrole[2,3-d]pyrimidine-2,4-diamine

Weigh N ⁴ -((4-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)methyl)-5-iodo-N ² -methyl-7- Tosyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (700.0mg), 3-((4-methoxybenzyl)oxy)-6-(4,4 , 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (443.5mg) and potassium carbonate (426.4mg), add 1,4-dioxane (10mL) Dissolve with water (1mL), replace nitrogen and add [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (75.0mg), replace nitrogen again after adding, heat up to 90°C for reaction 1 hour. After TLC showed that the reaction was complete, the system was cooled to room temperature, 10 mL of water was added, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 600.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 817.3.

Preparation 29: N ⁴ -((4-((tert-butyldimethylsilyloxy)methyl)pyrimidin-2-yl)methyl)-5-(3-((4-methoxybenzyl) )Oxy)quinolin-6-yl)-N ² -methyl-7-p-tolyl-7H-pyrrole[2,3-d]pyridine-2,4-diamine preparation

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Preparation Example 28 above.

MS (ESI) m/z (M+H) ⁺ = 816.3.

Preparation 30: 5-((5-(3-((4-methoxybenzyl)oxy)quinolin-6-yl)-2-(methylamino)-7-tolyl-7H-pyrrolo Preparation of [2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-3-ol

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Preparation Example 28 above.

MS (ESI) m/z (M+H) ⁺ = 688.2.

Preparation 31: 2-((5-(((2-(methylamino)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)quinolin-6-yl)- 7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)pyridin-3-yl ) Oxygen) the preparation of ethyl methanesulfonate

Step 1: 6-(4-((5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methoxy)-2-chloro-7 -((2-(Trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-((tetrahydro-2H-pyran -2-yl)oxyl)quinoline preparation

In an ice-water bath, (5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methanol (850mg) was dissolved in tetrahydrofuran (10mL), and added in batches Sodium hydride (240mg), reacted for 0.5 hours. Add 6-(2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl )-3-((tetrahydro-2H-pyran-2-yl)oxy)quinoline (1.6g), moved to room temperature for 1 hour. TLC showed that the reaction was complete, the system was poured into water (100 mL), extracted with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was separated by chromatography to obtain 2.3 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 792.3.

Step 2: 4-((5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methoxy)-N-methyl-5-( 3-((tetrahydro-2H-pyran-2-yl)oxy))quinolin-6-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)- Preparation of 7H-pyrrolo[2,3-d]pyrimidin-2-amine

6-(4-((5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methoxy)-2-chloro-7-( (2-(Trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-((tetrahydro-2H-pyran-2 -yl)oxy)quinoline (700 mg) was dissolved in 1,4-dioxane (10 mL), methylamine (1.0 mL, 4M in H ₂ O) was added, and the system was reacted in microwave at 100°C for 1 hour. TLC showed that the raw materials were completely consumed. After the system was cooled to room temperature, water (10 mL) was added, extracted with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was separated by chromatography to obtain 550 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 787.2.

Step 3: 2-((5-(((2-(methylamino)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)quinolin-6-yl)-7 -((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)pyridin-3-yl) Preparation of oxy)ethan-1-ol

4-((5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methoxy)-N-methyl-5-(3- ((tetrahydro-2H-pyran-2-yl)oxy))quinolin-6-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- Pyrrolo[2,3-d]pyrimidin-2-amine (550.0mg) was dissolved in tetrahydrofuran (5mL), tetrabutylammonium fluoride (1mL, 1M in THF) was added, and reacted at room temperature for 1 hour. TLC showed that the raw material was completely consumed. Water (10 mL) was added, extracted with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was separated by chromatography to obtain 400 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 673.2.

Step 4: 2-((5-(((2-(Methylamino)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)quinolin-6-yl)-7 -((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)pyridin-3-yl) Preparation of oxy)ethyl methanesulfonate

In an ice-water bath, 2-((5-(((2-(methylamino)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)quinolin-6-yl) -7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)pyridine-3- Base)oxy)ethan-1-ol (400.0mg) was dissolved in dichloromethane (10mL), triethylamine (181mg) and methanesulfonyl chloride (68mg) were added successively, and the reaction was carried out at room temperature for 1h. TLC showed that the reaction was complete. Pour the system into water (20 mL), adjust the pH to about 8 with saturated sodium bicarbonate solution, extract with dichloromethane, combine the organic phases, backwash once with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and filter , concentrated under reduced pressure. The obtained crude product was separated by column chromatography to obtain 300.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 751.3.

Preparation 32: N ⁴ -((4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-2-yl)methyl)-5-(3-(( 4-methoxybenzyl)oxy)quinolin-6- ^yl )-N 2 -methyl-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine preparation of

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Preparation Example 28 above.

MS (ESI) m/z (M+H) ⁺ = 846.4.

Preparation 33: (2-(2-(6-(2,4-dichloro-7-(2-(trimethylsilylethoxy)methyl)-7-(2,3-d)pyrimidine Preparation of -5-yl)quinolin-3-yl)ethoxy)pyridin-4-yl)methanol

Step 1: (2-(2-((6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)oxy ) ethoxy) pyridin-4-yl) the preparation of methanol

Dissolve (2-(2-(6-bromoquinolin-3-yl)ethoxy)pyridin-4-yl)methanol (200mg), pinacol diboronate (177mg) and potassium acetate (138mg) in 1,4-dioxane (5mL), add [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (75mg) after replacing the nitrogen, replace the nitrogen again after the addition, and raise the temperature React at 90°C for 3 hours. After TLC showed that the reaction was complete, the system was cooled to room temperature, 10 mL of water was added, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 210 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 423.1.

Step 2: (2-(2-(6-(2,4-dichloro-7-(2-(trimethylsilylethoxy)methyl)-7-(2,3-d)pyrimidine- Preparation of 5-yl)quinolin-3-yl)ethoxy)pyridin-4-yl)methanol

(2-(2-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)oxy)ethyl Oxy)pyridin-4-yl)methanol (210mg), 2,4-dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrole And[2,3-d]pyrimidine (220mg) and potassium carbonate (138mg) were dissolved in 1,4-dioxane (10mL) and water (1mL), and [1,1′-bis(di Phenylphosphino)ferrocene]palladium dichloride (73mg), after the addition, the nitrogen was replaced again, and the temperature was raised to 90°C for 3 hours. After TLC showed that the reaction was complete, the system was cooled to room temperature, 10 mL of water was added, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 150 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 612.2.

Preparation 34: N ⁴ -((5-(3-((tert-butyldimethylsilyl)oxy)propoxy)pyridin-3-yl)methyl)-5-(3-(( 4-methoxybenzyl)oxy)quinolin-6- ^yl )-N 2 -methyl-7-tolyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine preparation

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Preparation Example 28 above.

MS (ESI) m/z (M+H) ⁺ = 860.3.

Preparation 35: 2-((2-(((5-(3-((4-methoxybenzyl)oxy)quinolin-6-yl)-2-(methylamino)-7-(( 2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)pyridin-4-yl)oxy) Preparation of ethyl methanesulfonate

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 31.

MS (ESI) m/z (M+H) ⁺ = 787.3.

Preparation 36: 4-(((5-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methyl)thio)-5-(3 Preparation of -((4-methoxybenzyl)oxy)quinolin-6-yl)-N-methyl-7-tolyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Preparation Example 28 above.

MS (ESI) m/z (M+H) ⁺ = 863.2.

Preparation 37: N ⁴ -(3-(2-(tert-Butyldimethylsilyl)oxy)ethoxy)benzyl)-5-(3-((4-methoxybenzyl) Preparation of oxy)quinolin-6-yl)-N ² -methyl-7-tolyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Preparation Example 28 above.

MS (ESI) m/z (M+H) ⁺ = 845.4.

Preparation 38: tert-butyl((2-(2-((6-(2,4-dichloro-7-tolyl-7H-pyrrole[2,3-d]pyrimidin-5-yl)quinoline- Preparation of 3-yl)oxy)ethoxy)pyridin-4-yl)methyl)carbamate

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 33.

MS (ESI) m/z (M+H) ⁺ = 735.2.

Preparation 39: N ⁴ -((5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methyl)-N ² -(cyclopropyl Methyl)-5-(3-((4-methoxybenzyl)oxy)quinolin-6-yl)-7-tolyl-7H-pyrrolo[2,3-d]pyrimidine-2, Preparation of 4-diamine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Preparation Example 28 above.

MS (ESI) m/z (M+H) ⁺ = 886.3.

Preparation 40: 3-((5-(((2-(methylamino)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)quinolin-6-yl)- 7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)pyridin-3-yl ) Oxygen) The preparation of propyl mesylate

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 31.

MS (ESI) m/z (M+H) ⁺ = 765.2.

Preparation 41: (6-(2-((6-(2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7Hpyrrole[2,3- d] Preparation of pyrimidin-5-yl)quinolin-3-yl)oxyl)ethoxy)pyridin-2-yl)methanol

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 33.

MS (ESI) m/z (M+H) ⁺ = 612.1.

Preparation 42: 2-(3-(((5-(3-(Benzyloxy)quinolin-6-yl)-2-(methylamino)-7-((2-(trimethylsilyl) )ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)phenoxy)ethyl methanesulfonate

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 31.

MS (ESI) m/z (M+H) ⁺ = 756.2.

Preparation 43: tert-butyl((6-(2-((6-(2,4-dichloro-7-tolyl-7H-pyrrole[2,3-d]pyrimidin-5-yl)quinoline- Preparation of 3-yl)oxy)ethoxy)pyridin-2-yl)methyl)carbamate

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 33.

MS (ESI) m/z (M+H) ⁺ = 735.1.

Preparation 44: N-(4-((5-hydroxypyridin-3-yl)methyl)amino)-5-(3-((4-methoxybenzyl)oxy)quinolin-6-yl Preparation of )-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)cyclopropanecarboxamide

Step 1: Preparation of 2-chloro-5-iodo-4-(methylthio)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine

Dissolve 2,4-dichloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (2.0 g) in N, N-dimethylformamide (20 mL), add Sodium methyl mercaptide (2 mL), react at room temperature for 2 hours. After TLC showed that the reaction was complete, 30 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, backwashed twice with water, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product , used directly in the next step without purification.

MS (ESI) m/z (M+H) ⁺ = 480.0.

Step 2: Preparation of 5-iodo-4-(methylthio)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine

Dissolve 2-chloro-5-iodo-4-(methylthio)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine (2.2 g) in ammoniacal 1,4-dioxahexa The ring solution (20 mL) was reacted overnight at 120°C. After TLC showed that the reaction was complete, the system was lowered to room temperature, 10 mL of water was added, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 600.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 461.0.

Step 3: Preparation of N-(5-iodo-4-(methylthio)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)cyclopropanecarboxamide

Dissolve 5-iodo-4-(methylthio)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine (600.0 mg) in tetrahydrofuran (1 mL), add pyridine (200.0 mg), react at room temperature for 2 hours. After TLC showed that the reaction was complete, the system was concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 400.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 529.0.

Step 4: Preparation of N-(5-iodo-4-(methylsulfonyl)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)cyclopropanecarboxamide

N-(5-iodo-4-(methylthio)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)cyclopropanecarboxamide (400.0 mg) was dissolved in THF /aqueous solution (6 mL, 2:1=V:V), potassium peroxymonosulfonate (288.0 mg) was added, and reacted at room temperature for 1 hour. After TLC showed that the reaction was complete, 5 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 120.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 561.0.

Step 5: N-(4-(((5-hydroxypyridin-3-yl)methyl)amino)-5-iodo-7-tolyl-7H-pyrrolo[2,3-d]pyrimidine-2- Base) the preparation of cyclopropanecarboxamide

N-(5-iodo-4-(methylsulfonyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)cyclopropanecarboxamide (100.0 mg) was dissolved in N,N-Dimethylformamide (1 mL), triethylamine (36.0 mg) and 5-(aminomethyl)pyridin-3-ol (43.0 mg) were added and reacted at room temperature for 2 hours. After TLC showed that the reaction was complete, 5 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, backwashed twice with water, once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 100.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 605.0.

Step 6: N-(4-((5-hydroxypyridin-3-yl)methyl)amino)-5-(3-((4-methoxybenzyl)oxy)quinolin-6-yl) - Preparation of 7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)cyclopropanecarboxamide

N-(4-(((5-hydroxypyridin-3-yl)methyl)amino)-5-iodo-7-tolyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl) Cyclopropanecarboxamide (100.0mg), 3-((4-methoxybenzyl)oxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxane -2-yl)quinoline (77.6mg), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (12.1mg) and potassium carbonate (44.1mg) were dissolved in 1,4-dioxane /water (2 mL, 5:1=V:V), heated to 90°C for 1 hour. After TLC showed that the reaction was complete, the system was lowered to room temperature, 5 mL of water was added, extracted three times with ethyl acetate, the organic phases were combined, backwashed twice with water, once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and reduced Concentrate under pressure. The obtained crude product was purified by column chromatography to obtain 90.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 742.2.

Preparation 45: 2-((5-(((5-(3-(benzyloxy)quinolin-6-yl)-2-methoxy-7-((2-(trimethylsilyl) )ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)pyridin-3-yl)oxy)ethyl methanesulfonate

Step 1: 3-(Benzyloxy)-6-(4-((5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methoxy Preparation of -2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)quinoline

In an ice-water bath, (5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methanol (180 mg) was dissolved in tetrahydrofuran (5 mL), and sodium hydride was added (30 mg), reacted for 20 minutes, then added 3-(benzyloxy)-6-(2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)quinoline (0.24 g), moved to room temperature for 1 hour. After TLC showed that the reaction was complete, 10 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 0.27 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 798.2.

Step 2: 3-(Benzyloxy)-6-(4-((5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methoxy Base)-2-methoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)quinoline preparation of

3-(benzyloxy)-6-(4-((5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methoxy) -2-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)quinoline (0.24g) , palladium acetate (14mg), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (50mg) and cesium carbonate (0.2g) were dissolved in methanol (1.5mL) and toluene (4.5mL), nitrogen replacement Three times, the temperature was raised to 100°C for 2 hours. TLC showed that the reaction was complete, the system was cooled to room temperature, quenched with water, extracted three times with ethyl acetate, combined the organic phases, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain the title compound 0.10g.

MS (ESI) m/z (M+H) ⁺ = 794.1.

Step 3: 2-((5-(((5-(3-(benzyloxy)quinolin-6-yl)-2-methoxy-7-((2-(trimethylsilyl) Preparation of ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)pyridin-3-yl)oxy)ethan-1-ol

3-(benzyloxy)-6-(4-((5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methoxy) -2-methoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)quinoline (0.1 g) Dissolve in tetrahydrofuran (10 mL), add tetrabutylammonium fluoride-tetrahydrofuran solution (1M, 0.3 mL), and react at room temperature for 1 hour. After TLC showed that the reaction was complete, it was concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 60 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 680.1.

Step 4: 2-((5-(((5-(3-(benzyloxy)quinolin-6-yl)-2-methoxy-7-((2-(trimethylsilyl) Preparation of ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)pyridin-3-yl)oxy)ethyl methanesulfonate

2-((5-(((5-(3-(benzyloxy)quinolin-6-yl)-2-methoxy-7-((2-(trimethylsilyl)ethoxy Base)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)pyridin-3-yl)oxy)ethan-1-ol (60mg) was dissolved in di Chloromethane (5 mL), triethylamine (16 mg) and methanesulfonyl chloride (14 mg) were added and reacted at room temperature for 1 hour. After TLC showed that the reaction was complete, 10 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 60 mg of the product.

MS (ESI) m/z (M+H) ⁺ = 758.2.

Preparation 46: (5-(((2-(methylamino)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)quinolin-6-yl)-7-( (2-(Trimethylsilyl)ethoxy)methyl))-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)pyridin-3-yl)methyl Preparation of methyl sulfonate

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 31.

MS (ESI) m/z (M+H) ⁺ = 721.2.

Preparation 47: N ⁴ -((5-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)methyl)-N ² -methyl-5-(3 -((tetrahydro-2H-pyran-2-yl)oxy)quinolin-6-yl)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-di Amine preparation

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Preparation Example 28 above.

MS (ESI) m/z (M+H) ⁺ = 780.1.

Preparation 48: 2-((6-(((2-(methylamino)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)quinolin-6-yl)- 7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)pyrazine-2- base) oxy) ethyl methanesulfonate

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 31.

MS (ESI) m/z (M+H) ⁺ = 752.2.

Preparation 49: 2-((6-(((2-(methylamino)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)quinolin-6-yl)- 7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)pyridazine-4- base) oxy) ethyl methanesulfonate

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 31.

MS (ESI) m/z (M+H) ⁺ = 752.3.

Preparation 50: 3-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-6-(2,4-dichloro-7-((2-(trimethylsilyl) Preparation of base) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl) quinoline

Step 1: Preparation of 3-bromo-6-((4-methoxybenzyl)oxy)quinoline

3-Bromoquinolin-6-ol (3.36g) was dissolved in N,N-dimethylformamide (30mL), potassium carbonate (4.14g) and 4-methoxybenzyl chloride (2.82g) were added successively, The reaction was carried out at 50° C. for 3 hours. After TLC showed that the reaction was complete, the system was lowered to room temperature, quenched with water, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain The title compound 4.58g.

MS (ESI) m/z (M+H) ⁺ = 344.0, 346.0.

Step 2: Preparation of diethyl 2-(6-((4-methoxybenzyl)oxy)quinolin-3-yl)malonate

3-Bromo-6-((4-methoxybenzyl)oxy)quinoline (1.0g), diethyl malonate (0.93g), tris(dibenzylideneacetone)dipalladium (0.14 g), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (0.14 g) and cesium carbonate (1.89 g) were dissolved in 1,4-dioxane (20 mL), Nitrogen was replaced three times, and the temperature was raised to 100° C. for 3 hours. TLC showed that the reaction was complete, the system was cooled to room temperature, quenched with water, extracted three times with ethyl acetate, combined the organic phases, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain the product 0.76g.

MS (ESI) m/z (M+H) ⁺ = 424.1.

Step 3: Preparation of ethyl 2-(6-((4-methoxybenzyl)oxy)quinolin-3-yl)acetate

Diethyl 2-(6-((4-methoxybenzyl)oxy)quinolin-3-yl)malonate (0.76 g) was dissolved in dimethyl sulfoxide (8 mL) and water (1 mL ), add lithium chloride (0.23g), and react at 140° C. for 7 hours. After TLC showed that the reaction was complete, the system was lowered to room temperature, quenched with water, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain The title compound 0.48g.

MS (ESI) m/z (M+H) ⁺ = 352.1.

Step 4: Preparation of 2-(6-((4-methoxybenzyl)oxy)quinolin-3-yl)ethanol

In an ice-water bath, ethyl 2-(6-((4-methoxybenzyl)oxy)quinolin-3-yl)acetate (0.48g) was dissolved in tetrahydrofuran (10mL), and lithium aluminum hydride ( 80mg), reacted for 1 hour. After TLC showed that the reaction was complete, water (0.1mL), 15% aqueous sodium hydroxide solution (0.1mL), and water (0.3mL) were added successively, dried over anhydrous magnesium sulfate, filtered, the filtrate was collected, concentrated, and the crude product was purified by column chromatography to obtain 0.31 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 310.1.

Step 5: Preparation of 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-((4-methoxybenzyl)oxy)quinoline

In an ice-water bath, 2-(6-((4-methoxybenzyl)oxy)quinolin-3-yl)ethanol (0.31g) was dissolved in tetrahydrofuran (6mL), imidazole (0.2g) and tert Butyldimethylsilyl chloride (0.36g), moved to 40°C and heated for 1 hour. After TLC showed that the reaction was complete, it was quenched by adding water, extracted three times with ethyl acetate, combined the organic phases, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain 0.42 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 424.2.

Step 6: Preparation of 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)quinolin-6-ol

3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-((4-methoxybenzyl)oxy)quinoline (0.42 g) was dissolved in methanol ( 10 mL), palladium carbon (60 mg) was added, replaced by hydrogen 3 times, and reacted overnight under hydrogen atmosphere. After TLC showed that the reaction was complete, it was filtered, washed, and the filtrate was collected and concentrated. The crude product was purified by column chromatography to obtain 0.15 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 304.1.

Step 7: Preparation of 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)quinolin-6-yl triflate

In an ice-water bath, 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)quinolin-6-ol (0.15 g) was dissolved in dichloromethane (5 mL), and pyridine ( 0.1g) and trifluoromethanesulfonic anhydride (0.21g), moved to room temperature for 1 hour. After TLC showed that the reaction was complete, it was quenched by adding water, extracted three times with ethyl acetate, combined the organic phases, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain 0.18 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 436.1.

Step 8: 3-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxo Preparation of borazin-2-yl)quinoline

3-(2-((tert-Butyldimethylsilyl)oxy)ethyl)quinolin-6-yl triflate (0.18g), bispinacol diboron (0.16 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (30 mg) and potassium acetate (0.12 g) were dissolved in 1,4-dioxane (6 mL), nitrogen Replaced three times, heated up to 100°C for 2 hours. TLC showed that the reaction was complete, the system was cooled to room temperature and then quenched with water, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain the title Compound 0.15g.

MS (ESI) m/z (M+H) ⁺ = 414.2.

Step 9: 3-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-6-(2,4-dichloro-7-((2-(trimethylsilyl) )ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)quinoline preparation

3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborin Alkyl-2-yl)quinoline (0.10g), 2,4-dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo [2,3-d]pyrimidine (0.12g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (35mg) and potassium carbonate (0.10g, 0.72mmol) were dissolved in 1,4-Dioxane (5 mL) and water (0.5 mL) were replaced with nitrogen three times, and the temperature was raised to 90° C. for 3 hours. After TLC showed that the reaction was complete, the system was lowered to room temperature, quenched with water, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain Product 80mg.

MS (ESI) m/z (M+H) ⁺ = 603.2.

Preparation 51: 2-(6-(2-(Methylamino)-4-((5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-3-yl)methoxy) -7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)quinolin-3-yl)methanesulfonic acid Preparation of ethyl ester

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 31.

MS (ESI) m/z (M+H) ⁺ = 735.2.

Preparation 52: Preparation of (4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyrimidin-2-yl)methanol

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Preparation Example 23 above.

MS (ESI) m/z (M+H) ⁺ = 285.2.

Preparation 53: 2-((2-((2-(Methylamino)-5-(3-((tetrahydro2H-pyran-2-yl)oxy)quinolin-6-yl)-7- ((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methylpyrimidin-4-yl)oxy ) Preparation of ethyl methanesulfonate

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 31.

MS (ESI) m/z (M+H) ⁺ = 752.2.

Preparation 54: (5-(4-(6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl ) butyl) pyridin-3-yl) the preparation of methanol

Step 1: Preparation of 3-(but-3-yn-1-yl)-6-(4-methoxybenzyl)oxy)quinolone

Dissolve 3-(6-((4-methoxybenzyl)oxy)quinolin-3-yl)propanal (400.0mg, 1.25mmol) in methanol (10mL), and add potassium carbonate (350.0mg , 2.50mmol), (1-diazo-2-oxopropyl) dimethyl phosphonate (360.0mg, 1.87mmol), react at room temperature for 2 hours. TLC showed that the reaction was complete. After concentration under reduced pressure, 10 mL of water was added to the system, extracted three times with ethyl acetate, the combined organic phase was backwashed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 200.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 318.0.

Step 2: 6-((4-methoxybenzyl)oxy)-3-(4-(5-((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridine-3 Preparation of -yl)but-3-yn-1-yl)quinoline

Weigh successively 3-(but-3-yn-1-yl)-6-(4-methoxybenzyl)oxyl)quinolone (200.0mg, 0.63mmol), 3-bromo-5-((((four Hydrogen-2H-pyran-2-yl)oxy)methyl)pyridine (260.0mg, 0.95mmol), triethylamine (130.0mg, 1.30mmol) and cuprous iodide (10.5mg, 0.01mmol) in a test tube , replacing nitrogen. Add 1,4-dioxane (4 mL) to dissolve, replace the nitrogen again after the addition, and raise the temperature to 90° C. for 1 hour. After TLC showed that the reaction was complete, 5 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography to obtain 180.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 509.2.

Step 3: Preparation of 3-(4-(5-(((tetrahydro2H-pyran-2-yl)oxy)methyl)pyridin-3-yl)butyl)quinolin-6-ol

Weigh 6-((4-methoxybenzyl)oxy)-3-(4-(5-(((tetrahydro2H-pyran-2-yl)oxy)methyl)pyridine-3- Base) but-3-yn-1-yl) quinoline (180.0mg, 0.35mmol) in a 50mL one-necked bottle, add Pd/C (40.0mg) and dissolve it with methanol (20mL), feed hydrogen into it at room temperature React for 12 hours. After TLC showed that the reaction was complete, the system was directly filtered to remove palladium carbon and then concentrated under reduced pressure to obtain 170.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 393.2.

Step 4: 3-(4-(5-(((tetrahydro2H-pyran-2-yl)oxy)methyl)pyridin-3-yl)butyl)quinolin-6-yltrifluoromethanesulfonate Preparation of esters

Weigh 3-(4-(5-(((tetrahydro2H-pyran-2-yl)oxy)methyl)pyridin-3-yl)butyl)quinolin-6-ol (170.0mg, 0.43 mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (153.0mg, 0.43mmol) in a test tube, added dichloromethane (5mL) to dissolve, added dropwise triethylamine (86.8mg, 0.86mmol), React at room temperature for 1 hour. After TLC showed that the reaction was complete, 5 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 100.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 525.2.

Step 5: Preparation of 3-(4-(5-(hydroxymethyl)pyridin-3-yl)butyl)quinolin-6-yl triflate

3-(4-(5-(((tetrahydro2H-pyran-2-yl)oxy)methyl)pyridin-3-yl)butyl)quinolin-6-yl trifluoromethanesulfonate (100.0 mg, 0.19 mmol) was dissolved in 1,4-dioxane solution (3 mL) of hydrochloric acid, and reacted at room temperature for 2 hours. After TLC showed that the reaction was complete, the system was directly spin-dried. The obtained crude product was purified by column chromatography to obtain 80.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 441.1.

Step 6: (5-(4-(6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl) Preparation of butyl)pyridin-3-yl)methanol

3-(4-(5-(Hydroxymethyl)pyridin-3-yl)butyl)quinolin-6-yl triflate (80.0 mg, 0.18 mmol), pinacol diboronate ( 50.0mg, 0.20mmol), potassium acetate (40.0mg, 0.40mmol) and DPPF palladium dichloride (15.0mg, 0.02mmol) were weighed in a microwave test tube, nitrogen was replaced, and 1,4-dioxane (3mL ), the nitrogen was replaced again, and the temperature of the system was raised to 90° C. for 3 hours. After TLC showed that the reaction was complete, the system was directly used for the next reaction in one pot without treatment.

MS (ESI) m/z (M+H) ⁺ = 419.2.

Step 7: (5-(4-(6-(2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] Preparation of pyrimidin-5-yl)quinolin-3-yl)butyl)pyridin-3-yl)methanol

(5-(4-(6-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)butyl)pyridine -3-yl)methanol (80.0mg, 0.18mmol), 2,4-dichloro-5-iodo-7-[(2-(trimethylsilyl)ethoxy)methyl]-7H-pyrrolo[2 ,3-d] pyrimidine (0.9 mg, 0.20 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (15.0 mg, 0.02 mmol) and potassium carbonate (55.0 mg, 0.40 mmol) Weigh into a microwave test tube, replace nitrogen, add 1,4-dioxane (3mL) and water (0.2mL) and replace nitrogen again, raise the temperature of the system to 90°C and react for 2 hours. Add saturated brine to the reaction system, extract with ethyl acetate several times, and dry over anhydrous sodium sulfate. The solvent was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain 50.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 594.1.

Preparation 55: 2-((5-(((2-((cyclopropylmethyl)amino)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)quinoline -6-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl ) the preparation of pyridin-3-yl) oxygen group) ethyl methanesulfonate

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 31.

MS (ESI) m/z (M+H) ⁺ = 791.2.

Preparation 56: Preparation of (4-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)methanol

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using the similar preparation method in Steps 2 and 3 of Preparation Example 23 above.

MS (ESI) m/z (M+H) ⁺ = 255.2.

Preparation 57: (2-(((2-(methylamino)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)quinolin-6-yl)-7-( (2-(Trimethylsilyl)ethoxy)methyl))-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)pyrimidin-4-yl)methyl Preparation of sulfonate

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 31.

MS (ESI) m/z (M+H) ⁺ = 722.2.

Preparation 58: Preparation of 3-(2-hydroxyethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

Step 1: Preparation of 6-(benzyloxy)-3-bromoquinoline

Weigh 3-bromoquinolin-6-ol (1.5g, 6.70mmol) and dissolve it in N,N-dimethylformamide (30mL), add potassium carbonate (1.85g, 13.39mmol) and benzyl bromide (1.37g , 8.04mmol), reacted at 50°C for 3 hours. After TLC showed that the reaction was complete, it was quenched with water and extracted three times with ethyl acetate. The organic phases were combined and backwashed once with saturated brine, dried over anhydrous sodium sulfate, and purified on a silica gel column to obtain 2.0 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 314.0, 316.0.

Step 2: Preparation of diethyl 2-(6-(benzyloxy)quinolin-3-yl)malonate

Weigh 6-(benzyloxy)-3-bromoquinoline (2.0g, 6.37mmol), diethyl malonate (1.92g, 12mmol), tris(dibenzylideneacetone) dipalladium (0.55g, 0.60mmol), 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl (0.57g, 1.2mmol), cesium carbonate (4.89g, 15.0mmol) and 1,4-dioxo Hexacyclic (36 mL). Nitrogen was replaced three times, and the temperature was raised to 100° C. for 3 hours. TLC showed that the reaction was complete. It was quenched by adding water, extracted three times with ethyl acetate, combined the organic phases and backwashed once with saturated brine, dried over anhydrous sodium sulfate, and purified on a silica gel column to obtain 1.6 g of the product.

MS (ESI) m/z (M+H) ⁺ = 394.2.

Step 3: Preparation of ethyl 2-(6-(benzyloxy)quinolin-3-yl)acetate

Diethyl 2-(6-(benzyloxy)quinolin-3-yl)malonate (1.4 g, 3.55 mmol) was dissolved in dimethyl sulfoxide (8 mL) and water (1 mL), at room temperature Lithium chloride (0.45 g, 10.7 mmol) was added and reacted at 140° C. for 20 hours. After TLC showed that the reaction was complete, it was quenched with water and extracted three times with ethyl acetate. The organic phases were combined and backwashed once with saturated brine, dried over anhydrous sodium sulfate, and purified on a silica gel column to obtain 0.82 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 322.1.

Step 4: Preparation of 2-(6-(benzyloxy)quinolin-3-yl)ethanol

Dissolve ethyl 2-(6-(benzyloxy)quinolin-3-yl)acetate (0.82g, 2.55mmol) in tetrahydrofuran (10mL), add lithium aluminum tetrahydride (145mg, 3.82mmol) under ice-cooling , reacted at 0°C for 1 hour. After TLC showed that the reaction was complete, water (0.2mL), 15% aqueous sodium hydroxide solution (0.2mL), water (0.6mL) were added successively, anhydrous magnesium sulfate was added, filtered, washed, the filtrate was concentrated, and purified on a silica gel column to obtain the title compound 0.61 g.

MS (ESI) m/z (M+H) ⁺ = 280.1.

Step 5: Preparation of 3-(2-hydroxyethyl)-6-hydroxyquinoline

Dissolve 2-(6-(benzyloxy)quinolin-3-yl)ethanol (0.50g, 1.78mmol) in methanol (20mL), add palladium carbon (125mg), replace with hydrogen, and react under hydrogen atmosphere for 4.5 hours . After TLC showed that the reaction was complete, it was filtered, washed, and the filtrate was concentrated and purified on a silica gel column to obtain 0.32 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 190.2.

Step 6: Preparation of 3-(2-hydroxyethyl)quinolin-6-yl triflate

3-(2-Hydroxyethyl)-6-hydroxyquinoline (0.30g, 0.49mmol) was dissolved in tetrahydrofuran (20mL), triethylamine (0.32g, 3.16mmol) and 1,1,1-tris Fluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (0.84g, 2.37mmol) was reacted at 75°C for 5 hours. TLC showed that the reaction was not complete, and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (0.40 g, 1.12 mmol) was added, and the reaction was continued for 8 hours. LCMS monitored the reaction to be complete. Concentrate to dryness, and purify on a silica gel column to obtain 0.50 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 322.1.

Step 7: Preparation of 3-(2-hydroxyethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

Weigh (2-hydroxyethyl) quinolin-6-yl trifluoromethanesulfonate (0.15g, 0.47mmol) and dissolve it in 1,4-dioxane (10mL), add biboronic acid pinacol ester ( 0.18g, 0.70mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (38mg, 0.047mmol), potassium acetate (91mg, 0.93mmol), Nitrogen was replaced three times, and the temperature was raised to 100° C. for 3.5 hours. TLC showed that the reaction was complete. Concentrate to dryness, and purify on a silica gel column to obtain 0.10 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 300.2.

Preparation 59: Preparation of (5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-3-yl)methanamine

Step 1: Preparation of 3-(azidomethyl)-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridine

Dissolve (5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-3-yl)methanol (0.36mg, 1.72mmol) in toluene (5mL), and add azide successively under ice-cooling Diphenyl phosphate (0.71g, 2.58mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.78g, 5.2mmol), and react at 90°C for 1 hour. After TLC showed that the reaction was complete, it was concentrated to dryness and purified on a silica gel column to obtain 0.35 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 235.1.

Step 2: Preparation of (5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-3-yl)methanamine

Weigh 3-(azidomethyl)-5-((tetrahydro-2H-pyran-2-yl)oxy)pyridine (0.35g, 1.5mmol) in a 25mL dry flask, add tetrahydrofuran (8mL) and Water (1 mL) was dissolved, then triphenylphosphine (0.78 g, 3.0 mmol) was added, and reacted overnight at room temperature. After TLC showed that the reaction was complete, it was concentrated to dryness and purified by column chromatography to obtain 0.25 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 209.1.

Preparation 60: 2-(6-(2-(Methylamino)-4-(((5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-3-yl)methyl) Preparation of ethyl amino)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)quinolin-3-yl)methanesulfonate

The title compound was prepared by using the corresponding commercial reagents and the product in the above-mentioned Preparation Example as raw materials, using the preparation method similar to Step 1-3 of the above-mentioned Preparation Example 28, and subsequent steps.

Step 4: 2-(6-(2-(Methylamino)-4-(((5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-3-yl)methyl)amino Preparation of )-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)quinolin-3-yl)ethyl methanesulfonate

2-(6-(2-(methylamino)-4-(((5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-3-yl)methyl)amino)- 7-Tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)phenoxy)ethan-1-ol (165mg, 0.24mmol) was dissolved in dichloromethane (5 mL), triethylamine (100 μL, 0.73 mmol) and methanesulfonyl chloride (38 μL, 0.49 mmol) were successively added under ice-cooling, and reacted at room temperature for 0.5 hours. After TLC showed that the reaction was complete, the system was concentrated under reduced pressure, and the obtained crude product was purified by column chromatography to obtain 100 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 758.2.

Preparation 61: 2-((5-((2-(cyclopropanecarboxamido)-5-(3-((tetrahydro2H-pyran-2-yl)oxy)quinolin-6-yl) -7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)pyridine-3- Base) Oxygen) Preparation of Ethyl Methanesulfonate

Step 1: N-(4-((5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methoxy)-5-(3- ((Tetrahydro 2H-pyran-2-yl)oxy)quinolin-6-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2, Preparation of 3-d]pyrimidin-2-yl)cyclopropanecarboxamide

6-(4-((5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methoxy)-2-chloro-7-( (2-(Trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-((tetrahydro2H-pyran-2- Base) oxy) quinoline (300mg, 0.38mmol) was dissolved in toluene (10mL), palladium acetate (16.8mg, 0.07mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine ( 47mg, 0.07mmol), cesium carbonate (247mg, 0.76mmol), nitrogen replacement system three times, and heated to 100 ° C under protection for 3h reaction, LCMS showed that the reaction was complete, concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 246 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 841.1.

Step 2: N-(4-((5-(2-hydroxyethoxy)pyridin-3-yl)methoxy)-5-(3-((tetrahydro2H-pyran-2-yl)oxy Base) quinoline-6-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)ring Preparation of propanecarboxamide

N-(4-((5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methoxy)-5-(3-(( Tetrahydro 2H-pyran-2-yl)oxy)quinolin-6-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d] pyrimidin-2-yl)cyclopropanecarboxamide (246mg, 0.29mmol) was dissolved in tetrahydrofuran (5mL), tetrabutylammonium fluoride (5mL) was added, and reacted at 25°C for 1 h. After LCMS showed that the reaction was complete, less Concentrate under pressure. The obtained crude product was purified by column chromatography to obtain 250 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 727.1.

Step 3: 2-((5-((2-(cyclopropanecarboxamido)-5-(3-((tetrahydro2H-pyran-2-yl)oxy)quinolin-6-yl)- 7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)pyridin-3-yl ) Oxygen) the preparation of ethyl methanesulfonate

N-(4-((5-(2-hydroxyethoxy)pyridin-3-yl)methoxy)-5-(3-((tetrahydro2H-pyran-2-yl)oxy) Quinolin-6-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)cyclopropanemethyl Amide (250mg, 0.34mmol) was dissolved in dichloromethane (5mL), triethylamine (101mg, 1.12mmol) was added at 25°C, methanesulfonyl chloride (77.5mg, 0.68mmol) was added dropwise, reacted for 0.5h, LCMS After showing that the reaction was complete, it was quenched with water, extracted with dichloromethane, and the organic phase was concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 160 mg of the title compound.

MS (ESI) m/z (M+H)+ = 805.1.

Preparation 62: Preparation of (5-[(1-[(tert-butyldimethylsilyl)oxy]propan-2-yl)oxy]pyridin-3-yl)methanol

Step 1: Preparation of (2-bromopropoxy)(tert-butyl)dimethylsilane

Dissolve 2-bromopropan-1-ol (300.0mg, 2.17mmol) in dichloromethane (5mL), add methylimidazole (510.0mg, 3.72mmol), tert-butyldimethylsilyl chloride (420.0mg , 2.22mmol), reacted at room temperature for 1 hour. After TLC showed that the reaction was complete, saturated brine was added to the reaction system, extracted several times with dichloromethane, and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain 320.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 254.2.

In subsequent steps, the title compound was prepared by using the corresponding commercial reagents as raw materials and using a preparation method similar to that of Preparation Example 6 above.

MS (ESI) m/z (M+H) ⁺ = 298.2.

Preparation 63: 2-((5-((2-(Methylamino)-5-(3-((tetrahydro2H-pyran-2-yl)oxy)quinolin-6-yl)-7- ((2-(Trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)pyridin-3-yl)oxy base) preparation of propyl methanesulfonate

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 31.

MS (ESI) m/z (M+H) ⁺ = 765.3.

Preparation 64: Preparation of (3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)methanol

Using the corresponding commercially available reagents as raw materials, the title compound was prepared by using a preparation method similar to that of Preparation Example 25 above.

MS (ESI) m/z (M+H) ⁺ = 209.1.

Preparation 65: Preparation of (3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)methanamine

Using the corresponding commercially available reagents as raw materials, the title compound was prepared using a preparation method similar to the above Preparation Example 59.

MS (ESI) m/z (M+H) ⁺ = 208.1.

Preparation 66: 2-(6-(2-(Methylamino)-4-(((3-((tetrahydro-2H-pyran-2-yl)oxy)benzyl)amino)-7-toluene Preparation of ethyl sulfonyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)quinolin-3-yl)methanesulfonate

Using the corresponding commercially available reagents as raw materials, the title compound was prepared using a preparation method similar to that of Preparation Example 60 above.

MS (ESI) m/z (M+H) ⁺ = 757.2.

Preparation 67: Preparation of (5-(2-((6-bromoquinolin-3-yl)oxy)propoxy)pyridin-3-yl)methanol

Step 1: Preparation of 2-((6-bromoquinolin-3-yl)oxy)propan-1-ol

6-bromoquinoline-3-ol (485mg, 2.16mmol)) was dissolved in N,N-dimethylformamide (10mL), then cesium carbonate (2.111g, 6.48mmol) and 2-bromopropane- 1-alcohol (300.22mg, 2.16mmol), heated to 80°C and reacted overnight. TLC showed that the reaction of the raw materials was complete. After cooling down to room temperature, the system was poured into water (50mL), extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. . The resulting crude product was separated by chromatography to obtain 260 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 389.2.

Step 2: Preparation of 2-((6-bromoquinolin-3-yl)oxy)propyl methanesulfonate

2-((6-bromoquinolin-3-yl)oxy)propan-1-ol (260 mg, 0.91 mmol) was dissolved in dichloromethane (20 mL), and triethylamine (275.8 mg, 2.72 mmol) was added successively React with methanesulfonyl chloride (125.1 mg, 1.1 mmol) at room temperature for 1 hour. After TLC showed that the reaction was complete, 10 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 300 mg of crude product.

MS (ESI) m/z (M+H) ⁺ = 360.2.

Step 3: Preparation of (5-(2-((6-bromoquinolin-3-yl)oxy)propoxy)pyridin-3-yl)methanol

5-(Hydroxymethyl)pyridin-3-ol (103.52mg, 0.83mmol)) was dissolved in N,N-dimethylformamide (10mL), then cesium carbonate (808.7mg, 2.48mmol) and 2 -((6-Bromoquinolin-3-yl)oxy)propyl methanesulfonate (300mg, 0.84mmol), heated to 80°C for overnight reaction. TLC showed that the reaction of the raw materials was complete. After cooling down to room temperature, the system was poured into water (50mL), extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. . The resulting crude product was separated by chromatography to obtain 162 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 389.0.

Preparation 68: (5-(2-((6-(2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2 , 3-d] pyrimidin-5-yl) quinoline-3-yl) oxy)propoxy)pyridin-3-yl)methanol

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 33.

MS (ESI) m/z (M+H) ⁺ = 626.2.

Preparation 69: Preparation of 2-amino-6-bromoquinolin-3-ol

Step 1: Preparation of 2-((4-methoxybenzyl)oxy)acetonitrile

Under an ice-water bath, (4-methoxyphenyl)methanol (10 g, 72.38 mmol) was added dropwise to a suspension of sodium hydride (3.76 g, 94.09 mmol) in anhydrous tetrahydrofuran (100 mL), and stirring was continued for 2 hours. 2-Bromoacetonitrile (10.42 g, 86.86 mmol) was slowly added dropwise to the reaction solution, and the dropwise addition was completed after 1 hour. After the addition was complete and reacted overnight, saturated aqueous ammonium chloride (200 mL) was added carefully. After complete addition, the mixture was filtered. Extracted 3 times with ethyl acetate and combined the organic phases. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was separated by column chromatography to obtain 9.9 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 178.2.

Step 2: Preparation of 6-bromo-3-((4-methoxybenzyl)oxy)quinolin-2-amine

Weigh successively 2-amino-5-bromobenzaldehyde (2.0 g, 10 mmol), 2-((4-methoxybenzyl) oxy) acetonitrile (1.949 g, 11 mmol) and dissolve in DMSO (40 mL), divide Potassium tert-butoxide (1.683g, 15mmol) was added in batches and reacted at room temperature for 2 hours. After the reaction was completed, the reaction was quenched by adding saturated ammonium chloride aqueous solution, extracted three times with ethyl acetate, combined the organic phases, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was separated by chromatography to obtain 1.0 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 359.2.

Step 3: Preparation of 2-amino-6-bromoquinolin-3-ol

Weigh 6-bromo-3-((4-methoxybenzyl)oxy)quinolin-2-amine (900 mg), dissolve it in 10 mL of trifluoroacetic acid, react at room temperature for 1 hour, and monitor the completion of the reaction by TLC. The crude product obtained by spin-drying the solvent was directly used in the next reaction.

MS (ESI) m/z (M+H) ⁺ = 239.0.

Preparation 70: Preparation of 2-((5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridin-3-yl)oxy)ethyl methanesulfonate

Step 1: 3-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-5-((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridine preparation of

Weigh successively (5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methanol (6g, 21.17mmol), 4-pyridine methylbenzenesulfonate Onium (1.01g, 4.02mmol) was dried in 1,4-dioxane (120mL); after stirring well, DHP (15mL, 164.05mmol) was added and reacted at 90°C for 2 hours. After the reaction was completed, the sample was directly mixed and separated by a chromatographic column to obtain 8.0 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 368.2.

In Step 2-3, the title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a similar preparation method to Step 3-4 of the aforementioned Preparation Example 31.

MS (ESI) m/z (M+H) ⁺ = 332.2.

Preparation 71: (5-(2-((2-amino-6-(2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- Preparation of pyrrolo[2,3-d]pyrimidin-5-yl)quinolin-3-yl)oxy)ethoxy)pyridin-3-yl)methanol

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 33.

MS (ESI) m/z (M+H) ⁺ = 627.2.

Preparation 72: Preparation of 6-bromo-3-hydroxy-1,2,4a,8a-tetrahydroquinolin-2-one

Step 1: Preparation of ethyl 6-bromo-3-hydroxy-2-oxo-1,2-dihydroquinoline-4-carboxylate

5-Bromoisatin (5g, 22.12mmol) was dissolved in ethanol (110mL), and 1,8-diazacyclo[5,4,0]undecene-7 (0.51g, 3.35mmol), followed by adding ethyl diazoacetate (5.05g, 44.24mmol) and stirring at 25°C for 15h. After LCMS showed that the reaction was complete, most of the solvent was concentrated under reduced pressure, and 1M dilute hydrochloric acid (80mL) was slowly added, with some bubbles After generation and solid formation, the stirring was continued for 2 h, the filter cake was collected by filtration, washed twice with water and ether, and dried to obtain 5.0 g of the target compound.

MS (ESI) m/z (M+H) ⁺ = 312.1.

Step 2: Preparation of 6-bromo-3-hydroxy-1,2,4a,8a-tetrahydroquinolin-2-one

Dilute ethyl 6-bromo-3-hydroxy-2-oxo-1,2-dihydroquinoline-4-carboxylate (4.97g, 15.92mmol) in water (100mL), add sodium hydroxide ( 2.55g, 63.68mmol), sealed and heated to 130°C for 16h, LCMS showed that the reaction was complete, then lowered to room temperature, slowly adjusted pH = 2 with 4M hydrochloric acid, filtered, washed with water to obtain a filter cake, dried to obtain 3.0g of the target compound .

MS (ESI) m/z (M+H) ⁺ = 240.1.

Preparation 73: Preparation of (5-(2-((6-bromo-2-methoxyquinolin-3-yl)oxy)ethoxy)pyridin-3-yl)methanol

Step 1: 6-Bromo-3-(2-((5-(((tetrahydro2H-pyran-2-yl)oxy)methyl)pyridin-3-yl)oxy)ethoxy)quinone Preparation of Lin-2(1H)-one

Dissolve 6-bromo-3-hydroxy-1,2,4a,8a-tetrahydroquinolin-2-one (1.0 g, 4.17 mmol) in isopropanol (15 mL) and add 1,8-diazepine Cyclo[5,4,0]undecene-7 (1.0g, 6.67mmol), the color of the reaction solution became darker, adding 2-((5-(((tetrahydro2H-pyran-2-yl)oxy )methyl)pyridin-3-yl)oxy)ethyl methylsulfonate (1.2g, 3.75mmol), heated to 100°C for 4h, after LCMS showed that the reaction was complete, the reaction solution was concentrated under reduced pressure, and dichloro Diluted with methane, washed once with 1M aqueous sodium hydroxide solution, then washed once with 0.1M aqueous hydrochloric acid solution, dried over anhydrous sodium sulfate, filtered, and concentrated under pressure to obtain a crude product, which was separated and purified by column chromatography to obtain 1.1 g of the target compound.

MS (ESI) m/z (M+H) ⁺ = 475.1.

Step 2: 6-Bromo-2-methoxy-3-(2-((5-(((tetrahydro2H-pyran-2-yl)oxy)methyl)pyridin-3-yl)oxy ) Preparation of ethoxy) quinoline

6-bromo-3-(2-((5-(((tetrahydro2H-pyran-2-yl)oxy)methyl)pyridin-3-yl)oxy)ethoxy)quinoline- 2(1H)-Kone (600 mg, 1.26 mmol) was dissolved in tetrahydrofuran (15 mL). Add tributylphosphine (1274.62mg, 6.3mmol) and methanol (403.70mg, 12.6mmol) sequentially at 25°C; after stirring evenly, add N,N,N',N'-tetramethylazodimethazine in one go Amide (1084.80 mg, 6.3 mmol). Stir at room temperature for 1 h. After LCMS showed that the reaction was complete, the insoluble matter was filtered out and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography to obtain 100 mg of the target compound.

MS (ESI) m/z (M+H) ⁺ = 489.1.

Step 3: Preparation of (5-(2-((6-bromo-2-methoxyquinolin-3-yl)oxy)ethoxy)pyridin-3-yl)methanol

6-Bromo-2-methoxy-3-(2-((5-(((tetrahydro2H-pyran-2-yl)oxy)methyl)pyridin-3-yl)oxy)ethyl Oxy)quinoline (100mg, 0.20mmol) was dissolved in 1,4-dioxane (5mL), and dioxane hydrochloride solution (4M) (3mL) was added, and stirred at room temperature for 2h. After LCMS showed that the reaction was complete, The organic solvent was directly condensed under reduced pressure, and steamed twice with dichloromethane to obtain 100 mg of crude product, which was directly used in the next reaction.

MS (ESI) m/z (M+H) ⁺ = 405.1.

Preparation 74: (5-(2-((6-(2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2, 3-d] Preparation of pyrimidin-5-yl)-2-methoxyquinolin-3-yl)oxy)ethoxy)pyridin-3-yl)methanol

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 33.

MS (ESI) m/z (M+H) ⁺ = 642.1.

Preparation 75: Preparation of (3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-fluorophenyl)methanol

Step 1: Preparation of (2-(3-bromo-5-fluorophenoxy)ethoxy)(tert-butyl)dimethylsilane

3-Bromo-5-fluorophenol (1.9g, 9.95mmol) was dissolved in N,N-dimethylformamide (30mL), cesium carbonate (4.87g, 15mmol) was added successively at room temperature, (2-bromoethyl Oxy)(tert-butyl)dimethylsilane (2.87g, 12mmol), and reacted at 50°C for 1 hour. After TLC showed that the reaction was complete, it was quenched with water and extracted three times with ethyl acetate. The organic phases were combined and backwashed once with saturated brine, dried over anhydrous sodium sulfate, and purified on a silica gel column to obtain 3.3 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 349.1.

Step 2: Preparation of ethyl 3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-fluorobenzoate

Weigh (2-(3-bromo-5-fluorophenoxy)ethoxy)(tert-butyl)dimethylsilane (2.4g, 6.88mmol) into a 100mL dry autoclave, add [1, 1′-bis(diphenylphosphino)ferrocene]palladium dichloride (0.50g, 0.688mmol), triethylamine (2.08g, 20.6mmol), ethanol (20mL), after carbon monoxide replacement, react at 100°C After 20 hours, when the reaction system returned to room temperature, samples were taken for monitoring. The reaction was basically complete. The system was spin-dried and purified by a flash silica gel column to obtain 1.5 g of the target product.

MS (ESI) m/z (M+H) ⁺ = 343.2.

Step 3: Preparation of (3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-fluorophenyl)methanol

Weigh 3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-fluorobenzoic acid ethyl ester (1.4g, 4.0mmol) in a 100mL dry reaction flask, add tetrahydrofuran (20 mL) was dissolved, and lithium aluminum hydride (0.23 g, 6.0 mmol) was added in portions under ice bath, and reacted at room temperature for 0.5 hours. After TLC shows that the reaction is complete, add 0.3mL water and 0.3mL 15% sodium hydroxide solution to the system under an ice bath, stir for 5 minutes, then add 1.8mL water, then add an appropriate amount of anhydrous magnesium sulfate, stir for 10 minutes, filter , the filter cake was washed three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 0.98 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 301.2.

Preparation 76: 2-(3-Fluoro-5-(((2-(methylamino)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)quinoline-6- Base)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)phenoxy base) preparation of ethyl methanesulfonate

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 31.

Preparation 77: Preparation of 4-vinyl-N-methyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine

Step 1: Preparation of 2-chloro-4-((4-methoxybenzyl)oxy)-7H-pyrrolo[2,3-d]pyrimidine

Sequentially weigh 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (5.0g, 26.6mmol), 4-methoxybenzyl alcohol (4.41g, 31.9mmol) in the reaction flask, add 1,4-Dioxane (70 mL), potassium tert-butoxide (11.94 g, 106.4 mmol) was added at room temperature, and the temperature was raised to 50° C. for 2 hours. TLC showed that the reaction was complete. Add ethyl acetate and water, extract, concentrate the organic phase, and purify through a silica gel column to obtain 7.5 g of the product.

MS (ESI) m/z (M+H) ⁺ = 290.1.

Step 2: Preparation of 2-chloro-4-((4-methoxybenzyl)oxy)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine

Weigh 2-chloro-4-((4-methoxybenzyl)oxy)-7H-pyrrolo[2,3-d]pyrimidine (7.5g, 25.9mmol) and dissolve it in dichloromethane (50mL), Triethylamine (6.5g, 64.7mmol), 4-dimethylaminopyridine (0.31g, 2.6mmol) and p-toluenesulfonyl chloride (7.4g, 38.8mmol) were added sequentially, and reacted at room temperature for 1 hour. TLC showed that the reaction was complete. Add dichloromethane and water, extract, concentrate the organic phase, and purify through a silica gel column to obtain 11.2 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 444.1.

Step 3: Preparation of 4-((4-methoxybenzyl)oxy)-N-methyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine

Weigh 2-chloro-4-((4-methoxybenzyl)oxy)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine (11.2g, 25.2mmol) dissolved in tetrahydrofuran (60 mL), added methylamine aqueous solution (40 mL), heated to 50 ° C for 2 hours, TLC showed that the reaction was complete. Add ethyl acetate and water, extract, concentrate the organic phase, and purify by silica gel column to obtain 4.58 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 439.1.

Step 4: Preparation of 4-chloro-N-methyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine

Weigh 4-((4-methoxybenzyl)oxy)-N-methyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine (4.5g, 10.26 mmol), phosphorus oxychloride (30 mL) was added, and the temperature was raised to 100° C. for 1 hour, and TLC showed that the reaction was complete. Remove phosphorus oxychloride under pressure, add crushed ice and ethyl acetate, extract, concentrate the organic phase, and purify by silica gel column to obtain 1.22 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 337.1.

Step 5: Preparation of 4-vinyl-N-methyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine

Sequentially weigh 4-chloro-N-methyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine (1.22g, 3.62mmol), potassium vinyl trifluoroborate (0.73 g, 5.43mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.4g, 0.54mmol), potassium carbonate (1.25g, 9.04mmol), 1,4- Dioxane (15 mL) and water (3 mL) were replaced with nitrogen three times, and the temperature was raised to 100° C. for 3 hours. TLC showed that the reaction was complete. It was quenched by adding water, extracted three times with ethyl acetate, combined the organic phases and backwashed once with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column to obtain 1.15 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 329.1.

Preparation 78: Preparation of 3-bromo-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridine

Step 1: Preparation of 2-(2-bromoethoxy)tetrahydro-2H-pyran

Weigh 2-bromoethanol (1.25g, 10mmol) and dissolve it in dichloromethane (15mL), add 3,4-dihydro-2H-pyran (1.0g, 12mmol) and pyridine 4-methylbenzenesulfonate ( 0.25g, 1.0mmol), reacted overnight at room temperature, and TLC showed that the reaction was complete. Dichloromethane and water were added, extracted, and the organic phase was concentrated to obtain a crude product, which was directly used in the next reaction.

Step 2: Preparation of 3-bromo-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridine

Weigh 5-bromopyridin-3-ol (1.74g, 10mmol) and dissolve it in N,N-dimethylformamide (15mL), add 2-(2-bromoethoxy)tetrahydro-2H-pyran crude product React with cesium carbonate (6.52g, 20mmol) at 50°C for 2 hours, TLC showed that the reaction was complete. Add ethyl acetate and water, extract, concentrate the organic phase, and purify through a silica gel column to obtain 2.5 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 302.1.

Preparation 79: 2-((5-(2-(5-iodo-2-(methylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)ethene Base) the preparation of pyridin-3-yl) oxy)ethanol

Step 1: N-Methyl-4-(2-(5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-3-yl)vinyl)- Preparation of 7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine

Sequentially weigh 4-vinyl-N-methyl-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine (0.85g, 2.55mmol), 3-bromo-5-( 2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridine (1.06g, 3.5mmol), palladium acetate (86mg, 0.38mmol), tetrabutylammonium bromide (1.23g , 3.82mmol), sodium bicarbonate (0.21g, 2.55mmol) and N,N-dimethylformamide (12mL), nitrogen replacement three times, heated to 100 ° C for 18 hours, TLC showed that the reaction was complete. It was quenched by adding water, extracted three times with ethyl acetate, combined the organic phases and backwashed once with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column to obtain 0.94 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 550.2.

Step 2: N-Methyl-4-(2-(5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-3-yl)ethenyl)- Preparation of 7H-pyrrolo[2,3-d]pyrimidin-2-amine

Weigh N-methyl-4-(2-(5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-3-yl)vinyl)-7 -Tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine (0.94g, 1.71mmol) was dissolved in 1,4-dioxane (15mL), and 4M aqueous potassium hydroxide solution was added ( 10 mL), the temperature was raised to 100° C. for 2 hours, and TLC showed that the reaction was complete. Add ethyl acetate and water, extract, concentrate the organic phase, and purify by silica gel column to obtain 0.55 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 396.2.

Step 3: 2,2,2-Trifluoro-N-methyl-N-(4-(2-(5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy Preparation of (yl)pyridin-3-yl)vinyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide

Weigh N-methyl-4-(2-(5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-3-yl)vinyl)-7H -pyrrolo[2,3-d]pyrimidin-2-amine (0.16g, 0.4mmol) was dissolved in pyridine (1.5mL), trifluoroacetic anhydride (0.17g, 0.8mmol), reacted at room temperature for 1 hour, TLC showed The response is complete. Add ethyl acetate and water, separate liquid extraction, wash the organic phase with saturated ammonium chloride, concentrate the organic phase, and purify by silica gel column to obtain 0.17 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 492.1.

Step 4: 2,2,2-Trifluoro-N-methyl-N-(5-iodo-4-(2-(5-(2-((tetrahydro-2H-pyran-2-yl)oxy) Preparation of (yl)ethoxy)pyridin-3-yl)vinyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide

Weigh 2,2,2-trifluoro-N-methyl-N-(4-(2-(5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy )pyridin-3-yl)vinyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide (0.17g, 0.35mmol) was dissolved in dichloromethane (6mL), added under ice-cooling N-iodosuccinimide (0.12 g, 0.52 mmol) was reacted under ice-cooling for 10 minutes, and TLC showed that the reaction was complete. Add ethyl acetate and water, extract, concentrate the organic phase, and purify through a silica gel column to obtain 0.17 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 618.1.

Step 5: 2,2,2-Trifluoro-N-methyl-N-(5-iodo-4-(2-(5-(2-((tetrahydro-2H-pyran-2-yl)oxy) Preparation of (yl)ethoxy)pyridin-3-yl)vinyl)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide

Weigh 2,2,2-trifluoro-N-methyl-N-(5-iodo-4-(2-(5-(2-((tetrahydro-2H-pyran-2-yl)oxy) ) ethoxy) pyridin-3-yl) vinyl) -7H-pyrrolo[2,3-d] pyrimidin-2-yl) acetamide crude product was dissolved in dichloromethane (5mL), and triethylamine ( 0.1g, 1.0mmol), 4-dimethylaminopyridine (8mg, 0.07mmol) and p-toluenesulfonyl chloride (97mg, 0.51mmol), reacted at room temperature for 1 hour, and TLC showed that the reaction was complete. Add dichloromethane and water, extract, concentrate the organic phase, and purify by silica gel column to obtain 0.21 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 772.1.

Step 6: 2-((5-(2-(5-iodo-2-(methylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)ethenyl ) the preparation of pyridin-3-yl) oxy)ethanol

Weigh 2,2,2-trifluoro-N-methyl-N-(5-iodo-4-(2-(5-(2-((tetrahydro-2H-pyran-2-yl)oxy) )ethoxy)pyridin-3-yl)vinyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide (0.21g, 0.27mmol) was dissolved in di Chloromethane (6 mL) was added with 4M dioxane hydrochloride solution (2 mL), and reacted at room temperature for 2 hours. TLC showed that the reaction was complete. Concentrate to dryness to obtain 0.16g of crude product.

MS (ESI) m/z (M+H) ⁺ = 592.0.

Preparation 80: 2-((5-(2-(2-(methylamino)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)quinolin-6-yl Preparation of )-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)vinyl)pyridin-3-yl)oxy)methanesulfonate ethyl ester

Step 1: 2-((5-(2-(2-(Methylamino)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)quinolin-6-yl) - Preparation of 7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)vinyl)pyridin-3-yl)oxy)ethanol

Sequentially weigh 2-((5-(2-(5-iodo-2-(methylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)vinyl )pyridin-3-yl)oxy)ethanol (0.16g, 0.27mmol), 3-((tetrahydro-2H-pyran-2-yl)oxy)-6-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.14g, 0.39mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloro Palladium chloride (0.04g, 0.054mmol), potassium carbonate (0.11g, 0.81mmol), 1,4-dioxane (6mL) and water (1.2mL), replaced with nitrogen three times, heated to 90°C for 3 hours, TLC showed the reaction was complete. It was quenched by adding water, extracted three times with ethyl acetate, combined the organic phases and backwashed once with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column to obtain 0.17 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 693.2.

Step 2: 2-((5-(2-(2-(Methylamino)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)quinolin-6-yl) - Preparation of ethyl 7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)vinyl)pyridin-3-yl)oxy)methanesulfonate

2-((5-(2-(2-(methylamino)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)quinolin-6-yl)-7 -Tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)vinyl)pyridin-3-yl)oxy)ethanol (0.17g, 0.25mmol) was dissolved in dichloromethane (5mL) , added triethylamine (0.1 g, 1.0 mmol) and methanesulfonyl chloride (57 mg, 0.5 mmol) at room temperature, and reacted at room temperature for 0.5 hours after the addition was complete. After TLC showed that the reaction was complete, 10 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, and the organic phase was backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 0.19 g of crude product was obtained.

MS (ESI) m/z (M+H) ⁺ = 771.2.

Preparation 81: N-(4-((((tert-Butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)methyl)amino)-5-(3-((4- Preparation of methoxybenzyl)oxy)quinolin-6-yl)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)cyclopropanecarboxamide

Step 1: N-((4-((tert-butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)methyl)-2-chloro-5-(3-((4- Preparation of methoxybenzyl)oxy)quinolin-6-yl)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Weigh N-((4-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)methyl)-2-chloro-5-iodo-7-toluenesulfonyl -7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.2g, 1.75mmol), 3-((4-methoxybenzyl)oxy)-6-(4,4,5, 5-Tetramethyl-1,3,2-dioxobenzaldehyde-2-yl)quinoline (686.0mg, 1.75mmol) and potassium carbonate (483.0mg, 3.5mmol), add 1,4-dioxane (10mL) and water (1mL) were dissolved, and [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (128.0mg, 0.18mmol) was added after replacing the nitrogen, and the nitrogen was replaced again after the addition , heated to 90°C for 1 hour. After TLC showed that the reaction was complete, 10 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 1.1 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 822.1.

Step 2: N-(4-((((tert-butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)methyl)amino)-5-(3-((4-methyl Preparation of oxybenzyl)oxy)quinolin-6-yl)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)cyclopropanecarboxamide

Weigh N-((4-((tert-butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)methyl)-2-chloro-5-(3-((4- Methoxybenzyl)oxy)quinolin-6-yl)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.1g, 1.34mmol), cyclopropanamide (569mg, 6.70mmol), tris(dibenzylideneacetone)dipalladium (61.0mg, 0.07mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (63.0 mg, 0.13mmol), cesium carbonate (871mg, 2.68mmol) in a reaction flask, add the solvent dioxane (10mL) to dissolve, the system was ventilated three times with nitrogen, reacted at 90°C for 3 hours, and LCMS monitored the complete reaction of the raw materials. The system was quenched with water, extracted with ethyl acetate, concentrated, and the resulting crude product was separated by column chromatography to obtain 800 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 871.3.

Preparation 82: Preparation of (5-(2-((7-bromoquinoxalin-2-yl)oxy)ethoxy)pyridin-3-yl)methanol

Step 1: 7-Bromo-2-(2-((5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridin-3-yl)oxy)ethoxy) Preparation of quinoxaline

2-(((5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridin-3-yl)oxy)ethan-1-ol (0.9 g, 3.55 mmol) Dissolve in tetrahydrofuran (20mL), add sodium hydride (220mg, 5.3mmol) under ice-cooling, react at room temperature for 0.5 hours, then add 7-bromo-2-chloroquinoxaline. After TLC shows that the reaction is complete, add ice water (1 mL) to quench the reaction, add anhydrous sulfuric acid to dry, filter, collect the filtrate and concentrate, the obtained crude product is purified by column chromatography to obtain 1.55 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 460.1.

Step 2: Preparation of (5-(2-((7-bromoquinoxalin-2-yl)oxy)ethoxy)pyridin-3-yl)methanol

7-bromo-2-(2-((5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridin-3-yl)oxy)ethoxy)quinoxa Phenyl (500mg, 1.09mmol) was dissolved in dichloromethane (10mL), added with 4M hydrochloric acid/1,4-dioxane solution (5mL), and reacted at room temperature for 0.5 hours. After TLC showed that the reaction was complete, the system was concentrated under reduced pressure, and the obtained crude product was purified by column chromatography to obtain 400 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 376.0.

Preparation 83: (5-(2-((7-(2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2 , 3-d] pyrimidin-5-yl) quinoxalin-2-yl) oxy) ethoxy) pyridin-3-yl) the preparation of methanol

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 33.

MS (ESI) m/z (M+H) ⁺ = 613.1.

Preparation 84: Preparation of tert-butyl ((5-(2-((7-bromoquinoxalin-2-yl)oxy)methyl)pyridin-3-yl)methyl)carbamate

Step 1: Preparation of 2-(2-((5-(azidomethyl)pyridin-3-yl)oxy)ethoxy)-7-bromoquinoxaline

Weigh (5-(2-((7-bromoquinoxalin-2-yl)oxy)methyl)pyridin-3-yl)methanol (0.4g, 1.06mmol), diphenyl phosphoric azide (0.36 mL, 1.59mmol) was dissolved in toluene (10mL), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.32mL, 2.12mmol) was slowly added dropwise. Nitrogen was replaced three times, and the temperature was raised to 90° C. for 1 hour. TLC showed that the reaction was complete. The system was concentrated and purified on a silica gel column to obtain 330 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 401.2.

Step 2: Preparation of (5-(2-((7-bromoquinoxalin-2-yl)oxy)methyl)pyridin-3-yl)methanamine

Weigh 2-(2-((5-(azidomethyl)pyridin-3-yl)oxy)ethoxy)-7-bromoquinoxaline (330mg, 0.825mmol) dissolved in tetrahydrofuran (10mL) and To water (1 mL), triphenylphosphine (0.432 g, 1.65 mmol) was added at room temperature, and reacted overnight at room temperature. After TLC showed that the reaction was complete, the system was concentrated and purified on a silica gel column to obtain 0.265 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 375.2.

Step 3: Preparation of tert-butyl ((5-(2-((7-bromoquinoxalin-2-yl)oxy)methyl)pyridin-3-yl)methyl)carbamate

Weigh (5-(2-((7-bromoquinoxalin-2-yl)oxy)methyl)pyridin-3-yl)methanamine (0.33g, 0.694mmol) and dissolve in dichloromethane (10mL) In the mixture, triethylamine (0.2 mL, 1.4 mmol) was added under ice-cooling, and di-tert-butyl dicarbonate (0.243 mL, 1.06 mmol) was added dropwise, and reacted at room temperature for 1 hour. After TLC showed that the reaction was complete, the system was concentrated and purified on a silica gel column to obtain 0.33 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 475.3.

Preparation 85: tert-Butyl((5-(2-((7-(2,4-dichloro-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)quinone Preparation of oxalin-2-yl)oxy)ethoxy))pyridin-3-yl)methyl)carbamate

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 33.

MS (ESI) m/z (M+H) ⁺ = 735.2.

Preparation 86: 3-((4-Methoxybenzyl)oxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 Preparation of -yl)-2-(trifluoromethyl)quinoline

Step 1: Preparation of 6-bromo-3-hydroxy-2-(trifluoromethyl)quinoline-4-carboxylic acid

Sequentially weigh 5-bromoindoline-2,3-dione (4.0g, 17.7mmol) and calcium hydroxide (1.3g, 17.7mmol) in a one-mouth bottle; add water (120mL), and react at 80°C for 1h , cooled to 60°C. At this temperature, 3-bromo-1,1,1-trifluoroacetone (3.38 g, 17.7 mmol) was added, and the temperature was raised to 80° C. to react overnight. TLC showed that the reaction of the starting material was complete. The reaction system was poured into water (50mL), extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and the resulting crude product was separated by column chromatography to obtain 800.0 mg of the title compound .

MS (ESI) m/z (M+H) ⁺ = 336.0.

Step 2: Preparation of 6-bromo-2-(trifluoromethyl)quinolin-3-ol

Add water (8mL) to 6-bromo-3-hydroxy-2-(trifluoromethyl)quinoline-4-carboxylic acid (400mg, 1.2mmol), and slowly add 12M hydrochloric acid (4.0mL) at room temperature. After the addition, The system was reacted overnight at 120°C. TLC showed that the raw material was completely consumed. The system was added with 50 ml of water, extracted three times with ethyl acetate, backwashed twice with saturated sodium chloride, dried and concentrated to obtain 800 mg of crude product, which was directly used in the next reaction.

MS (ESI) m/z (M+H) ⁺ = 292.0.

Step 3: Preparation of 6-bromo-3-((4-methoxybenzyl)oxy)-2-(trifluoromethyl)quinoline

Dissolve 6-bromo-2-(trifluoromethyl)quinolin-3-ol (800mg, 2.7mmol) in N,N-dimethylformamide (20mL), and add cesium carbonate (3.8g, 27.4mmol) and p-methoxybenzylamine (510mg, 3.3mmol). It was reacted at room temperature for 5 h, and TLC showed that the reaction was complete. Pour the reaction system into water (100 mL), extract with ethyl acetate, combine the organic phases, backwash once with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate. The obtained crude product was separated by column chromatography to obtain 750 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 412.1.

Step 4: 3-((4-methoxybenzyl)oxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- base)-2-(trifluoromethyl)quinoline preparation

6-Bromo-3-((4-methoxybenzyl)oxy)-2-(trifluoromethyl)quinoline (740mg, 1.8mmol), biboronic acid pinacol ester (690mg, 2.7mmol) , potassium acetate (530mg, 5.4mmol), and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (130mg, 0.2mmol) were added to the reaction flask all at once. After nitrogen replacement, 1,4-dioxane (15 mL) was added to dissolve the system, nitrogen replacement system was performed three times, and under nitrogen atmosphere, the temperature was raised to 90°C for 2 hours of reaction. TLC showed that the reaction was complete, and saturated brine was added, extracted three times with ethyl acetate, the organic phases were combined and backwashed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 830 mg of crude product.

MS (ESI) m/z (M+H) ⁺ = 460.2.

Preparation 87: N-((4-((tert-Butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)methyl)-2-chloro-5-(3-((4 -Methoxybenzyl)oxy)-2-(trifluoromethyl)quinolin-6-yl)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine preparation

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 33.

MS (ESI) m/z (M+H) ⁺ = 885.2.

Preparation 88: Preparation of (5-(1-(((6-bromoquinolin-3-yl)oxy)methyl)cyclopropoxy)pyridin-3-yl)methanol

Step 1: Preparation of 5-(hydroxymethyl)pyridin-3-ol

Dissolve methyl 5-hydroxypyridine-3-carboxylate (5g, 32.65mmol) in tetrahydrofuran (200mL), add lithium aluminum hydride (1.37g, 36.04mmol) in batches under ice-cooling, and raise the temperature to 50°C after addition , reacted for 8h, after the reaction was complete, cooled to 0°C, added dropwise water (1.37mL), 15% aqueous sodium hydroxide solution (1.37mL), water (4mL) precipitated a large amount of off-white solid, filtered, and used DCM:MeOH=10 : 1 to wash the filter cake, concentrate the filtrate to obtain the crude product, and finally separate and purify by column chromatography to obtain 2.2 g of the target compound.

MS (ESI) m/z (M+H) ⁺ = 126.1.

Step 2: Preparation of ethyl 4-bromo-2-((5-(hydroxymethyl)pyridin-3-yl)oxy)butanoate

5-(Hydroxymethyl)pyridin-3-ol (1700mg, 13.59mmol) was dissolved in DMF (30mL), and methyl 2,4-dibromobutyrate (5298.47mg, 20.38mmol), carbonic acid Potassium (3756.55 mg, 27.18 mmol). React at 25°C for 1.5 hours, LCMS monitors that the reaction is complete, pour the reaction system into water to quench the reaction, extract three times with ethyl acetate, combine the organic phases, backwash once with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate . Separation and purification by column chromatography yielded 1.1 g of the target compound.

MS (ESI) m/z (M+H) ⁺ = 318.1.

Step 3: Preparation of methyl 4-bromo-2-[(5-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-3-yl)oxy]butanoate

Dissolve ethyl 4-bromo-2-((5-(hydroxymethyl)pyridin-3-yl)oxy)butanoate (1100 mg, 3.62 mmol) in dichloromethane (50 mL), and add t- Butyldimethylsilyl chloride (818.41mg, 5.43mmol) and N-methylimidazole (594.40mg, 7.24mmol) were reacted at room temperature for 2h. TLC monitoring shows that a small amount of raw material remains in the reaction, and the reaction is terminated. The reaction system is poured into water (10mL) to quench the reaction, extracted 3 times with dichloromethane, combined with the organic phase, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, Filter and concentrate. The obtained crude product was separated and purified by column chromatography to obtain 500 mg of the target compound.

MS (ESI) m/z (M+H) ⁺ = 432.1.

Step 4: Preparation of ethyl 1-((5-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)oxy)cyclopropane-1-carboxylate

4-Bromo-2-[(5-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-3-yl)oxy]butanoic acid methyl ester (500mg, 1.20mmol) was dissolved In tetrahydrofuran (40 mL), potassium tert-butoxide (161.58 mg, 1.44 mmol) was added to react at 25° C. for 1.5 hours. After TLC showed that the reaction was complete, 10 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 375 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 352.1.

Step 5: Preparation of (1-[(5-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-3-yl)oxy]cyclopropyl)methanol

Ethyl 1-((5-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)oxy)cyclopropane-1-carboxylate (375 mg, 1.11 mmol) Dissolve in tetrahydrofuran (20 mL), and add lithium aluminum hydride (46.34 mg, 1.22 mmol) at 25°C to react for 1.5 hours. After LCMS showed that the reaction was complete, 47uL of water, 47uL of 15% sodium hydroxide, and 141uL of water were added to the system to quench the reaction, filtered, and concentrated under reduced pressure. Obtained 400 mg crude product of the title compound, which was directly used in the next reaction.

MS (ESI) m/z (M+H) ⁺ = 310.1.

Step 6: Preparation of methyl (1-((5-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)oxy)cyclopropyl)methylsulfonate

Dissolve (1-[(5-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-3-yl)oxy]cyclopropyl)methanol (350mg, 1.13mmol) in di Chloromethane (15 mL), diisopropylethylamine (290 mg, 2.26 mmol) and methanesulfonyl chloride (190 mg, 1.69 mmol) were added, and reacted at 25°C for 1 hour. After TLC showed that the reaction was complete, 50 mL of water was added to the system, extracted three times with dichloromethane, the organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 356 mg of the crude product of the title compound.

MS (ESI) m/z (M+H) ⁺ = 388.1.

Step 7: 6-Bromo-3-((1-((5-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)oxy)cyclopropyl)methyl Preparation of oxy)quinoline

Methyl (1-((5-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)oxy)cyclopropyl)methanesulfonate (300 mg, 0.97 mmol) was dissolved in N,N-dimethylformamide (10 mL), 7-bromonaphthalene-2-ol (259.65 mg, 1.16 mmol) and cesium carbonate (632.09 mg, 1.94 mmol) were added, and reacted at 50°C for 10 h. After TLC showed that the reaction was complete, 50 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 375 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 515.1.

Step 8: Preparation of (5-(1-(((6-bromoquinolin-3-yl)oxy)methyl)cyclopropoxy)pyridin-3-yl)methanol

6-bromo-3-((1-((5-((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)oxy)cyclopropyl)methoxy) Quinoline (375mg, 0.73mmol) was dissolved in tetrahydrofuran (4mL), tetra-n-butylammonium fluoride (1.05g, 4mmol) was added, and reacted at 25°C for 1 hour. After TLC showed that the reaction was complete, 10 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 280 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 401.1.

Preparation 89: (5-(1-{[(7-(2,4-dichloro-7-[(2-(trimethylsilyl)ethoxy)methyl]-7H-pyrrolo[ Preparation of 2,3-d]pyrimidin-5-yl)naphthalene-2-yl)oxy]methyl}cyclopropoxy)pyridin-3-yl)methanol

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 33.

MS (ESI) m/z (M+H) ⁺ = 638.2.

Preparation 90: Preparation of (S)-(5-(2-((6-bromoquinolin-3-yl)oxy)propoxy)pyridin-3-yl)methanol

Step 1: Preparation of (R)-1-(tert-butyldimethyl)oxy)propan-2-ol

Dissolve (R)-propane-1,2-diol (1.0g, 13.14mmol) in dichloromethane (20mL), add 1H-imidazole (1.3g, 19.71mmol) and tert-butyldimethyl chloride in sequence Silane (2.4 g, 15.76 mmol) was reacted at room temperature for 1 hour. After TLC showed that the reaction was complete, saturated brine was added, extracted several times with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain 1.8 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 191.1.

Step 2: Preparation of (S)-6-bromo-3-((1-((tert-butyldimethylsilyl)oxy)propan-2-yl)oxy)quinoline

(R)-1-(tert-butyldimethyl)oxy)propan-2-ol (0.5g, 2.63mmol) was dissolved in tetrahydrofuran (10mL), and 6-bromoquinolin-3-ol (0.7 g, 3.16mmol) and triphenylphosphine (1.5g, 5.79mmol), and finally diisopropyl azodicarboxylate (1.0g, 5.26mmol) was added dropwise, and reacted at room temperature for 1 hour. After TLC showed that the reaction was complete, saturated brine was added, extracted several times with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain 780.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 396.1.

Step 3: Preparation of (S)-2-((6-bromoquinolin-3-yl)oxy)propan-1-ol

Dissolve (S)-6-bromo-3-((1-((tert-butyldimethylsilyl)oxy)propan-2-yl)oxy)quinoline (450.0mg, 1.14mmol) in A solution of hydrochloric acid in dioxane (5 mL) was reacted at room temperature for 1 hour. After TLC showed that the reaction was complete, the system was directly spin-dried for the next reaction.

MS (ESI) m/z (M+H) ⁺ = 282.0.

Step 4: Preparation of (S)-2-((6-bromoquinolin-3-yl)oxy)propyl methanesulfonate

Dissolve (S)-2-((6-bromoquinolin-3-yl)oxy)propan-1-ol (250.0 mg, 0.89 mmol) in dichloromethane (5 mL), and add triethylamine ( 180.0mg, 1.78mmol) and methanesulfonyl chloride (110.0mg, 0.93mmol), react at room temperature for 2 hours. After TLC showed that the reaction was complete, saturated brine was added, extracted several times with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain 280.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 360.0.

Step 5: Preparation of (S)-(5-(2-((6-bromoquinolin-3-yl)oxy)propoxy)pyridin-3-yl)methanol

(S)-2-((6-bromoquinolin-3-yl)oxy)propyl methanesulfonate (280.0 mg, 0.78 mmol) was dissolved in N,N-dimethylformamide (10 mL) , cesium carbonate (507.0mg, 1.56mmol) and 5-(hydroxymethyl)pyridin-3-ol (97.0mg, 0.78mmol) were added and reacted at room temperature for 12 hours. After TLC showed that the reaction was complete, saturated brine was added, extracted several times with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain 260 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 389.0.

Preparation 91: (S)-(5-(2-((6-(2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- Preparation of pyrrolo[2,3-d]pyrimidin-5-yl)quinolin-3-yl)oxy)propoxy)pyridin-3-yl)methanol

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 33.

MS (ESI) m/z (M+H) ⁺ = 626.2.

Preparation 92: Preparation of (R)-(5-(2-((6-bromoquinolin-3-yl)oxy)propoxy)pyridin-3-yl)methanol

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 90.

MS (ESI) m/z (M+H) ⁺ = 389.0.

Preparation 93: (R)-(5-(2-((6-(2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- Preparation of pyrrolo[2,3-d]pyrimidin-5-yl)quinolin-3-yl)oxy)propoxy)pyridin-3-yl)methanol

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 33.

MS (ESI) m/z (M+H) ⁺ = 626.2.

Preparation 94: Preparation of (2-(methylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanesulfonate

Step 1: Preparation of (((4-methoxybenzyl)oxy)methyl)potassium trifluoroborate

Weigh 4-methoxybenzyl alcohol (6.22g, 45mmol) and dissolve it in tetrahydrofuran (45mL), add sodium hydride (1.80g, 45mmol) in batches under an ice-water bath, stir for 15 minutes, then raise the temperature to 35°C for 30 minutes . The temperature was cooled in an ice-water bath, potassium (bromomethyl)trifluoroborate (3.01 g, 15 mmol) was added, and the temperature was raised to 35° C. for 5 hours. A 4.5M aqueous solution of potassium hydrogen fluoride (7.5 mL) was added at room temperature, followed by stirring for 0.5 hours. The system was concentrated to dryness, slurried by adding ether, and filtered to collect the solid. Add acetonitrile to the solid, heat to reflux, filter while hot, repeat the operation several times, and concentrate the filtrate to dryness. 3.0 g of the title compound were obtained.

MS (ESI) m/z (M) ⁺ = 219.1.

Step 2: 4-(((4-methoxybenzyl)oxy)methyl)-N-methyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine preparation of

Weigh successively 4-chloro-N-methyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine (0.87g, 2.58mmol), (((4-methoxy Benzyl)oxy)methyl)potassium trifluoroborate (0.67g, 2.58mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.21g, 0.258mmol) , potassium carbonate (1.07g, 7.74mmol), 1,4-dioxane (15mL) and water (1.5mL), replaced with nitrogen three times, heated to 110°C for 7 hours, TLC showed that some raw materials remained. Add (((4-methoxybenzyl)oxy)methyl)potassium trifluoroborate (0.67g, 2.58mmol), [1,1′-bis(diphenylphosphino)ferrocene]di Palladium chloride (0.21g, 0.258mmol) was reacted overnight at 110°C. TLC showed that the reaction of the starting material was almost complete. Ethyl acetate and water were added, separated and extracted, the combined organic phases were backwashed once with saturated brine, dried over anhydrous sodium sulfate, and purified on a silica gel column to obtain 0.77 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 453.1.

Step 3: Preparation of (2-(methylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanol

Weigh 4-(((4-methoxybenzyl)oxy)methyl)-N-methyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine ( 0.77g, 1.70mmol) was dissolved in dichloromethane (10mL), trifluoroacetic acid (5mL) was added, and reacted at room temperature for 1 hour, TLC showed that the raw material was completely reacted. Concentrate to dryness, make basic with triethylamine, and purify on a silica gel column to obtain 0.42 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 333.1.

Step 4: Preparation of (2-(methylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanesulfonate

Weigh (2-(methylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanol (0.42g, 1.26mmol) and dissolve in dichloromethane (5mL) In , triethylamine (0.52mL, 3.75mmol) and methanesulfonic anhydride (0.33g, 1.89mmol) were added, and reacted at room temperature for 1 hour. TLC showed that the raw materials were completely reacted. Concentrate to dryness, and purify on a silica gel column to obtain 0.37 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 441.1.

Preparation 95: Preparation of 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-ol

Step 1: Preparation of 3-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridine

Weigh 5-bromopyridin-3-ol (3.48g, 20mmol) and dissolve it in N,N-dimethylformamide (50mL), add (2-bromoethoxy)(tert-butyl)dimethylsilane (5.74g, 24mmol) and cesium carbonate (13.12g, 40mmol) were reacted at 40°C for 2 hours, and TLC showed that the reaction was complete. Ethyl acetate and water were added, separated and extracted, the organic phase was concentrated to dryness, and the crude product was purified by column chromatography to obtain 6.14 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 332.0.

Step 2: 3-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-di Preparation of Oxaborolan-2-yl)pyridine

Sequentially weigh 3-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridine (1.0g, 3.0mmol), biboronic acid pinacol ester (0.9g, 3.6mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (20.22g, 0.3mmol), potassium acetate (0.9g, 9.0mmol) and 1,4-diox Hexacyclic (15 mL), replaced by nitrogen three times, heated to 100°C for 5 hours, TLC showed that the reaction was complete. Filter, wash with ethyl acetate, and concentrate to obtain a crude product, which is directly used in the next reaction.

MS (ESI) m/z (M+H) ⁺ = 380.2.

Step 3: Preparation of 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-ol

Weigh 3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-diox The crude borolan-2-yl)pyridine was dissolved in 1,4-dioxane (15 mL), hydrogen peroxide (0.5 mL, 4.5 mmol) was added, and the reaction was carried out at room temperature for 2 hours. TLC showed that the reaction was complete. Ethyl acetate and water were added, separated and extracted, the organic phase was concentrated to dryness, and the crude product was purified by column chromatography to obtain 0.62 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 270.1.

Preparation 96: N-(4-(((5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)oxy)methyl)-5 Preparation of -iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2,2-trifluoro-N-methylacetamide

Step 1: 4-((((5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)oxy)methyl)-N-methyl - Preparation of 7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine

Weigh (2-(methylamino)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanesulfonate (0.37g, 0.9mmol) and dissolve in N, To N-dimethylformamide (5 mL), add cesium carbonate (0.59 g, 1.8 mmol) and 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridine-3 -Alcohol (0.29g, 1.08mmol), reacted at 30°C for 1 hour, TLC showed that the starting material was completely reacted. Ethyl acetate and water were added, separated and extracted, the combined organic phases were backwashed once with saturated brine, dried over anhydrous sodium sulfate, and purified on a silica gel column to obtain 0.30 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 584.2.

For the synthesis of steps 2-5, the title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to the aforementioned Preparation Example 79.

MS (ESI) m/z (M+H) ⁺ = 806.1.

Preparation 97: 2-((5-((2-(methylamino)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)quinolin-6-yl)- Preparation of ethyl 7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methoxy)pyridin-3-yl)oxy)methanesulfonate

Step 1: 4-(((5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)oxy)methyl)-N-methyl- 5-(3-((tetrahydro-2H-pyran-2-)yl)oxy)quinolin-6-yl)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine- Preparation of 2-amine

N-(4-(((5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)oxy)methyl)-5- Iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2,2-trifluoro-N-methylacetamide (0.14g, 0.17mmol), 3 -((tetrahydro-2H-pyran-2-yl)oxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Quinoline (86mg, 0.24mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (24mg, 0.032mmol), potassium carbonate (67mg, 0.48mmol), 1,4 - Dioxane (5 mL) and water (1 mL), replaced by nitrogen three times, heated to 90° C. for 3 hours, TLC showed that the reaction was complete. It was quenched by adding water, extracted three times with ethyl acetate, combined the organic phases and backwashed once with saturated brine, dried over anhydrous sodium sulfate, and purified on a silica gel column to obtain 0.13 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 811.3.

Step 2: 2-((5-((2-(Methylamino)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)quinolin-6-yl)-7 - Preparation of tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methoxy)pyridin-3-yl)oxy)-1-ethanol

Weigh 4-(((5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)oxy)methyl)-N-methyl-5 -(3-((tetrahydro-2H-pyran-2-)yl)oxy)quinolin-6-yl)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine-2 - Amine (0.13g, 0.16mmol) was dissolved in dichloromethane (5mL), 1.0M tetrabutylammonium fluoride solution in tetrahydrofuran (0.2mL) was added, and reacted at room temperature for 2 hours, and the rest of the raw materials were left. It was quenched with water, extracted three times with dichloromethane, combined the organic phases and backwashed once with saturated brine, dried over anhydrous sodium sulfate, and purified on a silica gel column to obtain 40 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 697.2.

Step 3: 2-((5-((2-(Methylamino)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)quinolin-6-yl)-7 -Preparation of ethyl tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methoxy)pyridin-3-yl)oxy)methanesulfonate

2-((5-((2-(methylamino)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)quinolin-6-yl)-7-toluene Sulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methoxy)pyridin-3-yl)oxy)-1-ethanol (40 mg, 0.057 mmol) was dissolved in dichloromethane (3 mL ), added triethylamine (18 mg, 0.17 mmol) and methanesulfonyl chloride (8 mg, 0.068 mmol) at room temperature, and reacted at room temperature for 1 hour after the addition was complete. After TLC showed that the reaction was complete, 10 mL of water was added to the system, extracted three times with dichloromethane, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 44 mg of crude product was obtained, which was directly used in the next reaction.

MS (ESI) m/z (M+H) ⁺ = 775.2.

Preparation 98: Preparation of (5-((1-((6-bromoquinolin-3-yl)oxy)cyclopropyl)methoxy)pyridin-3-yl)methanol

Step 1: Preparation of methyl 4-bromo-2-((6-bromoquinolin-3-yl)oxy)butanoate

6-Bromoquinolin-3-ol (1000 mg, 4.46 mmol) was dissolved in DMF (80 mL), methyl 2,4-dibromobutyrate (1275.17 mg, 4.91 mmol) and potassium carbonate (1232.83 mg, 8.92 mmol) were added ), reacted at 25°C for 2 hours. After LCMS showed that the reaction was complete, 100 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 950 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 402.1.

Step 2: Preparation of methyl 1-(6-bromoquinolin-3-yl)oxy)cyclopropane-1-carboxylate

Dissolve methyl 4-bromo-2-((6-bromoquinolin-3-yl)oxy)butanoate (950 mg, 2.36 mmol) in tetrahydrofuran (100 mL), add potassium tert-butoxide (529.63 mg, 4.72 mmol), reacted at 25°C for 2 hours. After LCMS showed that the reaction was complete, 100 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 580 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 322.1.

Step 3: Preparation of (1-((6-bromoquinolin-3-yl)oxy)cyclopropyl)methanol

Dissolve methyl 1-(6-bromoquinolin-3-yl)oxy)cyclopropane-1-carboxylate (480mg, 1.49mmol) in tetrahydrofuran (25mL), add lithium aluminum hydride (56.55mg, 1.49mmol) for 20 minutes. After LCMS showed that the reaction was complete, 57uL of water, 57uL of 15% aqueous sodium hydroxide solution, and 171uL of water were added to the system, dried by adding anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 400 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 294.1.

Step 4: Preparation of methyl (1-((6-bromoquinolin-3-yl)oxy)cyclopropyl)methanesulfonate

Dissolve (1-((6-bromoquinolin-3-yl)oxy)cyclopropyl)methanol (200mg, 0.68mmol) in dichloromethane (15mL) and add N,N-diisopropylethylamine (175.77mg, 1.36mmol), methanesulfonyl chloride (116.84mg, 1.02mmol) were reacted at 25°C for 20 minutes. After TLC showed that the reaction was complete, 10 mL of water was added to the system, extracted three times with dichloromethane, the organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 220 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 372.1.

Step 5: Preparation of (5-((1-((6-bromoquinolin-3-yl)oxy)cyclopropyl)methoxy)pyridin-3-yl)methanol

Dissolve methyl (1-((6-bromoquinolin-3-yl)oxy)cyclopropyl)methanesulfonate (200 mg, 0.54 mmol) in N,N-dimethylformamide (10 mL), add 5-(Hydroxymethyl)pyridin-3-ol (81.08mg, 0.65mmol) and cesium carbonate (351.89mg, 1.08mmol) were reacted at 80°C for 3 hours. After LCMS showed that the reaction was complete, 30 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 180 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 401.1.

Preparation 99: Preparation of 2-((5-((((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridazin-3-yl)oxy)ethan-1-ol

Step 1: Preparation of 3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-chloropyridazine

Dissolve (2-bromoethoxy)(tert-butyl)dimethylsilane (7.8g, 40.30mmol) in tetrahydrofuran (100mL), add sodium hydride (1.7g, 60%, 43.56mmol) under ice-cooling, After maintaining the temperature for 0.5 hours, 3,5-dichloropyridazine (5.0 g, 33.57 mmol) was added in batches and reacted at room temperature for 1 hour. TLC showed that the reaction was complete, quenched with ice water, extracted three times with ethyl acetate, combined the organic phases and backwashed once with saturated brine, dried over anhydrous sodium sulfate, and purified on a silica gel column to obtain 3.4 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 289.1.

Step 2: Preparation of (6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridazin-4-yl)methanol

Weigh 3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-chloropyridazine (2.8g, 9.69mmol) in a 150mL dry flask, dissolve in 1,4 - Dioxane (30 mL)/water (3 mL), then potassium acetoxymethyltrifluoroborate (5.23 g, 29.07 mmol), tris(dibenzylideneacetone) dipalladium (444 mg, 0.48 mmol) were added sequentially , Sodium Carbonate (1.65 g, 15.57 mmol). After the addition was completed, nitrogen was replaced three times, and the temperature was raised to 100° C. for 24 hours. LCMS showed that the reaction was complete. Filter, spin dry, and purify through a silica gel column to obtain 2.2 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 285.2.

Step 3: 3-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl ) preparation of pyridazine

Dissolve (6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridazin-4-yl)methanol (1.1 g, 3.86 mmol) in 1,4-dioxahexa Ring (25mL), add 3,4-dihydro-2H-pyran (389mg, 4.63mmol) and pyridinium p-toluenesulfonate (97mg, 0.38mmol) successively under ice bath, after stirring for 10 minutes, at 60℃ React for 1.5 hours. After TLC showed that the reaction was complete, the system was cooled to room temperature, water (20 mL) was added, extracted three times with ethyl acetate, the combined organic phase was backwashed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 975 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 369.2.

Step 4: Preparation of 2-((5-((((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridazin-3-yl)oxy)ethan-1-ol

3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridine Dissolve oxazine (975mg, 2.64mmol) in tetrahydrofuran (10mL), add 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (2.9mL, 2.9mmol), and react at room temperature for 1 hour. After TLC showed that the reaction was complete, the system was concentrated under reduced pressure and purified by flash silica gel column to obtain 610 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 255.1.

Preparation 100: Preparation of 3-(2-((5-(hydroxymethyl)pyridazin-3-yl)oxy)ethoxy)quinolin-6-yl triflate

Step 1: 6-((4-methoxybenzyl)oxy)-3-(2-((5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridium Preparation of oxazin-3-yl)oxy)ethoxy)quinoline

2-((5-((((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridazin-3-yl)oxy)ethan-1-ol (0.55g, 2.16 mmol) was dissolved in toluene (20mL), and 3-bromo-6-((4-methoxybenzyl)oxy)quinoline (0.81g, 2.37mmol), allylpalladium chloride (34mg, 0.11mmol), 2-(di-tert-butylphosphonium)-3-methoxy-6-methyl-2′4′6′-triisopropyl-biphenyl (101mg, 0.22mmol), cesium carbonate ( 1.05g, 3.23mmol). After the addition, nitrogen was replaced three times, and the temperature was raised to 100°C for 24 hours. LCMS showed that the reaction was complete. Filtered, spin-dried, and purified by silica gel column to obtain 0.73g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 518.2.

Step 2: Preparation of 3-(2-((5-(hydroxymethyl)pyridazin-3-yl)oxy)ethoxy)quinolin-6-ol

6-((4-methoxybenzyl)oxy)-3-(2-((5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridazine- 3-yl)oxy)ethoxy)quinoline (0.72g, 1.39mmol) was dissolved in 6M hydrochloric acid/1,4-dioxane (10mL) and reacted at 80°C for 5 hours. After LCMS showed that the reaction was complete, the system was concentrated under reduced pressure to obtain 1.1 g of crude hydrochloride, which was directly used in the next reaction.

MS (ESI) m/z (M+H) ⁺ = 314.1.

Step 3: Preparation of 3-(2-((5-(hydroxymethyl)pyridazin-3-yl)oxy)ethoxy)quinolin-6-yl triflate

Weigh 3-(2-((5-(hydroxymethyl)pyridazin-3-yl)oxy)ethoxy)quinolin-6-ol (1.1g, hydrochloride) and dissolve in tetrahydrofuran (10mL) , added triethylamine (0.7mL, 5mmol) and N,N-bis(trifluoromethanesulfonyl)aniline (1.47g, 4.12mmol) sequentially, heated to 60°C for 3 hours, LCMS showed that the reaction was complete. Filtered, spin-dried, and purified by silica gel column to obtain 600 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 446.1.

Preparation 101: 2-((5-((2-Chloro-5-(3-((4-methoxybenzyl)oxy)quinolin-6-yl)-7-tosyl-7H- Preparation of ethyl pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-3-yl)oxy)methylsulfonate

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Preparation Example 28 above.

MS (ESI) m/z (M+H) ⁺ = 815.2.

Preparation 102: Preparation of 2-((5-((tert-butoxycarbonyl)amino)methyl)pyridin-3-yl)oxy)ethyl methanesulfonate

Step 1: Preparation of tert-butyl (5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methyl)carbamate

Weigh (5-(2)-(tert-butyldimethyloxy)ethoxy)pyridin-3-yl)methane (2g, 7.08mmol) and dissolve it in methanol (10mL), add di-tert-butyl dicarbonate Ester (1.85g, 8.50mmol) was reacted at 60°C for 1 hour. After LCMS showed that the reaction was complete, it was directly concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 2.5 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 383.1.

Step 2: Preparation of tert-butyl ((5-(2-hydroxyethoxy)pyridin-3-yl)methyl)carbamate

Weigh (5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methyl)tert-butyl carbamate (2.5g, 6.53mmol) was dissolved in Add tetrahydrofuran (10 mL), tetrabutylammonium fluoride (4.75 g, 18.17 mmol), and react at 25°C for 2 hours. After LCMS showed that the reaction was complete, 20 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 1.6 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 269.1.

Step 3: Preparation of 2-((5-((tert-butoxycarbonyl)amino)methyl)pyridin-3-yl)oxy)ethyl methanesulfonate

Weigh tert-butyl ((5-(2-hydroxyethoxy)pyridin-3-yl)methyl)carbamate (1.60g, 5.96mmol) and dissolve it in dichloromethane (10mL), then add N , N-diisopropylethylamine (0.77g, 5.96mmol), methanesulfonyl chloride (1.02g, 8.88mmol), react at 25°C for 1 hour. After LCMS showed that the reaction was complete, 10 mL of water was added to the system, extracted three times with dichloromethane, the organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 1.8 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 347.1.

Preparation 103: Preparation of tert-butyl (5-(2-((6-bromo-2-hydroxyquinolin-3-yl)oxy)ethoxy)pyridin-3-yl)methyl)carbamate

Step 1: Preparation of ethyl 6-bromo-3-hydroxy-2-oxo-1,2-dihydroquinoline-4-carboxylate

Weigh 5-bromoisatin (10g, 44.24mmol) and dissolve it in ethanol (220mL) and N,N-dimethylformamide (44mL), and add 1,8-diazabicyclo[5.4. 0]-7-Undecene (1.01g, 6.64mmol), then ethyl diazoacetate (10.10g, 88.48mmol) was added, and stirred at 25°C for 15 hours. After LCMS showed that the reaction was complete, most of the solvent was concentrated under reduced pressure; 1M dilute hydrochloric acid (160ml) was slowly added, and some bubbles and solids were formed. After stirring for 2 h, the filter cake was filtered out, washed twice with water and ether, and dried to obtain 13 g of the target compound.

MS (ESI) m/z (M+H) ⁺ = 312.1.

Step 2: Preparation of 6-bromo-3-hydroxyquinolin-2(1H)-one

Weigh 6-bromo-3-hydroxy-2-oxo-1,2-dihydroquinoline-4-carboxylic acid ethyl ester (13g, 41.65mmol) into a reaction flask, add water (400mL) and stir well, Sodium hydroxide (6.66 g, 166.6 mmol) was added at room temperature. Seal and heat up to 130°C to react for 16 hours. After LCMS showed that the reaction was complete, lower it to room temperature, slowly adjust the pH to 2 with 4M hydrochloric acid, filter, wash with water to obtain a filter cake, and dry to obtain 8.5 g of the target compound.

MS (ESI) m/z (M+H) ⁺ = 240.1.

Step 3: Preparation of tert-butyl (5-(2-((6-bromo-2-hydroxyquinolin-3-yl)oxy)ethoxy)pyridin-3-yl)methyl)carbamate

Weigh 6-bromo-3-hydroxyquinolin-2(1H)-one (1.3g, 5.42mmol) and dissolve it in isopropanol (20mL), add 1,8-diazabicyclo[5.4.0 ] Undec-7-ene (1.32g, 8.67mmol), 2-((5-((tert-butoxycarbonyl)amino)methyl)pyridin-3-yl)oxy)ethyl methanesulfonate (1.69g, 4.88mmol), react at 90°C for 3 hours. After LCMS showed that the reaction was complete, 30 mL of water was added to the system, extracted three times with dichloromethane, the organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 1.7 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 490.1.

Preparation 104: tert-Butyl ((5-(2-((6-(2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)- 2-hydroxyquinolin-3-yl)oxyl)ethoxy)pyridin-3-yl)methyl)carbamate)

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 33.

MS (ESI) m/z (M+H) ⁺ = 751.1.

Preparation 105: Preparation of tert-butyl (S)-(5-(2-((6-bromoquinolin-3-yl)oxy)propoxy)pyridin-3-yl)methyl)carbamate

Step 1: Preparation of (S)-3-((1-((5-(azidomethyl)pyridin-3-yl)oxy)prop-2-yl)oxy)-6-bromoquinoline

Dissolve (S)-(5-(2-((6-bromoquinolin-3-yl)oxy)propoxy)pyridin-3-yl)methanol (310.0 mg, 0.80 mmol) in toluene (10 mL) In , diphenylphosphoryl azide (260.0 mg, 0.96 mmol) and DBU (240.0 mg, 1.60 mmol) were added, and the system was heated to 90° C. for 1 hour. After TLC showed that the reaction was complete, the system was directly spin-dried to obtain 500.0 mg of the title compound, which was directly used in the next reaction.

MS (ESI) m/z (M+H) ⁺ = 414.0.

Step 2: Preparation of (S)-(5-(2-((6-bromoquinolin-3-yl)oxy)propoxy)pyridin-3-yl)methanamine

(S)-3-((1-((5-(Azidomethyl)pyridin-3-yl)oxy)propan-2-yl)oxy)-6-bromoquinoline (310.0mg, 0.80 mmol) was dissolved in toluene (10 mL), triphenylphosphine (260.0 mg, 0.96 mmol) was added, and reacted at room temperature for 2 hours. After TLC showed that the reaction was complete, the system was directly spin-dried to obtain 250.0 mg of the title compound, which was directly used in the next reaction.

MS (ESI) m/z (M+H) ⁺ = 388.0.

Step 3: Preparation of tert-butyl (S)-(5-(2-((6-bromoquinolin-3-yl)oxy)propoxy)pyridin-3-yl)methyl)carbamate

Dissolve (S)-(5-(2-((6-bromoquinolin-3-yl)oxy)propoxy)pyridin-3-yl)methanamine (300.0 mg, 0.77 mmol) in THF (10 mL ), add di-tert-butyl dicarbonate (200.0 mg, 0.92 mmol) and triethylamine (150.0 mg, 1.52 mmol), and react at room temperature for 1 hour. After TLC showed that the reaction was complete, saturated brine was added to the reaction system, extracted several times with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain 330.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 488.1.

Preparation 106: (S)-2 ² -Chloro-8-methyl-2 ⁷ -tosyl-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinone Preparation of phylloline-2(5,4)-pyrrolo[2,3-d]pyrimidine-5(3,5)-pyridocyclane

Step 1: (S)-((5-(2-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinone Preparation of tert-butyl carbamate (ol-3-yl)oxy)propoxy)pyridin-3-yl)methyl)carbamate

(S)-(5-(2-((6-bromoquinolin-3-yl)oxy)propoxy)pyridin-3-yl)methyl)carbamate tert-butyl ester (300.0mg, 0.61mmol ), pinacol borate (190.0mg, 0.73mmol), DPPF palladium dichloride (89.0mg, 0.12mmol) and potassium acetate (120.0mg, 1.22mmol) were weighed in a microwave test tube, replaced with nitrogen, and added 1 , 4-dioxane (5 mL) and nitrogen was replaced again, and the system was heated to 90° C. for 2 hours. After TLC showed that the reaction was complete, the system was directly carried out to the next step without treatment.

MS (ESI) m/z (M+H) ⁺ = 536.3.

Step 2: (S)-((5-(2-((6-(2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)quinone Preparation of tert-butyl carbamate (ol-3-yl)oxy)propoxy)pyridin-3-yl)methyl)carbamate

(S)-((5-(2-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline- 3-yl)oxy)propoxy)pyridin-3-yl)methyl)tert-butyl carbamate (300.0mg, 0.56mmol), 2,4-dichloro-5-iodo-7-toluenesulfonyl- 7H-pyrrolo[2,3-d]pyrimidine (288.mg, 0.62mmol), DPPF palladium dichloride (81.9mg, 0.11mmol) and potassium carbonate (155.0mg, 1.12mmol) were weighed in a microwave test tube, Nitrogen was replaced, 1,4-dioxane (8 mL) and water (1 mL) were added, nitrogen was replaced again, and the system was heated to 90° C. for 1 hour. Add saturated brine to the reaction system, extract several times with ethyl acetate, and dry over anhydrous sodium sulfate. The solvent was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain 300 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 749.2.

Step 3: (S)-(5-(2-((6-(2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)quinoline Preparation of -3-yl)oxy)propoxy)pyridin-3-yl)methanamine

(S)-((5-(2-((6-(2,4-dichloro-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)quinoline- 3-yl)oxy)propoxy)pyridin-3-yl)methyl)carbamate tert-butyl ester (300.0 mg, 0.40 mmol) was dissolved in 1,4-dioxane (80 mL) of hydrochloric acid at room temperature The reaction was carried out for 1 hour. After TLC showed that the reaction was complete, the system was directly spin-dried to obtain 250.0 mg of the title compound, which was directly used in the next reaction.

MS (ESI) m/z (M+H) ⁺ = 649.1.

Step 4: (S)-2 ² -Chloro-8-methyl-2 ⁷ -tosyl-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline - Preparation of 2(5,4)-pyrrolo[2,3-d]pyrimidine-5(3,5)-pyridocyclane

(S)-(5-(2-((6-(2,4-dichloro-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)quinoline-3 -yl)oxy)propoxy)pyridin-3-yl)methanamine (200.0 mg, 0.31 mmol) was dissolved in N,N-dimethylformamide (100 mL), ethyldiisopropylamine (80.1 mg , 0.62mmol), after the addition, the system was heated to 60°C and reacted for 12 hours. After TLC showed that the reaction was complete, saturated brine was added to the reaction system, extracted several times with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was concentrated to obtain a crude product, which was separated and purified by chromatography on a silica gel column to obtain 60.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 613.1.

Preparation 107: Preparation of (5-(trans-3-((tert-butyldimethylsilyl)oxy)cyclobutoxy)pyridin-3-yl)methanol

Step 1: Preparation of 3-(benzyloxy)cyclobutan-1-ol

3-(Benzyloxy)cyclobutan-1-one (5g, 28.38mmol) was dissolved in ethanol (50mL), sodium borohydride (1.07g, 28.38mmol) was added in batches, and reacted at 25°C for 1 hour. After LCMS showed that the reaction was complete, add 10 mL of water to the system to quench the reaction, concentrate under reduced pressure to remove ethanol, extract three times with ethyl acetate, combine the organic phases, backwash once with saturated saline, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure . The resulting crude product 5.0 g was directly used in the next reaction.

MS (ESI) m/z (M+H) ⁺ = 179.1.

Step 2: Preparation of (cis-3-(benzyloxy)cyclobutoxy)(tert-butyl)dimethylsilane

Dissolve cis-3-(benzyloxy)cyclobutan-1-ol (2.50g, 14.03mmol) in dichloromethane (15mL), add N-methylimidazole (1.73g, 21.04mmol), tert Butyldimethylchlorosilane (2.54g, 16.84mmol) was reacted at 25°C for 2 hours. After LCMS showed that the reaction was complete, 10 mL of water was added to the system, extracted three times with dichloromethane, the organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 3.5 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 293.1.

Step 3: Preparation of cis-3-((tert-butyldimethylsilyl)oxy)cyclobutan-1-ol

Dissolve (cis-3-(benzyloxy)cyclobutoxy)(tert-butyl)dimethylsilane (3.50 g, 11.97 mmol) in ethanol (30 mL) and add 10% wet Pd/C ( 496.80mg, 4.67mmol), the hydrogen replacement system was three times, and reacted at 25°C for 3 hours under a hydrogen atmosphere. After LCMS showed that the reaction was complete, it was filtered and concentrated under reduced pressure. The resulting crude product 2.3g was directly used in the next reaction.

MS (ESI) m/z (M+H) ⁺ = 203.1.

Step 4: Preparation of cis-3-((tert-butyldimethylsilyl)oxy)cyclobutyl 4-methylbenzenesulfonate

Dissolve cis-3-((tert-butyldimethylsilyl)oxy)cyclobutan-1-ol (2.30 g, 11.37 mmol) in dichloromethane (20 mL), add methylimidazole (1.40 g , 17.05mmol), p-toluenesulfonyl chloride (2.60g, 13.64mmol), react at 25°C for 16 hours. TLC showed that a small amount of raw materials remained, and 10 mL of water was added to the system, extracted three times with dichloromethane, the organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 2.1 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 357.1.

Step 5: Preparation of methyl 5-(trans-3-((tert-butyldimethylsilyl)oxy)cyclobutoxy)nicotinate

Dissolve cis-3-((tert-butyldimethylsilyl)oxy)cyclobutyl 4-methylbenzenesulfonate (1.5 g, 4.21 mmol) in N,N-dimethylformamide (10 mL), sequentially added cesium carbonate (2.74 g, 8.41 mmol), methyl 5-hydroxynicotinate (0.77 g, 5.01 mmol), and reacted at 70° C. for 5 hours. After LCMS showed that the reaction was complete, 50 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 1.4 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 338.1.

Step 6: Preparation of (5-(trans-3-((tert-butyldimethylsilyl)oxy)cyclobutoxy)pyridin-3-yl)methanol

Dissolve methyl 5-(trans-3-((tert-butyldimethylsilyl)oxy)cyclobutoxy)nicotinate (1500mg, 4.44mmol) in tetrahydrofuran (20mL) and divide at 5°C Lithium aluminum hydride (202.20 mg, 5.33 mmol) was added in batches and reacted for 2 hours. After LCMS showed that the reaction was complete, 202uL of water, 202uL of 15% aqueous sodium hydroxide solution, and 606uL of water were added to the system to quench the reaction, diatomaceous earth was used as a filter aid, and the filtrate was concentrated under reduced pressure. The resulting crude product 1200mg was directly used in the next reaction.

MS (ESI) m/z (M+H) ⁺ = 310.1.

Preparation 108: trans-3-((5-((2-(methylamino)-5-(3-((tetrahydro2H-pyran-2-yl)oxy)quinolin-6-yl) -7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)pyridine-3- Base) Oxygen) Preparation of Cyclobutyl Methanesulfonate

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 31.

MS (ESI) m/z (M+H) ⁺ = 777.1.

Preparation 109: Preparation of (5-(cis-3-((tert-butyldimethylsilyl)oxy)cyclobutoxy)pyridin-3-yl)methanol

Step 1: Preparation of trans-3-(benzyloxy)cyclobutyl 4-nitrobenzoate

Dissolve cis-3-(benzyloxy)cyclobutan-1-ol (2.5g, 14.03mmol) in tetrahydrofuran (25mL), add 4-nitrobenzoic acid (2.3g, 14.03mmol) and three Phenylphosphine (7.3g, 28.06mmol), and finally diisopropyl azodicarboxylate (4.2g, 21.04mmol) was added, and the system was reacted at room temperature for 1 hour after the addition was complete. After TLC showed that the reaction was complete, saturated brine was added to the reaction system, extracted several times with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain 4.1 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 328.1.

Step 2: Preparation of trans-3-(benzyloxy)cyclobutan-1-ol

Dissolve cis-3-(benzyloxy)cyclobutyl 4-nitrobenzoate (4.0g, 12.22mmol) in methanol (40mL), add lithium hydroxide (1.0g, 24.03mmol) in water (4mL ), after the addition, the system was reacted at room temperature for 1 hour. After TLC showed that the reaction was complete, saturated brine was added to the reaction system, extracted several times with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain 2.4 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 179.1.

In the synthesis of steps 3-7, the title compound was prepared by using the corresponding commercial reagents and the product in the above-mentioned preparation example as raw materials, and using a preparation method similar to the above-mentioned preparation example.

MS (ESI) m/z (M+H) ⁺ = 310.2.

Preparation 110: cis-3-((5-((2-(methylamino)-5-(3-((tetrahydro2H-pyran-2-yl)oxy)quinolin-6-yl) -7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)pyridine-3- Base) Oxygen) Preparation of Cyclobutyl Methanesulfonate

The title compound was prepared by using the corresponding commercial reagent and the product in the above-mentioned Preparation Example as raw materials, and using a preparation method similar to the above-mentioned Preparation Example.

MS (ESI) m/z (M+H) ⁺ = 777.3.

Preparation 111: Preparation of (5-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)methanamine

Step 1: Preparation of 5-(((tert-butyldimethylsilyl)oxy)methyl)thiazole

Thiazol-5-ylmethanol (5g, 43.47mmol) was dissolved in dichloromethane (40mL), triethylamine (12mL, 86.95mmol) was added dropwise, and tert-butyldimethylsilyl chloride ( 7.86 g, 52.1 mmol). After the dropwise addition was completed, the reaction was carried out at room temperature for 1.5 hours. After TLC showed that the reaction was complete, it was quenched by adding water, extracted three times with dichloromethane, combined the organic phases and backwashed once with saturated brine, dried over anhydrous sodium sulfate, and purified on a silica gel column to obtain 9.3 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 230.1.

Step 2: Preparation of 5-(((tert-butyldimethylsilyl)oxy)methyl)thiazole-2-carbaldehyde

Weigh 5-(((tert-butyldimethylsilyl)oxy)methyl)thiazole (2.0g, 8.73mmol) and dissolve it in tetrahydrofuran (40mL), replace with nitrogen three times, add dropwise at -78°C 2.5M butyllithium solution (4.2mL), stirred at -78°C for 30 minutes after addition, added dropwise N,N-dimethylformamide (1.29g, 17.46mmol), and reacted at -78°C for 2 hours. After LCMS showed that the reaction was complete, the system was quenched by adding saturated ammonium chloride solution, extracted three times with ethyl acetate, the organic phase was dried and concentrated, and purified on a silica gel column to obtain 2.2 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 258.1.

Step 3: Preparation of (E)-5-(((tert-butyldimethylsilyl)oxy)methyl)thiazole-2-carbaldehyde oxime

Weigh 5-(((tert-butyldimethylsilyl)oxy)methyl)thiazole-2-carbaldehyde (3.26g, 12.68mmol) and dissolve it in ethanol (24mL), add hydroxylamine hydrochloride under ice-water bath conditions (1.75g, 25.37mmol), sodium methoxide (1.37g, 25.37mmol), react at room temperature for 3 hours. LCMS showed that after the reaction was complete, a white solid appeared in the system, which was filtered and the filtrate was concentrated to obtain 3.4 g of a crude product.

MS (ESI) m/z (M+H) ⁺ = 273.1.

Step 4: Preparation of (5-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)methanamine

Dissolve (E)-5-(((tert-butyldimethylsilyl)oxy)methyl)thiazole-2-carbaldehyde oxime (3.4 g, 12.6 mmol) in methanol (100 mL), (30 mL) water , add zinc powder (4.92g, 75.6mmol) and ammonium chloride (4g, 75.6mmol) at room temperature, and stir at 45°C for 4 hours after the addition is complete. After LCMS showed that the reaction was complete, the system was concentrated and purified on a silica gel column to obtain 2.8 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 259.1.

Preparation 112: 6-(2-Chloro-4-(((5-(chloromethyl)thiazol-2-yl)methyl)amino)-7-tosyl-7H-pyrrolo[2,3- d] preparation of pyrimidin-5-yl) quinoline-3-alcohol

Step 1: N-((5-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)methyl)-2-chloro-5-iodo-7-toluenesulfonate Preparation of Acyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Dissolve (5-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)methanamine (2 g, 7.75 mmol) in tetrahydrofuran (75 mL) and add triethylamine ( 2.1mL, 15.5mmol), 2,4-dichloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (3.98g, 8.52mmol), heated to 50°C for reaction 4 Hour. After LCMS showed that the reaction was complete, the system was concentrated, and the obtained crude product was purified by column chromatography to obtain 2.45 g of the title compound.

MS (ESI) m/z (M+H)+ = 690.1.

Step 2: (2-(((2-Chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)thiazol-5-yl ) Preparation of Methanol

Weigh N-((5-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)methyl)-2-chloro-5-iodo-7-toluenesulfonyl -7H-pyrrolo[2,3-d]pyrimidin-4-amine (2.4g, 3.48mmol) was dissolved in dichloromethane (100mL), and 4M hydrochloric acid 1,4-oxane solution was added dropwise at room temperature ( 100 mL) at room temperature for 3 hours. After LCMS showed that the reaction was complete, the system was concentrated under reduced pressure. The crude product 2.3g was directly used in the next reaction.

MS (ESI) m/z (M+H) ⁺ = 576.1.

Step 3: (2-(((2-chloro-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)quinolin-6-yl)-7-tosyl-7H - Preparation of pyrrolo[2,3-d])pyrimidin-4-yl)amino)methyl)thiazol-5-yl)methanol

Weigh (2-(((2-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)thiazol-5-yl) Methanol (800mg, 1.24mmol), 3-((tetrahydro-2H-pyran-2-yl)oxy)-6-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)quinoline (526.7mg, 1.48mmol) was dissolved in 1,4-dioxane solution (30mL) and water (3mL), potassium carbonate (513mg, 3.72mmol) was added, Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (90mg, 0.124mmol) was replaced with nitrogen three times, and reacted at 100°C for 4 hours. LCMS showed that the reaction was complete, the system was filtered through celite, the filtrate was concentrated to dryness, and purified on a silica gel column to obtain 645 mg of the title compound.

MS (ESI) m/z (M+H)+ = 677.1.

Step 4: 6-(2-Chloro-4-(((5-(chloromethyl)thiazol-2-yl)methyl)amino)-7-tosyl-7H-pyrrolo[2,3-d The preparation of ]pyrimidin-5-yl)quinolin-3-alcohol

Weigh (2-(((2-chloro-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)quinolin-6-yl)-7-toluenesulfonyl-7H- Pyrrolo[2,3-d])pyrimidin-4-yl)amino)methyl)thiazol-5-yl)methanol (645mg, 0.95mmol) was dissolved in dichloromethane (15mL), and 2 Drop N,N-dimethylformamide, thionyl chloride (0.142 mL, 0.19 mmol) and stir at room temperature for 1.5 hours. After LCMS showed that the reaction was complete, water was added to the system, and dichloromethane extracted 3 times. The organic phase was dried and concentrated under reduced pressure, and the crude product was separated and purified on a silica gel column to obtain 500 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 611.0.

Preparation 113: 2-((2-(Aminomethyl)thiazol-5-yl)oxy)ethan-1-ol

Step 1: Preparation of 2-(((triisopropylsilyl)oxy)methyl)thiazole

Weigh (1,3-thiazol-2-yl)methanol (2.88g, 25.01mmol) and dissolve it in dichloromethane (50mL), add 1-methyl-1H-imidazole (4.11g, 50.06mmol) and three Isopropylsilyl chloride (5.79g, 30.01mmol) was reacted at 25°C for 2 hours, and a sample was taken to detect that the conversion of the raw material was complete. Saturated brine was added to the reaction system, extracted several times with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain 6.0 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 272.2.

Step 2: Preparation of 5-bromo-2-((triisopropylsilyl)oxy)methyl)thiazole

Weigh 2-(((triisopropylsilyl)oxy)methyl)thiazole (6g, 22.10mmol) and dissolve it in N,N-dimethylformamide (50mL), add N- Bromosuccinimide (7.87g, 44.25mmol) was reacted at 25°C for 2 hours, and a sample was taken for detection, and about 10% of the raw material remained. Ethyl acetate and water were added, separated and extracted, and concentrated to dryness. The crude product was separated and purified by silica gel column chromatography to obtain 5.8 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 350.2.

Step 3: Preparation of 5-(2-(benzyloxy)ethoxy)-2-((triisopropylsilyl)oxy)methyl)thiazole

Weighed 2-benzyloxyethanol (7.56 g, 49.65 mmol) and dissolved it in tetrahydrofuran (30 mL), and added sodium hydride (1.99 g, 49.82 mmol) in batches under an ice-water bath, and reacted for 0.5 hours. Add 5-bromo-2-((triisopropylsilyl)oxy)methyl)thiazole (5.8 g, 16.55 mmol) and react at 35°C overnight under nitrogen protection. Sampling and testing showed that the reaction of the raw materials was complete. The reaction was quenched by adding ammonium chloride, extracted with ethyl acetate, and concentrated to dryness. The crude product was separated and purified by silica gel column chromatography to obtain 2.48 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 422.2.

Step 4: Preparation of (5-(2-(benzyloxy)ethoxy)thiazol-2-yl)methanol

Weigh 5-(2-(benzyloxy)ethoxy)-2-((triisopropylsilyl)oxy)methyl)thiazole (1 g, 2.37 mmol) in dichloromethane (10 mL) , added tetrabutylammonium fluoride (1.24g, 4.74mmol), reacted at room temperature for 0.5 hours, and took a sample to detect that the reaction of the raw materials was complete. The reaction system was concentrated to dryness, and the crude product was separated and purified by silica gel column chromatography to obtain 0.59 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 266.1.

Step 5: Preparation of 2-(azidomethyl)-5-(2-(benzyloxy)ethoxy)thiazole

Weigh ((5-(2-(benzyloxy)ethoxy)thiazol-2-yl)methanol (0.59g, 2.22mmol) and dissolve it in tetrahydrofuran (6mL), add diphenylphosphoryl azide (0.73g , 2.65mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.47g, 3.09mmol), reacted at 50°C for 1 hour. Sampling detection, raw material reaction was complete, concentrated To dryness, the crude product was separated and purified by silica gel column chromatography to obtain 0.63 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 291.2.

Step 6: Preparation of 2-((2-(aminomethyl)thiazol-5-yl)oxy)ethan-1-ol

Weigh 2-(azidomethyl)-5-(2-(benzyloxy)ethoxy)thiazole (0.31g, 1.55mmol) and dissolve it in methanol (10mL), add palladium on carbon (0.31g, 2.91mmol ), hydrogen replacement; under hydrogen atmosphere, react at room temperature for 0.5 hours. Sampling and detection showed that the conversion of raw materials was complete. Filter, wash with methanol, and concentrate the filtrate to obtain 0.27 g of crude product, which is directly used in the next reaction.

MS (ESI) m/z (M+H) ⁺ = 175.1.

Preparation 114: 2-((2-(((2-(methylamino)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)quinolin-6-yl) - Preparation of 7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)thiazol-5-yl)oxy)ethan-1-ol

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Preparation Example 28 above.

MS (ESI) m/z (M+H) ⁺ = 702.2.

Preparation 115: Preparation of 3-(2-(aminomethyl)thiazol-5-yl)propan-1-ol

Step 1: Preparation of 2-((((tetrahydro-2H-pyran-2-yl)oxy)methyl)thiazole

Weigh thiazol-2-ylmethanol (1.15g, 9.99mmol) and dissolve in dichloromethane (15mL), then add dihydropyran (1.68g, 19.98mmol) and p-toluenesulfonic acid (0.17g, 0.99mmol) ), reacted at 25°C for 1 hour. Sampling and testing showed that the reaction of the raw materials was complete. Concentrate to dryness, and the crude product is separated and purified by silica gel column chromatography to obtain 1.8 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 200.1.

Step 2: Preparation of 2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)thiazole-5-carbaldehyde

Weigh 3-(2-(aminomethyl)thiazol-5-yl)propan-1-ol (2.98g, 14.95mmol) in a dry reaction flask, replace with nitrogen three times, add tetrahydrofuran (30mL) to dissolve, cool to -78°C. Slowly add n-butyllithium (17.94mmol) dropwise, and stir at -78°C for 1 hour after the dropwise completion. N,N-Dimethylformamide (3.45 mL, 44.85 mmol) was added dropwise, reacted for 0.5 hour, and sampled for detection, the conversion of the raw material was complete. Add saturated ammonium chloride aqueous solution dropwise to quench, add ethyl acetate and water, separate liquid extraction, and purify by column chromatography to obtain 2.27 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 228.1.

Step 3: Preparation of (E)-ethyl 3-(2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)thiazol-5-yl)acrylate

Weigh 2-(diethoxyphosphoryl) ethyl acetate (2.69g, 11.99mmol) and dissolve it in acetonitrile (30mL), then add 1,8-diazabicyclo[5.4.0]undecyl -7-ene (1.83g, 11.99mmol) and lithium chloride (0.51g, 12.03mmol), stirred at room temperature for 10 minutes. Finally, 2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)thiazole-5-carbaldehyde (2.27g, 9.99mmol) was added and reacted at 25°C for 1 hour. Sampling and detection showed that the conversion of raw materials was complete. Concentrate, add ethyl acetate and water, separate liquid extraction, and purify by column chromatography to obtain 2.52 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 298.1.

Step 4: Preparation of ethyl 3-(2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)thiazol-5-yl)propanoate

Weigh (E)-3-(2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)thiazol-5-yl)ethyl acrylate (2.5g, 8.41mmol) and dissolve in Add palladium carbon (2.5g, 23.49mmol) to methanol (40mL), replace with hydrogen three times, react overnight at 25°C, and take a sample to detect that the reaction of the raw materials is basically complete. After filtration and concentration, 2.28 g of crude product was obtained, which was directly used in subsequent reactions.

MS (ESI) m/z (M+H) ⁺ = 300.1.

Step 5: Preparation of ethyl 3-(2-(hydroxymethyl)thiazol-5-yl)propionate

Weigh 3-(2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)thiazol-5-yl)propionic acid ethyl ester (2.28g, 7.62mmol) and dissolve in dichloromethane (10 mL), was added 4M dioxane hydrochloride solution (5 mL), and reacted at room temperature for 2 hours. Sampling and detection showed that the reaction of the raw materials was complete; concentrated to dryness, added triethylamine to adjust the base, and purified by column chromatography to obtain 1 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 216.1.

Step 6: Preparation of ethyl 3-(2-(azidomethyl)thiazol-5-yl)propionate

Weigh 3-(2-(hydroxymethyl)thiazol-5-yl) ethyl propionate (1g, 4.65mmol) and dissolve it in tetrahydrofuran (10mL), add diphenylphosphoryl azide (1.54g, 5.58mmol) , 1,8-diazabicyclo[5.4.0]undec-7-ene (0.99g, 6.51mmol), reacted at 50°C for 1 hour. Sampling and detection showed that the reaction of the raw materials was complete; the reaction solution was concentrated to dryness and purified by column chromatography to obtain 1 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 241.1.

Step 7: Preparation of ethyl 3-(2-(((tert-butoxycarbonyl)amino)methyl)thiazol-5-yl)propanoate

Weigh 3-(2-(azidomethyl)thiazol-5-yl) ethyl propionate (1g, 4.16mmol) and dissolve in tetrahydrofuran (20mL) and water (2mL), add triphenylphosphine (2.18g , 8.31mmol), reacted at 80°C for 1.5 hours. Sampling and testing, the raw materials have been reacted. After cooling to room temperature, di-tert-butyldicarbonate (1.36g, 6.24mmol) and triethylamine (0.84g, 8.32mmol) were added and reacted at room temperature for 1 hour. Sampling was performed to detect that the conversion of the intermediate was complete. Ethyl acetate and water were added, separated and extracted, concentrated to dryness and purified by column chromatography to obtain 1.3 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 315.2.

Step 8: Preparation of tert-butyl ((5-(3-hydroxypropyl)thiazol-2-yl)methyl)carbamate

Weigh 3-(2-(((tert-butoxycarbonyl)amino)methyl)thiazol-5-yl)propanoic acid ethyl ester (1.26g, 4.01mmol) dissolved in tetrahydrofuran (15mL) and methanol (1.5mL) Lithium borohydride (0.17g, 7.82mmol) was added to react at 40°C for 1 hour. Sampling and testing revealed that most of the raw materials remained. Lithium borohydride (0.17g, 7.82mmol) was added, and after reacting for 1 hour, lithium borohydride (0.17g, 7.82mmol) was added again, and the reaction was continued at 40°C for 1 hour. Sampling was carried out to detect that the conversion of the raw material was complete, ice water and sodium carbonate solution were added, ethyl acetate was added to extract, concentrated, and purified by column chromatography to obtain 0.84 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 273.2.

Step 9: Preparation of 3-(2-(aminomethyl)thiazol-5-yl)propan-1-ol

Dissolve tert-butyl ((5-(3-hydroxypropyl)thiazol-2-yl)methyl)carbamate (840mg, 3mmol) in dichloromethane (10mL), add 4M hydrochloric acid 1,4 - Dioxane solution (10 mL). And react at room temperature for 3 hours. After LC-MS showed that the reaction was complete, the system was concentrated to obtain 850 mg of the crude title compound, which was directly used in the next reaction.

MS (ESI) m/z (M+H) ⁺ = 173.1.

Preparation 116: 3-(2-(((2-(methylamino)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)quinolin-6-yl)- Preparation of 7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)thiazol-5-yl)propan-1-ol

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Preparation Example 28 above.

MS (ESI) m/z (M+H) ⁺ = 700.2.

Example 1: N-methyl-2 ⁷ H-7-oxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrole[2,3-d]pyrimidine- Preparation of 5(2,4)-Pyrimidine Heterocyclic Heptafan-2 ² -Amine

Step 1: 6-(4-((4-(Hydroxymethyl)pyrimidin-2-yl)methyl)amino)-2-(methylamino)-7-p-tolyl-7H-pyrrole[2,3- d] preparation of pyrimidin-5-yl) quinoline-3-alcohol

N ⁴ -((4-((tert-butyldimethylsilyloxy)methyl)pyrimidin-2-yl)methyl)-5-(3-((4-methoxybenzyl)oxy )quinolin-6-yl)-N ² -methyl-7-p-tolyl-7H-pyrrole[2,3-d]pyrimidine-2,4-diamine (600.0mg) was dissolved in trifluoroacetic acid (10mL ), heated up to 50°C for 2 hours. After TLC showed that the reaction was complete, the system was directly spin-dried, the residue was adjusted to pH 6 with saturated sodium bicarbonate solution, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, Filter and concentrate under reduced pressure. The obtained crude product was purified by reverse phase to obtain 350 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 583.1.

Step 2: 6-(4-((4-(Bromomethyl)pyrimidin-2-yl)methyl)amino)-2-(methylamino)-7-p-tolyl-7H-pyrrole[2,3- d] preparation of pyrimidin-5-yl) quinoline-3-alcohol

6-(4-((4-(hydroxymethyl)pyrimidin-2-yl)methyl)amino)-2-(methylamino)-7-p-tolyl-7H-pyrrole[2,3-d] Pyrimidin-5-yl)quinolin-3-ol (150mg) was dissolved in phosphorus oxybromide (0.5mL), and reacted at 60°C for 1 hour. After TLC showed that the reaction was complete, the system was added to a saturated sodium bicarbonate solution under ice-bath conditions, the pH was adjusted to about 6, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, anhydrous sulfuric acid Dry over sodium, filter, and concentrate under reduced pressure. The obtained crude product was purified by preparative TLC to obtain 15 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 645.1.

Step 3: N-Methyl-2 ⁷ -p-toluenesulfonyl-2 ⁷ H-7-oxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrole[2 , 3-d] the preparation of pyrimidine-5 (2,4)-pyrimidine heterocyclic heptafan-2 ² -amine

6-(4-((4-(bromomethyl)pyrimidin-2-yl)methyl)amino)-2-(methylamino)-7-p-tolyl-7H-pyrrole[2,3-d] Pyrimidin-5-yl)quinolin-3-ol (15mg) was dissolved in N,N-dimethylformamide (20mL), cesium carbonate (29.3mg) was added, and reacted at room temperature for 0.5 hours. After TLC showed that the reaction was complete, 20 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, backwashed twice with water, once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by preparative TLC to obtain 3.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 565.1.

Step 4: N-Methyl-2 ⁷ H-7-oxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrole[2,3-d]pyrimidine-5 Preparation of (2,4)-pyrimidine heterocyclic heptafan-2 ² -amine

N-methyl-2 ⁷ -p-toluenesulfonyl-2 ⁷ H-7-oxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrole[2,3 -d] Pyrimidine-5(2,4)-pyrimidine heterocyclic heptaphen-2 ² -amine (5.0mg) was dissolved in methanol (1mL), and sodium hydroxide aqueous solution (2M, 0.3mL) was added, and the temperature was raised to 60°C for reaction 1 hour. TLC showed that the reaction was complete. After the system was cooled to room temperature, the pH was adjusted to about 7 with 2M dilute hydrochloric acid. The mother liquor was purified by preparative HPLC and lyophilized to obtain 2.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 411.1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.23(s, 1H), 8.93(s, 1H), 8.71(d, J=5.1Hz, 1H), 8.59(s, 1H), 8.45(s, 1H), 7.88(d, J=8.5Hz, 1H), 7.64-7.56(m, 1H), 7.49(d, J=5.1Hz, 1H), 6.95(d, J=2.3Hz, 1H), 6.39( t, J=4.4Hz, 1H), 6.24-6.18(m, 1H), 5.49(s, 2H), 4.38(d, J=8.0Hz, 2H), 2.80(d, J=4.8Hz, 3H).

Example 2: N-methyl-2 ⁷ H-7-thia-3-aza-1(6,3)-quinoline-2(5,4)-pyrrole[2,3-d]pyrimidine-5 Preparation of (2,4)-pyridine heterocyclic heptafan-2 ² -amine

Step 1: 6-(4-(((4-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)methyl)amino)-2-(methylamino Preparation of )-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)quinolin-3-ol

N ⁴ -((4-((tert-butyldimethylsilyloxy)methyl)pyrimidin-2-yl)methyl)-5-(3-((4-methoxybenzyl)oxy )quinolin-6-yl)-N 2 -methyl-7-p-tolyl-7H-pyrrole[2,3-d]pyridine-2,4-diamine ( ^3.0 g) was dissolved in methanol (100 mL), Palladium carbon (0.9 g) was added, hydrogen was replaced three times, and the system was reacted at room temperature in a hydrogen atmosphere for 2 hours. After TLC showed that the reaction was complete, the palladium carbon was removed by filtration, and the mother liquor was concentrated under reduced pressure. 1.5 g of the title compound was obtained, and the crude product was directly used in the next step without purification.

MS (ESI) m/z (M+H) ⁺ = 696.1.

Step 2: 6-(4-(((4-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)methyl)amino)-2-(methylamino Preparation of )-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)quinolin-3-yl trifluoromethanesulfonate

6-(4-(((4-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)methyl)amino)-2-(methylamino)- 7-Tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)quinolin-3-ol (1.5g) was dissolved in dichloromethane (20mL), and N,N-diisopropyl Ethylamine (0.56g) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (1.54g) were reacted at room temperature for 2 hours. After TLC showed that the reaction was complete, 10 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 1.2 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 828.1.

Step 3: Methyl 3-((6-(4-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)amino)-2-(methylamino)-7-p-tolyl Preparation of -7H-pyrrole[2,3-d]pyrimidin-5-yl)quinolin-3-yl)thio)propionic acid methyl ester

6-(4-(((4-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)methyl)amino)-2-(methylamino)- 7-Toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)quinolin-3-yl trifluoromethanesulfonate (1.2g), methyl 3-mercaptopropionate (261mg) and N,N-diisopropylethylamine (0.56g) were dissolved in 1,4-dioxane (20mL), and 4,5-bisdiphenylphosphine-9,9-dimethyl was added after nitrogen replacement After the addition of xanthene (116 mg) and tris(dibenzylideneacetone) dipalladium (92 mg), nitrogen was replaced again, and the temperature was raised to 80° C. for 3 hours. After TLC showed that the reaction was complete, the system was cooled to room temperature, 10 mL of water was added, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 1.1 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 798.2.

Step 4: 6-(4-(((4-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)methyl)amino)-2-(methylamino Preparation of )-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)quinoline-3-thiol

Methyl 3-((6-(4-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)amino)-2-(methylamino)-7-p-tolyl-7H -pyrrole[2,3-d]pyrimidin-5-yl)quinolin-3-yl)thio)propionic acid methyl ester (1.1g) was dissolved in ethanol (10mL) and tetrahydrofuran (10mL), added sodium ethoxide (188mg ), reacted at room temperature for 3 hours. After TLC showed that the reaction was complete, 10 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 0.8g of crude product was obtained.

MS (ESI) m/z (M+H) ⁺ = 712.2.

Step 5: (2-((5-(3-((6-(4-(Hydroxymethyl)pyridin-2-yl)methyl)amino)-2-(methylamino)-7-p-tolyl- 7H-pyrrole[2,3-d]pyrimidin-5-yl)quinolin-3-yl)disulfone-yl)quinolin-6-yl)-2-(methylamino)-7-p-tolyl-7H- Preparation of pyrrole[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-4-yl)methanol

6-(4-(((4-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)methyl)amino)-2-(methylamino)- 7-Tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)quinoline-3-thiol (0.8g) was dissolved in hydrochloric acid-1,4-dioxane solution (4M, 20 mL), react at room temperature for 1 hour. After TLC showed that the reaction was complete, it was concentrated under reduced pressure. 0.7 g of crude product was obtained.

MS (ESI) m/z (M+H) ⁺ = 1193.3.

Step 6: (2-(((2-(methylamino)-5-(3-((6-(2-(methylamino)-4-(((4-(((methylsulfonyl)oxy) Methyl)pyridin-2-yl))methyl)amino)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)quinolin-3-yl)disulfanyl ) quinoline-6-yl)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-4-yl)methylsulfonate preparation

(2-((5-(3-((6-(4-(hydroxymethyl)pyridin-2-yl)methyl)amino)-2-(methylamino)-7-p-tolyl-7H- Pyrrole [2,3-d] pyrimidin-5-yl) quinoline-3-yl) disulfone base) quinoline-6-yl)-2-(methylamino)-7-p-tolyl-7H-pyrrole [ 2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-4-yl)methanol (0.7g) was dissolved in dichloromethane (20mL), N,N-diisopropylethylamine (0.56 g) react with methanesulfonyl chloride (145 mg) at room temperature for 1 hour. After TLC showed that the reaction was complete, 10 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 0.4 g of crude product was obtained.

MS (ESI) m/z (M+H) ⁺ = 1349.2.

Step 7: N-Methyl-2 ⁷ -p-toluenesulfonyl-2 ⁷ H-7-thia-3-aza-1(6,3)-quinoline-2(5,4)-pyrrole[2, 3-d] Preparation of pyrimidine-5(2,4)-pyridine heterocyclic heptaphen-2 ² -amine

(2-(((2-(methylamino)-5-(3-((6-(2-(methylamino)-4-(((4-(((methylsulfonyl)oxy)methyl )pyridin-2-yl))methyl)amino)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)quinolin-3-yl)disulfanyl)quinoline Pyrin-6-yl)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-4-yl)methylsulfonate (0.4g) Dissolve in N,N-dimethylformamide (80 mL), add potassium carbonate (596 mg), and react at 60°C for 1 hour. After TLC showed that the reaction was complete, the system was cooled to room temperature, 100 mL of water was added, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain 18 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 580.2.

Step 8: N-methyl-2 ⁷ H-7-thia-3-aza-1(6,3)-quinoline-2(5,4)-pyrrole[2,3-d]pyrimidine-5( Preparation of 2,4)-pyridine heterocyclic heptafan-2 ² -amine

N-methyl-2 ⁷ -p-toluenesulfonyl-2 ⁷ H-7-thia-3-aza-1(6,3)-quinoline-2(5,4)-pyrrole[2,3- d] Pyrimidine-5(2,4)-pyridine heterocyclic heptaphen-2 ² -amine (18mg) was dissolved in ethanol (2mL) and water (0.5mL), added sodium hydroxide (8mg), and reacted at 50°C for 1 hour . After TLC showed that the reaction was complete, the system was cooled to room temperature, 10 mL of water was added, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by high pressure preparation to obtain 2.7 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 426.2.

¹ H NMR (600MHz, DMSO-d ₆ ) δ11.23(s, 1H), 8.59(d, J=2.3Hz, 1H), 8.30(d, J=5.2Hz, 1H), 8.10(d, J= 2.1Hz, 1H), 7.84(d, J=8.6Hz, 1H), 7.80(d, J=2.0Hz, 1H), 7.74(dd, J=8.6, 2.0Hz, 1H), 7.69(s, 1H) , 7.35(dd, J=5.2, 1.6Hz, 1H), 7.08(d, J=2.2Hz, 1H), 6.21(d, J=5.0Hz, 1H), 4.74(t, J=4.6Hz, 1H) , 4.33(s, 2H), 2.81(d, J=4.8Hz, 3H), 2.51-2.50(m, 2H).

Example 3: N-methyl-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo[2,3- d] Preparation of pyrimidine-5(3,5)-pyridine heterocyclic nonapheno-2 ² -amine

Step 1: N ⁴ -((5-(2-chloroethoxy)pyridin-3-yl)methyl)-5-(3-((4-methoxybenzyl)oxy)quinoline-6 Preparation of -yl)-N ² -methyl-7-tolyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

5-((5-(3-((4-methoxybenzyl)oxy)quinolin-6-yl)-2-(methylamino)-7-methylphenyl-7H-pyrrolo[2, 3-d]pyrimidin-4-yl)amino)methyl)pyridin-3-ol (65.0 mg) was dissolved in N,N-dimethylformamide (1 mL), potassium carbonate (26.0 mg) and 1-bromo -2-Chloroethane (20.0mg), heated at 80°C for 1 hour. After TLC showed that the reaction was complete, the system was lowered to room temperature, 5 mL of water was added, extracted three times with ethyl acetate, the organic phases were combined, backwashed twice with water, once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and reduced Concentrate under pressure. The obtained crude product was purified by column chromatography to obtain 60.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 750.2.

Step 2: 6-(4-((5-(2-Chloroethoxy)pyridin-3-yl)methyl)amino)-2-(methylamino)-7-tolyl-7H-pyrrolo[ Preparation of 2,3-d]pyrimidin-5-yl)quinolin-3-ol

N ⁴ -((5-(2-chloroethoxy)pyridin-3-yl)methyl)-5-(3-((4-methoxybenzyl)oxy)quinolin-6-yl )-N ² -methyl-7-tolyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (60.0 mg) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid ( 1 mL), react at room temperature for 1 hour. After TLC showed that the reaction was complete, it was concentrated under reduced pressure to obtain 55.0 mg of the title compound, which was directly used in the next step without purification.

MS (ESI) m/z (M+H) ⁺ = 630.1.

Step 3: N-Methyl-2 ⁷ -tosyl-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrole Preparation of a[2,3-d]pyrimidine-5(3,5)-pyridine heterocyclic nonapheno-2 ² -amine

6-(4-((5-(2-chloroethoxy)pyridin-3-yl)methyl)amino)-2-(methylamino)-7-tolyl-7H-pyrrolo[2, 3-d] Pyrimidin-5-yl)quinolin-3-ol (55.0mg) was dissolved in N,N-dimethylformamide (1mL), cesium carbonate (75.0mg) was added, and the reaction was heated at 50°C for 1 hour. After TLC showed that the reaction was complete, the system was lowered to room temperature, 5 mL of water was added, extracted three times with ethyl acetate, the organic phases were combined, backwashed twice with water, once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and reduced Concentrate under pressure. The obtained crude product was purified by column chromatography to obtain 20.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 594.1.

Step 4: N-Methyl-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo[2,3-d Preparation of ]pyrimidine-5(3,5)-pyridine heterocyclic nonapheno-2 ² -amine

N-methyl-2 ⁷ -tosyl- ^{2 7} H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo[ 2,3-d]pyrimidine-5(3,5)-pyridine heterocyclic nonapheno- ^{2 2} -amine (20.0mg) was dissolved in methanol (2mL), sodium hydroxide aqueous solution (2M, 0.06mL) was added dropwise, and the temperature was raised Reflux reaction at 80°C for 2 hours. After TLC showed that the reaction was complete, an appropriate amount of dilute hydrochloric acid was added to the system to adjust the system to be neutral, and concentrated under reduced pressure. The obtained crude product was purified by preparative HPLC and lyophilized to obtain 3.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 440.2.

¹ H NMR (600MHz, DMSO-d ₆ ) δ11.20(s, 1H), 8.53(d, J=2.9Hz, 1H), 8.45(d, J=2.7Hz, 1H), 8.18(d, J= 1.7Hz, 1H), 7.88(d, J=8.6Hz, 1H), 7.70(dd, J=8.6, 2.0Hz, 1H), 7.53(d, J=1.9Hz, 1H), 7.48(t, J= 2.2Hz, 1H), 7.38(d, J=2.8Hz, 1H), 7.00(d, J=2.3Hz, 1H), 6.18(d, J=5.2Hz, 1H), 5.68(t, J=5.7Hz , 1H), 4.66(d, J=4.9Hz, 2H), 4.61(t, J=7.3Hz, 4H), 2.83(d, J=4.8Hz, 3H).

Example 4: N-methyl-2 ⁷ H-3,6,9-trioxa-1(6,3)-quinoline-2(5,4)-pyrrolo[2,3-d]pyrimidine Preparation of -5(3,5)-pyridine heterocyclic nonapheno-2 ² -amine

Step 1: 2-((5-(((5-(3-hydroxyquinolin-6-yl)-2-(methylamino)-7-((2-(trimethylsilyl)ethoxy )methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxyl)methyl)pyridin-3-yl)oxyl)methylsulfonic acid ethyl ester

2-((5-(((2-(methylamino)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)quinolin-6-yl)-7-( (2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)pyridin-3-yl)oxy ) ethyl methanesulfonate (300mg) was dissolved in tetrahydrofuran (2mL), acetic acid (4mL) and water (1mL) were added, and reacted overnight at room temperature. LCMS monitors that the reaction of the raw materials is complete, pours the reaction system into water (20mL), extracts with ethyl acetate, combines the organic phases, backwashes once with saturated sodium chloride solution, dries over anhydrous sodium sulfate, filters, and concentrates under reduced pressure to obtain 200 mg of the crude product. It can be used in the next reaction after purification.

MS (ESI) m/z (M+H) ⁺ = 667.2.

Step 2: N-Methyl-2 ⁷ -((2-(trimethylsilyl)ethoxy)methyl)-2 ⁷ H-3,6,9-trioxa-1(6,3 Preparation of )-quinoline-2(5,4)-pyrrolo[2,3-d]pyrimidine-5(3,5)-pyridine heterocyclic nonapheno- ^{2 2} -amine

2-((5-(((5-(3-hydroxyquinolin-6-yl)-2-(methylamino)-7-((2-(trimethylsilyl)ethoxy)methyl Base)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)pyridin-3-yl)oxy)methylsulfonate (300mg) was dissolved in N,N- Dimethylformamide (5 mL) was added with cesium carbonate (300 mg), and reacted at room temperature for 4 hours. TLC showed that the raw materials were completely consumed. The reaction system was poured into water (20 mL), extracted with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 120 mg of crude product. It can be used in the next reaction after purification.

MS (ESI) m/z (M+H) ⁺ = 571.2.

Step 3: N-Methyl-2 ⁷ H-3,6,9-trioxa-1(6,3)-quinoline-2(5,4)-pyrrolo[2,3-d]pyrimidine- Preparation of 5(3,5)-pyridine heterocyclic nonapheno-2 ² -amine

N-methyl-2 ⁷ -((2-(trimethylsilyl)ethoxy)methyl)-2 ⁷ H-3,6,9-trioxa-1(6,3)- Quinoline-2(5,4)-pyrrolo[2,3-d]pyrimidine-5(3,5)-pyridine heterocyclic nonapheno-2 ² -amine (120 mg) was dissolved in dichloromethane (5 mL), Add trifluoroacetic acid (5 mL), react at room temperature for 1 h, and then concentrate to remove trifluoroacetic acid. Ammonia-methanol solution (7M, 5.0 mL) was added and reacted overnight at room temperature. The complete reaction of the starting material was monitored by LCMS, and the system was concentrated to obtain a crude product, which was purified by preparative HPLC and lyophilized to obtain 23.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 441.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.62(s, 1H), 8.62(d, J=2.8Hz, 1H), 8.52(d, J=2.9Hz, 1H), 8.37(d, J= 1.6Hz, 1H), 8.12(d, J=1.7Hz, 1H), 7.86-7.79(m, 2H), 7.59(t, J=2.2Hz, 1H), 7.38(s, 1H), 7.31(d, J=2.9Hz, 1H), 6.72(q, J=4.7Hz, 1H), 5.50(s, 2H), 4.79-4.74(m, 2H), 4.63-4.56(m, 2H), 2.89(d, J =4.7Hz, 3H).

Example 5: N-methyl-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo[2,3- d] Preparation of pyrimidine-5(2,4)-pyridine heterocyclic nonapheno-2 ² -amine

Step 1: 2-((2-(((5-(3-((4-methoxybenzyl)oxy)quinolin-6-yl)-2-(methylamino)-7-toluenesulfonyl Preparation of -7H-pyrrole[2,3-d])pyrimidin-4-yl)amino)methyl)pyridin-4-yl)oxy)ethan-1-ol

N ⁴ -((4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-2-yl)methyl)-5-(3-((4-methyl Oxybenzyl)oxy)quinolin-6- ^yl )-N 2 -methyl-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (500.0mg ) was dissolved in tetrahydrofuran (5 mL), tetrabutylammonium fluoride (1 mL, 1M in THF) was added, and reacted at room temperature for 1 hour. TLC showed that the raw material was completely consumed. Water (10 mL) was added, extracted with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was separated by column chromatography to obtain 300 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 732.2.

Step 2: 2-((2-((5-(3-((4-methoxybenzyl)oxy)quinolin-6-yl)-2-(methylamino)-7-tolyl-7H -Preparation of pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-4-yl)oxy)methylsulfonic acid ethyl ester

In an ice-water bath, 2-((2-(((5-(3-((4-methoxybenzyl)oxy)quinolin-6-yl)-2-(methylamino)-7-toluene Sulfonyl-7H-pyrrole[2,3-d])pyrimidin-4-yl)amino)methyl)pyridin-4-yl)oxy)ethan-1-ol (250.0 mg) was dissolved in dichloromethane ( 4 mL), triethylamine (100 mg) and methanesulfonyl chloride (57 mg) were added in sequence, and the mixture was naturally returned to room temperature for 1 h. TLC showed that the reaction was complete. Pour the system into water (20 mL), adjust the pH to about 8 with saturated sodium bicarbonate solution, extract with ethyl acetate, combine the organic phases, backwash once with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and filter , concentrated under reduced pressure. The obtained crude product was separated by column chromatography to obtain 200.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 810.2.

Subsequent steps use corresponding commercial reagents, and refer to steps 2-4 of Example 3 to complete.

MS (ESI) m/z (M+H) ⁺ = 440.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.24(s, 1H), 8.53(d, J=2.9Hz, 1H), 8.38(d, J=5.8Hz, 1H), 7.90(d, J= 8.7Hz, 1H), 7.71(dd, J=8.7, 1.9Hz, 1H), 7.58(d, J=1.9Hz, 1H), 7.44(d, J=2.9Hz, 1H), 7.15(dd, J= 5.8, 2.5Hz, 1H), 7.07(d, J=2.4Hz, 1H), 7.02(d, J=2.3Hz, 1H), 6.22(d, J=5.0Hz, 1H), 5.71(t, J= 5.8Hz, 1H), 4.65(dt, J=12.5, 5.5Hz, 6H), 2.83(d, J=4.7Hz, 3H).

Example 6: N-methyl-2 ⁷ H-3,6,9-trioxopyrimidine-1(6,3)-quinoline-2(5,4)-pyrrole[2,3-d]pyrimidine- Preparation of 5(4,2)-pyridine heterocyclic nonapheno-2 ² -amine

Step 1: 2 ² -Chloro-2 ⁷ -((2-(trimethylsilyl)ethoxy)methyl)-2 ⁷ H-3,6,9-trioxy-1(6,3) Preparation of -quinoline-2(5,4)-pyrrole[2,3-d]pyrimidine-5(4,2)-pyridine heterocyclic nonacene

(2-(2-(6-(2,4-dichloro-7-(2-(trimethylsilylethoxy)methyl)-7-(2,3-d)pyrimidine-5- Base) quinolin-3-yl) ethoxy) pyridin-4-yl) methanol (150mg) was dissolved in tetrahydrofuran (50mL), sodium hydride (20mg) was added, and reacted at room temperature for 2 hours. After TLC showed that the reaction was complete, 10 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 40 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 576.1.

Step 2: N-Methyl-2 ⁷ -((2-(trimethylsilyl)ethoxy)methyl)-2 ⁷ H-3,6,9-trioxy-1(6,3) Preparation of -quinoline-2(5,4)-pyrrole[2,3-d]pyrimidine-5(4,2)-pyridine heterocyclic nonapheno- ^{2 2} -amine

2 ² -chloro-2 ⁷ -((2-(trimethylsilyl)ethoxy)methyl)-2 ⁷ H-3,6,9-trioxy-1(6,3)-quinone Phenyl-2(5,4)-pyrrole[2,3-d]pyrimidine-5(4,2)-pyridine heterocyclic nonacene (40mg) was placed in a microwave tube, and methylamine/tetrahydrofuran solution (1M, 2mL) was added , microwave reaction at 105°C for 3 hours. After TLC showed that the reaction was complete, the system was cooled to room temperature, 25 mL of water was added, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 40 mg of crude product.

MS (ESI) m/z (M+H) ⁺ = 571.1.

Step 3: N-Methyl-2 ⁷ H-3,6,9-trioxopyrimidine-1(6,3)-quinoline-2(5,4)-pyrrole[2,3-d]pyrimidine-5 Preparation of (4,2)-pyridine heterocyclic nonapheno-2 ² -amine

N-methyl-2 ⁷ -((2-(trimethylsilyl)ethoxy)methyl)-2 ⁷ H-3,6,9-trioxy-1(6,3)-quinone Line-2(5,4)-pyrrole[2,3-d]pyrimidine-5(4,2)-pyridine heterocyclic nonapheno- ² 2 -amine (40.0mg) was dissolved in dichloromethane (4mL), added Trifluoroacetic acid (1 mL) was reacted at room temperature for 1 hour. TLC showed that the reaction was complete, concentrated under reduced pressure to remove trifluoroacetic acid, added ammonia methanol solution (7M, 5 mL) to the system, and reacted at room temperature for 5 hours. TLC showed that the reaction was complete, and concentrated under reduced pressure. The obtained crude product was purified by preparative HPLC and lyophilized to obtain 5.92 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 441.1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.62(s, 1H), 8.52(d, J=2.9Hz, 1H), 8.27(d, J=5.2Hz, 1H), 8.07(d, J= 1.8Hz, 1H), 7.87-7.77(m, 2H), 7.40(d, J=2.2Hz, 1H), 7.23-7.13(m, 2H), 6.99(s, 1H), 6.71(d, J=5.0 Hz, 1H), 5.46(s, 2H), 4.94-4.85(m, 2H), 4.56(d, J=5.5Hz, 2H), 2.88(d, J=4.8Hz, 3H).

Example 7: N-methyl-2 ⁷ H-6,10-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo[2,3- d] Preparation of pyrimidine-5 (3,5)-pyridine heterocyclic dedec-2 ² -amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Example 5 above.

MS (ESI) m/z (M+H) ⁺ = 454.1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.37(s, 1H), 8.49(d, J=2.9Hz, 1H), 8.25(d, J=2.7Hz, 1H), 8.14(d, J= 1.7Hz, 1H), 7.94(t, J=2.2Hz, 1H), 7.89-7.77(m, 3H), 7.65(m, 1H), 7.00(d, J=1.9Hz, 1H), 6.45(s, 1H), 5.63(s, 1H), 4.63(t, J=5.8Hz, 2H), 4.52(d, J=4.6Hz, 2H), 4.16(t, J=5.4Hz, 2H), 2.86(d, J=3.7Hz, 3H), 2.21(m, 2H).

Example 8: N-methyl-2 ⁷ H-3,6,9-trioxa-1(6,3)-quinoline-2(5,4)-pyrrolo[2,3-d]pyrimidine Preparation of -5(2,4)-pyridine heterocyclic nonapheno-2 ² -amine

Step 1: 2-((2-(((5-(3-hydroxyquinolin-6-yl)-2-(methylamino)-7-((2-(trimethylsilyl)ethoxy )methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxyl)methyl)pyridin-4-yl)oxyl)methylsulfonic acid ethyl ester

2-((2-(((5-(3-((4-methoxybenzyl)oxy)quinolin-6-yl)-2-(methylamino)-7-((2-( Trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)pyridin-4-yl)oxy)ethylmethyl The sulfonate (35.0mg) was dissolved in methanol (10mL), palladium carbon (8.0mg) was added, replaced by hydrogen three times, and reacted at room temperature in a hydrogen atmosphere for 2h. After TLC showed that the reaction was complete, the palladium carbon was removed by filtration, and the filtrate was collected and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 10.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 667.2.

Subsequent steps use corresponding commercial reagents, and refer to steps 2-3 of Example 4 to complete.

MS (ESI) m/z (M+H) ⁺ = 441.2.

Example 9: N-methyl-2 ⁷ H-6,9-dioxa-3-thio-1(6,3)-quinoline-2(5,4)-pyrrole[2,3-d] Preparation of Pyrimidine-5(3,5)-Pyridine Heterocyclic Nonapheno-2 ² -Amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Example 5 above.

MS (ESI) m/z (M+H) ⁺ = 457.1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.58(s, 1H), 8.57(d, J=2.9Hz, 1H), 8.43(d, J=2.8Hz, 1H), 8.17(d, J= 1.7Hz, 1H), 7.87(d, J=8.5Hz, 1H), 7.66(dd, J=8.5, 2.0Hz, 1H), 7.52(s, 1H), 7.45(d, J=1.9Hz, 1H) , 7.24(dd, J=15.2, 2.6Hz, 2H), 6.87(d, J=5.5Hz, 1H), 4.61(s, 4H), 4.52(s, 2H), 2.92(d, J=4.7Hz, 3H).

Example 10: N-methyl-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo[2,3- d] Preparation of pyrimidine-5(1,3)-benzeneheterocyclic nonapheno-2 ² -amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Example 5 above.

MS (ESI) m/z (M+H) ⁺ = 439.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.23(s, 1H), 8.53(d, J=2.9Hz, 1H), 7.90(d, J=8.6Hz, 1H), 7.70(dd, J= 8.6, 2.0Hz, 1H), 7.51(d, J=2.0Hz, 1H), 7.43(d, J=3.0Hz, 1H), 7.30(t, J=7.8Hz, 1H), 7.11-7.05(m, 2H), 7.00(d, J=2.3Hz, 1H), 6.93(d, J=7.5Hz, 1H), 6.21(q, J=4.8Hz, 1H), 5.55(t, J=5.5Hz, 1H) , 4.65-4.54(m, 6H), 2.85(d, J=4.8Hz, 3H).

Example 11: N-methyl-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrole[2,3-d ]Preparation of pyrimidine-5(4,2)-pyridine heterocyclic nonapheno-2 ² -amine

Step 1: (2-(2-(2,4-Dichloro-7-p-tolyl-7H-pyrrole[2,3-d]pyrimidin-5-yl)quinolin-3-yl)oxy)ethyl Preparation of oxy)pyridin-4-yl)carboxamide

Tert-butyl ((2-(2-((6-(2,4-dichloro-7-tolyl-7H-pyrrole [2,3-d] pyrimidin-5-yl) quinoline-3-yl )oxy)ethoxy)pyridin-4-yl)methyl)carbamate (280 mg) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (2 mL), and reacted at room temperature for 1 hour. After TLC showed that the reaction was complete, the system was directly concentrated under reduced pressure to obtain 350 mg of crude product.

MS (ESI) m/z (M+H) ⁺ = 635.2.

Step 2: 2 ² -Chloro-2 ⁷ -p-toluenesulfonyl-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)- Preparation of pyrrolo[2,3-d]pyrimidine-5(4,2)-pyridine heterocyclic nonacene

(2-(2-(2,4-dichloro-7-p-tolyl-7H-pyrrole[2,3-d]pyrimidin-5-yl)quinolin-3-yl)oxy)ethoxy )pyridin-4-yl)formamide (350mg) was dissolved in N,N-dimethylformamide (150mL), triethylamine (202mg) was added, and reacted at room temperature for 2 hours. After TLC showed that the reaction was complete, concentrated to remove most of the solvent, added 100 mL of water to the system, extracted three times with ethyl acetate, combined the organic phases, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 120 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 599.1.

Step 3: N-methyl-2 ⁷ -p-toluenesulfonyl-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)- Preparation of pyrrolo[2,3-d]pyrimidine-5(4,2)-pyridine heterocyclic nonaden- ^{2 2} -amine

2 ² -chloro-2 ⁷ -p-toluenesulfonyl-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrole [ 2,3-d]pyrimidine-5(4,2)-pyridine heterocyclic nonaffin (120 mg) was placed in a microwave tube, and methylamine in tetrahydrofuran (1M, 2 mL) was added, and reacted under microwave at 95°C for 2 hours. After TLC showed that the reaction was complete, the system was concentrated under reduced pressure to obtain 140 mg of crude product.

MS (ESI) m/z (M+H) ⁺ = 594.1.

Step 4: N-Methyl- ^27H -6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrole[2,3-d] Preparation of Pyrimidine-5(4,2)-Pyridine Heterocyclic Nonapheno-2 ² -Amine

N-methyl-2 ⁷ -p-toluenesulfonyl-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrole [ 2,3-d]pyrimidine-5(4,2)-pyridine heterocyclic nonapheno-2 ² -amine (140mg) was dissolved in methanol (4mL) and water (1mL), added sodium hydroxide (40mg), and reacted at room temperature 1 hour. After TLC showed that the reaction was complete, it was concentrated under reduced pressure. The obtained crude product was purified by preparative HPLC and lyophilized to obtain 13.1 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 440.1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.24(s, 1H), 8.54(d, J=2.9Hz, 1H), 8.18(d, J=5.1Hz, 1H), 7.90(d, J= 8.6Hz, 1H), 7.70(dd, J=8.6, 2.0Hz, 1H), 7.33(d, J=2.0Hz, 1H), 7.05(d, J=3.0Hz, 1H), 7.03-6.97(m, 2H), 6.87(s, 1H), 6.23(q, J=4.8Hz, 1H), 5.64(t, J=5.7Hz, 1H), 4.88-4.81(m, 2H), 4.66-4.56(m, 4H ), 2.85 (d, J=4.8Hz, 3H).

Example 12: N-(cyclopropylmethyl)-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo Preparation of [2,3-d]pyrimidine-5(3,5)-pyridine heterocyclic nonapheno-2 ² -amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Example 5 above.

MS (ESI) m/z (M+H) ⁺ = 480.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.21(s, 1H), 8.55(d, J=2.9Hz, 1H), 8.48(d, J=2.8Hz, 1H), 8.21(d, J= 1.8Hz, 1H), 7.90(d, J=8.6Hz, 1H), 7.72(m, 1H), 7.61-7.48(m, 2H), 7.39(d, J=2.9Hz, 1H), 7.02(d, J=2.4Hz, 1H), 6.29(t, J=6.0Hz, 1H), 5.73(t, J=5.6Hz, 1H), 4.66(m, 6H), 3.22(t, J=6.3Hz, 2H) , 1.15(m, 1H), 0.52-0.38(m, 2H), 0.33-0.20(m, 2H).

Example 13: N-methyl-2 ⁷ H-3,6,10-trioxa-1(6,3)-quinoline-2(5,4)-pyrrolo[2,3-d]pyrimidine- Preparation of 5(3,5)-pyridine heterocyclic dedec-2 ² -amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Example 4 above.

MS (ESI) m/z (M+H) ⁺ = 455.1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.56(s, 1H), 8.45(d, J=2.8Hz, 1H), 8.33(d, J=2.8Hz, 1H), 8.22(d, J= 1.8Hz, 1H), 8.15(dd, J=2.7, 1.8Hz, 1H), 8.09(d, J=1.9Hz, 1H), 7.76(d, J=8.8Hz, 1H), 7.70(dd, J= 8.7, 1.9Hz, 1H), 7.64(d, J=2.9Hz, 1H), 7.23(d, J=1.5Hz, 1H), 6.69(q, J=4.7Hz, 1H), 5.34(s, 2H) , 4.62(t, J=5.9Hz, 2H), 4.20(t, J=5.4Hz, 2H), 2.89(d, J=4.7Hz, 3H), 2.21(p, J=5.5Hz, 2H).

Example 14: N-methyl-2 ⁷ H-3,6,9-trioxopyrimidine-1(6,3)-quinoline-2(5,4)-pyrrole[2,3-d]pyrimidine- Preparation of 5(2,6)-pyridine heterocyclic nonapheno-2 ² -amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a preparation method similar to that of Example 6 above.

MS (ESI) m/z (M+H) ⁺ = 441.1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.57(s, 1H), 8.48(d, J=2.9Hz, 1H), 8.25(d, J=1.3Hz, 1H), 7.84-7.78(m, 4H), 7.36(d, J=1.4Hz, 1H), 7.21(d, J=7.2Hz, 1H), 7.09(d, J=8.4Hz, 1H), 6.72-6.69(m, 1H), 5.37( s, 2H), 4.75-4.70 (m, 2H), 4.66-4.61 (m, 2H), 2.89 (d, J=4.7Hz, 3H).

Example 15: N-methyl-2 ⁷ H-3,6,9-trioxy-1(6,3)-quinoline-2(5,4)-pyrrole[2,3-d]pyrimidine- Preparation of 5(4,2)-Benzene Heterocyclic Nonapheno-2 ² -Amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Example 8 above.

MS (ESI) m/z (M+H) ⁺ = 440.1.

¹ H NMR (600MHz, DMSO-d ₆ ) δ11.59(s, 1H), 8.50(d, J=2.9Hz, 1H), 8.17(s, 1H), 7.86-7.79(m, 2H), 7.39( m 3H), 7.23-7.21(m, 2H), 7.06(d, J=7.4Hz, 1H), 6.69(d, J=4.8Hz, 1H), 5.46(s, 2H), 4.46(dd, J= 6.9, 3.9Hz, 2H), 4.56(d, J=5.1Hz, 2H), 2.88(d, J=4.7Hz, 3H).

Example 16: N-methyl-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrole[2,3-d Preparation of ]pyrimidine-5(2,6)-pyridine heterocyclic nonapheno-2 ² -amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a preparation method similar to that of Example 11 above.

MS (ESI) m/z (M+H) ⁺ = 440.1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.28(s, 1H), 8.57(d, J=2.9Hz, 1H), 7.97(d, J=2.9Hz, 1H), 7.93(d, J= 9.2Hz, 1H), 7.79(dd, J=8.3, 7.3Hz, 1H), 7.72-7.69(m, 2H), 7.09-7.04(m, 2H), 6.92(d, J=8.2Hz, 1H), 6.22-6.19(m, 1H), 5.90(m, 1H), 4.73-4.71(m, 2H), 4.63-4.60(m, 4H), 2.85(d, J=4.8Hz, 3H).

Example 17: N-(2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo[2,3-d] Preparation of pyrimidin-5(3,5)-pyridine heterocyclic nonaden-2 ² -yl)cyclopropanecarboxamide

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Example 3 above.

MS (ESI) m/z (M+H) ⁺ = 494.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.82(s, 1H), 10.18(s, 1H), 8.58(d, J=2.9Hz, 1H), 8.49(d, J=2.8Hz, 1H) , 8.23(d, J=1.8Hz, 1H), 7.95(d, J=8.7Hz, 1H), 7.78(dd, J=8.6, 2.0Hz, 1H), 7.58-7.53(m, 1H), 7.41( d, J=3.0Hz, 1H), 7.36(s, 1H), 7.20(s, 1H), 6.66(s, 1H), 6.12(t, J=5.6Hz, 1H), 5.33(dd, J=5.5 , 4.2Hz, 1H), 4.81-4.55(m, 4H), 2.02-1.98(m, 1H), 0.94-0.75(m, 4H).

Example 18: 2 ² -methoxy-2 ⁷ H-3,6,9-trioxy-1(6,3)-quinoline-2(5,4)-pyrrole[2,3-d] Preparation of Pyrimidine-5(3,5)-Pyridine Heterocyclic Nonazone

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Example 8 above.

MS (ESI) m/z (M+H) ⁺ = 442.1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.19 (d, J=2.5Hz, 1H), 8.62 (d, J=2.8Hz, 1H), 8.55 (d, J=2.9Hz, 1H), 8.40 (d, J=1.8Hz, 1H), 8.14(d, J=1.8Hz, 1H), 7.91-7.80(m, 2H), 7.66(d, J=2.5Hz, 1H), 7.64-7.57(m, 1H), 7.34(d, J=2.9Hz, 1H), 5.55(s, 2H), 4.83-4.73(m, 2H), 4.67-4.56(m, 2H), 3.98(s, 3H).

Example 19: N-methyl-2 ⁷ H-3,7-dioxa-1(6,3)-quinoline-2(5,4)-pyrrole[2,3-d]pyrimidine-5( Preparation of 3,5)-pyridine heterocyclic heptafan-2 ² -amine

Step 1: 4-((5-(Bromomethyl)pyridin-3-yl)methoxy)-N-methyl-5-(3-(((tetrahydro-2H-pyran-2-yl) Oxygen) quinoline-6-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine preparation

(5-(((2-(methylamino)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)quinolin-6-yl)-7-((2- (Trimethylsilyl)ethoxy)methyl))-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)pyridin-3-yl)methanesulfonate The ester (170mg) was dissolved in N,N-dimethylformamide (5mL), potassium bromide (71mg) was added, and the reaction was carried out at room temperature for 1 hour. After TLC showed that the reaction was complete, 10 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 190 mg of crude product, which was directly used in the next reaction without purification.

MS (ESI) m/z (M+H) ⁺ = 705.2.

Subsequent steps use corresponding commercial reagents, and refer to the preparation method of Example 4 to complete.

MS (ESI) m/z (M+H) ⁺ = 411.1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.48(s, 1H), 8.66(d, J=2.3Hz, 1H), 8.48(d, J=2.0Hz, 1H), 8.33(dd, J= 8.3, 2.4Hz, 2H), 8.01(dd, J=6.5, 2.4Hz, 2H), 7.66(d, J=8.6Hz, 1H), 7.54(dd, J=8.6, 1.9Hz, 1H), 7.23( s, 1H), 6.65(q, J=4.7Hz, 1H), 5.59(s, 2H), 5.22(s, 2H), 2.87(d, J=4.8Hz, 3H).

Example 20: N-methyl-2 ⁷ H-7-oxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrole[2,3-d]pyrimidine- Preparation of 5(3,5)-pyridine heterocyclic heptaphen-2 ² -amine

Step 1: (5-((5-(3-((4-methoxybenzyl)oxy)quinolin-6-yl)-2-(methylamino)-7-toluenesulfonyl-7H- Preparation of pyrrole[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-3-yl)methanol

N ⁴ -((5-((tert-butyldimethylsilyloxy)methyl)pyrimidin-2-yl)methyl)-5-(3-((4-methoxybenzyl)oxy )quinolin-6-yl)-N ² -methyl-7-p-tolyl-7H-pyrrole[2,3-d]pyridine-2,4-diamine (210mg) dissolved in tetrabutyl ammonium fluoride /THF solution (1.0M, 10mL), react at room temperature for 1 hour. After TLC showed that the reaction was complete, it was concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 180 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 702.2.

Step 2: (5-((5-(3-((4-methoxybenzyl)oxy)quinolin-6-yl)-2-(methylamino)-7-p-tolyl-7H- Preparation of pyrrole[2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-3-ylmethylsulfonate

(5-((5-(3-((4-methoxybenzyl)oxy)quinolin-6-yl)-2-(methylamino)-7-toluenesulfonyl-7H-pyrrole[ 2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-3-yl)methanol (180 mg) was dissolved in dichloromethane (5 mL), triethylamine (56 mg) and methanesulfonyl chloride (34 mg ), reacted at room temperature for 1 hour. After TLC showed that the reaction was complete, 10 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 230 mg of the title compound, which was directly used in the next reaction without purification.

MS (ESI) m/z (M+H) ⁺ = 780.2.

Step 3: N ⁴ -((5-(bromomethyl)pyridin-3-yl)methyl)-5-(3-((4-methoxybenzyl)oxy)quinolin-6-yl) Preparation of -N ² -methyl-7-p-tolyl-7H-pyrrole[2,3-d]pyrimidine-2,4-diamine

(5-((5-(3-((4-methoxybenzyl)oxy)quinolin-6-yl)-2-(methylamino)-7-p-tolyl-7H-pyrrole[ 2,3-d]pyrimidin-4-yl)amino)methyl)pyridin-3-ylmethylsulfonate (230mg) was dissolved in N,N-dimethylformamide (5mL) and potassium bromide was added (71mg), react at room temperature for 1 hour. After TLC showed that the reaction was complete, 10 mL of water was added to the system, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 270 mg of the title compound, which was directly used in the next reaction without purification.

MS (ESI) m/z (M+H) ⁺ = 764.2.

Step 4: 6-(4-((5-(Bromomethyl)pyridin-3-yl)methyl)amino)-2-(methylamino)-7-tosyl-7H-pyrrole[2,3- d] preparation of pyrimidin-5-yl) quinoline-3-alcohol

N ⁴ -((5-(bromomethyl)pyridin-3-yl)methyl)-5-(3-((4-methoxybenzyl)oxy)quinolin-6-yl)-N ² -Methyl-7-p-tolyl-7H-pyrrole[2,3-d]pyrimidine-2,4-diamine (270mg) was dissolved in dichloromethane (10mL), added trifluoroacetic acid (2mL), room temperature React for 1 hour. After TLC showed that the reaction was complete, the system was directly concentrated under reduced pressure to obtain 310 mg of crude product, which was directly used in the next reaction without purification.

MS (ESI) m/z (M+H) ⁺ = 644.2.

Step 5: N-Methyl-2 ⁷ -p-toluenesulfonyl-2 ⁷ H-7-oxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrole[2 , 3-d] the preparation of pyrimidine-5(3,5)-pyridine heterocycle heptaphen-2 ² -amine

6-(4-((5-(bromomethyl)pyridin-3-yl)methyl)amino)-2-(methylamino)-7-toluenesulfonyl-7H-pyrrole[2,3-d] Pyrimidin-5-yl)quinolin-3-ol (310 mg) was dissolved in N,N-dimethylformamide (50 mL), cesium carbonate (652 mg) was added, and reacted at room temperature for 2 hours. After TLC showed that the reaction was complete, concentrated to remove part of the solvent, added 100 mL of water to the system, extracted three times with ethyl acetate, combined the organic phases, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 20 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 564.1.

Step 6: N-Methyl-2 ⁷ H-7-oxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrole[2,3-d]pyrimidine-5 Preparation of (3,5)-pyridine heterocyclic heptaphen-2 ² -amine

N-methyl-2 ⁷ -p-toluenesulfonyl-2 ⁷ H-7-oxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrole[2,3 -d] Pyrimidine-5(3,5)-pyridine heterocyclic heptaphen-2 ² -amine (20mg) was dissolved in methanol (4mL) and water (1mL), sodium hydroxide (17mg) was added and reacted at room temperature for 1 hour. After TLC showed that the reaction was complete, the product was concentrated to remove part of the solvent to obtain a crude product. The obtained crude product was purified by preparative HPLC and lyophilized to obtain 3.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 410.1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.25(s, 1H), 8.54(d, J=2.2Hz, 1H), 8.48(d, J=1.9Hz, 1H), 8.38(d, J= 2.7Hz, 1H), 8.25(d, J=1.9Hz, 1H), 8.13(d, J=2.9Hz, 1H), 7.92(d, J=1.9Hz, 1H), 7.77(d, J=8.6Hz , 1H), 7.61-7.56(m, 1H), 7.09(d, J=2.3Hz, 1H), 6.25(q, J=4.7Hz, 1H), 5.59(d, J=12.2Hz, 1H), 5.51 (d, J = 12.3Hz, 1H), 4.63 (dd, J = 12.7, 5.3Hz, 1H), 4.42 (dd, J = 5.5, 2.5Hz, 1H), 4.09 (dd, J = 12.7, 2.4Hz, 1H), 2.84(d, J=4.7Hz, 3H).

Example 21: N-methyl-2 ⁷ H-3,6,9-trioxy-1(6,3)-quinoline-2(5,4)-pyrrole[2,3-d]pyrimidine- Preparation of 5(2,6)-pyrazine heterocyclic nonapheno-2 ² -amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Example 4 above.

MS (ESI) m/z (M+H) ⁺ = 441.1.

¹ H NMR (400MHz, DMSO-d6) δ11.59(s, 1H), 8.59(s, 1H), 8.50(d, J=3.0Hz, 2H), 8.13(d, J=1.9Hz, 1H), 7.85-7.75(m, 2H), 7.67(d, J=3.0Hz, 1H), 7.35(d, J=2.4Hz, 1H), 6.75(d, J=5.3Hz, 1H), 5.45(s, 2H ), 4.94-4.85(m, 2H), 4.68(t, J=4.1Hz, 2H), 2.89(d, J=4.7Hz, 3H).

Example 22: N-methyl-2 ⁷ H-3,6,9-trioxa-1(6,3)-quinoline-2(5,4)-pyrrole[2,3-d]pyrimidine- Preparation of 5(3,5)-Pyridazine Heterocyclic Nonapheno-2 ² -amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Example 4 above.

MS (ESI) m/z (M+H) ⁺ = 442.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.65(s, 1H), 9.49(d, J=2.9Hz, 1H), 8.55(d, J=2.9Hz, 1H), 8.04(d, J= 1.7Hz, 1H), 7.86(d, J=8.7Hz, 1H), 7.81(dd, J=8.8, 1.9Hz, 1H), 7.39(s, 1H), 7.32(d, J=2.8Hz, 1H) , 7.29(d, J=2.9Hz, 1H), 6.79(d, J=4.8Hz, 1H), 5.73(s, 2H), 4.91(d, J=5.7Hz, 2H), 4.63(d, J=5.7Hz, 2H), 4.63(d, J= 5.6Hz, 2H), 2.90(d, J=4.7Hz, 3H).

Example 23: N-methyl-2 ⁷ H-3,6,-dioxa-1(6,3)-quinoline-2(5,4)-pyrrole[2,3-d]pyrimidine-5 Preparation of (3,5)-pyridine heterocyclic octafan-2 ² -amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Example 4 above.

MS (ESI) m/z (M+H) ⁺ = 425.1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.53(s, 1H), 8.69(d, J=2.1Hz, 1H), 8.34(s, 1H), 8.22(d, J=2.7Hz, 1H) , 8.17(d, J=1.8Hz, 1H), 8.08(d, J=1.8Hz, 1H), 8.01(t, J=2.2Hz, 1H), 7.85-7.74(m, 2H), 7.24(d, J=2.3Hz, 1H), 6.69(d, J=5.2Hz, 1H), 5.23(s, 2H), 4.52(t, J=5.1Hz, 2H), 3.17(t, J=4.5Hz, 2H) , 2.87 (d, J=4.1Hz, 3H).

Example 24: N-methyl-2 ⁷ H-3,6,9-trioxa-1(6,3)-quinoline-2(5,4)-pyrrolo[2,3-d]pyrimidine - Preparation of 5(2,4)-pyrimidocycloalkan-2 ² -amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Example 4 above.

MS (ESI) m/z (M+H) ⁺ = 442.2.

Example 25: N-methyl-2 ⁷ H-3-oxa-1(6,3)-quinoline-2(5,4)-pyrrolo[2,3-d]pyrimidine-5(3, 5) Preparation of -pyridocycloalcane-2 ² -amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Example 4 above.

MS (ESI) m/z (M+H) ⁺ = 437.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.62(s, 1H), 8.63(d, J=2.0Hz, 1H), 8.45(dd, J=14.9, 2.0Hz, 2H), 8.22(d, J=1.9Hz, 1H), 8.04(t, J=2.1Hz, 1H), 7.97-7.83(m, 2H), 7.74(d, J=2.1Hz, 1H), 7.36(d, J=2.4Hz, 1H), 6.74(q, J=4.7Hz, 1H), 5.50(s, 2H), 2.95(t, J=6.1Hz, 2H), 2.89(d, J=4.7Hz, 3H), 2.58(t, J=7.5Hz, 2H), 1.79(p, J=6.4Hz, 2H), 1.37(q, J=7.3Hz, 2H).

Example 26: N-cyclopropylmethyl-2 ⁷ H-3,6,9-trioxa-1(6,3)-quinoline-2(5,4)-pyrrolo[2,3- d] Preparation of pyrimidine-5(3,5)-pyridine heterocyclic nonapheno-2 ² -amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Example 4 above.

MS (ESI) m/z (M+H) ⁺ = 481.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.58(s, 1H), 8.62(s, 1H), 8.53(s, 1H), 8.37(s, 1H), 8.12(s, 1H), 7.82( q, J=8.8Hz, 2H), 7.60(s, 1H), 7.38(s, 1H), 7.31(s, 1H), 6.82(t, J=5.8Hz, 1H), 5.50(s, 2H), 4.76(d, J=5.1Hz, 2H), 4.67-4.53(m, 2H), 3.24(t, J=6.4Hz, 2H), 1.28-1.08(m, 1H), 0.51-0.40(m, 2H) , 0.27 (d, J=4.9Hz, 2H).

Example 27: N-methyl-2 ⁷ H-3,7-dioxo-1(6,3)-quinoline-2(5,4)-pyrrolo[2,3-d]pyrimidine-5( 2,4)-Pyrimidine heterocyclic nonadenol-2 ² -amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Example 4 above.

MS (ESI) m/z (M+H) ⁺ = 412.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.53(s, 1H), 8.65(d, J=5.1Hz, 1H), 8.40(d, J=2.8Hz, 1H), 8.26(d, J= 2.9Hz, 1H), 8.04(s, 1H), 7.67(d, J=8.7Hz, 1H), 7.59(d, J=8.5Hz, 1H), 7.54(d, J=5.1Hz, 1H), 7.30 (s, 1H), 6.71(d, J=5.2Hz, 1H), 5.64(s, 2H), 5.36(s, 2H), 2.86(d, J=4.6Hz, 3H).

Example 28: N-methyl-2 ⁷ H-6-oxyl-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo[2,3-d]pyrimidine- Preparation of 5(3,5)-pyridine heterocyclic nonapheno-2 ² -amine

Step 1: 2-(6-(4-(((5-Hydroxypyridin-3-yl)methyl)amino)-2-(methylamino)-7-tosyl-7H-pyrrolo[2, Preparation of 3-d]pyrimidin-5-yl)quinolin-3-yl)ethyl methanesulfonate

Weigh 2-(6-(2-(methylamino)-4-(((5-((tetrahydro-2H-pyran-2-yl)oxy)pyridin-3-yl)methyl)amino) -7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)quinolin-3-yl)ethyl methanesulfonate (120mg, 0.16mmol) was dissolved in acetic acid (4mL) water ( 1 mL) tetrahydrofuran (2 mL), react overnight at room temperature. After TLC shows that the reaction is complete, add 10 mL of water to the system, adjust the pH to 8 with sodium bicarbonate, extract three times with ethyl acetate, combine the organic phases, backwash the organic phases with saturated sodium chloride solution once, dry over anhydrous sodium sulfate, and depressurize concentrate. The obtained crude product was purified by column chromatography to obtain 85 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 674.2.

Step 2: N-Methyl-2 ⁷ -toluenesulfonyl-2 ⁷ H-6-oxyl-3-aza-1(6,3)-quinoline-2(5,4)-pyrrole[2, Preparation of 3-d]pyrimidine-5(3,5)-pyridine heterocyclic nonapheno-2 ² -amine

2-(6-(4-(((5-hydroxypyridin-3-yl)methyl)amino)-2-(methylamino)-7-tosyl-7H-pyrrolo[2,3- d] pyrimidin-5-yl)quinolin-3-yl)ethyl methanesulfonate (70mg, 0.11mmol) was dissolved in N,N-dimethylformamide (30mL), added cesium carbonate (171mg), in 2 hours at room temperature. After TLC showed that the reaction was complete, the system was directly filtered, the mother liquor was concentrated under reduced pressure, and purified by column chromatography to obtain 40 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 591.2.

Step 3: N-Methyl-2 ⁷ H-6-oxyl-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo[2,3-d]pyrimidine-5 Preparation of (3,5)-pyridine heterocyclic nonapheno-2 ² -amine

N-methyl-2 ⁷ -toluenesulfonyl-2 ⁷ H-6-oxyl-3-aza-1(6,3)-quinoline-2(5,4)-pyrrole[2,3- d] Pyrimidine-5(3,5)-pyridine heterocyclic nonapheno-2 ² -amine (40mg) was dissolved in tetrahydrofuran (5mL) and sodium hydroxide solution (15%, 5mL) and reacted at 60°C for 2 hours. After LCMS monitoring showed that the reaction was complete, the pH was adjusted to 7-8 with dilute hydrochloric acid, concentrated under reduced pressure, and the crude product was purified by high-pressure preparation to obtain 5 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 438.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.26(s, 1H), 8.71(s, 1H), 8.42(s, 1H), 8.15(d, J=2.1Hz, 1H), 8.04(s, 1H), 7.99(s, 1H), 7.88(d, J=8.2Hz, 2H), 7.75(d, J=8.7Hz, 1H), 7.04(s, 1H), 6.55(s, 1H), 6.25( d, J=4.8Hz, 1H), 4.87(s, 2H), 4.52-4.44(m, 2H), 4.37(d, J=3.5Hz, 2H), 3.20-3.13(m, 2H), 2.84(d , J=4.6Hz, 3H).

Example 29: N-cyclopropylformyl-2 ⁷ H-3,6,9-trioxa-1(6,3)-quinoline-2(5,4)-pyrrolo[2,3- d] Preparation of pyrimidine-5(3,5)-pyridine heterocyclic nonapheno-2 ² -amine

Step 1: 2-((5-((2-(cyclopropanecarboxamido)-5-(3-hydroxyquinolin-6-yl)-7-((2-(trimethylsilyl)ethyl Preparation of oxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)pyridin-3-yl)oxy)ethyl methylsulfonate

2-((5-((2-(cyclopropanecarboxamido)-5-(3-((tetrahydro2H-pyran-2-yl)oxy)quinolin-6-yl)-7- ((2-(Trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)pyridin-3-yl)oxy Base) ethyl methanesulfonate (100mg, 0.12mmol) was dissolved in tetrahydrofuran (2mL), acetic acid (4mL), water (1mL), and reacted at 25°C for 72h. After LCMS showed that the reaction was complete, it was quenched by adding sodium bicarbonate reaction, extracted with ethyl acetate, and concentrated the organic phase under reduced pressure. 100 mg of the crude product of the title compound was obtained.

MS (ESI) m/z (M+H) ⁺ = 721.1.

Step 2: N-(2 ⁷ -((2-(trimethylsilyl)ethoxy)methyl)-2 ⁷ H-3,6,9-trioxa-1(6,3)- Preparation of quinoline-2(5,4)-pyrrolo[2,3-d]pyrimidine-5(3,5)-pyridocycloalkan-2 ² -yl)cyclopropanecarboxamide

2-((5-((2-(cyclopropanecarboxamido)-5-(3-hydroxyquinolin-6-yl)-7-((2-(trimethylsilyl)ethoxy )methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)pyridin-3-yl)oxy)ethyl methylsulfonate (100mg, 0.14mmol) In N,N-dimethylformamide (70mL), cesium carbonate (100mg, 0.31mmol) was added at 25°C to react for 2h. After LCMS showed that the reaction was complete, the reaction was quenched by adding water, extracted with ethyl acetate, and concentrated under reduced pressure. Mutually. The crude product of the title compound (100 mg) was obtained.

MS (ESI) m/z (M+H) ⁺ = 625.1.

Step 3: N-cyclopropylformyl-2 ⁷ H-3,6,9-trioxa-1(6,3)-quinoline-2(5,4)-pyrrolo[2,3-d Preparation of ]pyrimidine-5(3,5)-pyridine heterocyclic nonapheno-2 ² -amine

N-(2 ⁷ -((2-(trimethylsilyl)ethoxy)methyl)-2 ⁷ H-3,6,9-trioxa-1(6,3)-quinoline -2(5,4)-pyrrolo[2,3-d]pyrimidine-5(3,5)-pyridocycloalkan-2 ² -yl)cyclopropanecarboxamide (100mg, 0.16mmol) dissolved in trifluoro In acetic acid (3mL), react at 25°C for 1h, concentrate under reduced pressure, add ammonia methanol solution (5mL, 7M), react at 25°C for 16h, after LCMS shows that the reaction is complete, concentrate under reduced pressure. The obtained crude product was purified by Pre-HPLC to obtain 2 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 495.1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.26(s, 1H), 10.62(s, 1H), 8.63(d, J=2.7Hz, 1H), 8.56(d, J=2.8Hz, 1H) , 8.37(d, J=1.6Hz, 1H), 8.16(d, J=1.7Hz, 1H), 7.91-7.78(m, 2H), 7.74(s, 1H), 7.64(s, 1H), 7.36( d, J=2.9Hz, 1H), 5.58(s, 2H), 4.77(d, J=5.2Hz, 2H), 4.62(s, 2H), 2.23(s, 1H), 1.24(s, 2H), 0.88-0.84(m, 2H).

Example 30: N,7-Dimethyl-2 ⁷ H-3,6,9-trioxa-1(6,3)-quinoline-2(5,4)-pyrrolo[2,3- In the preparation of pyrimidine-5(3,5)-pyridine heterocyclic nonapheno-2 ² -amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Example 4 above.

MS (ESI) m/z (M+H) ⁺ = 455.2..

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.62(s, 1H), 8.62(d, J=3.1Hz, 1H), 8.54(d, J=3.1Hz, 1H), 8.36(s, 1H) , 8.13(s, 1H), 7.82(s, 2H), 7.55(s, 1H), 7.40(s, 1H), 7.27(d, J=3.1Hz, 1H), 6.73(s, 1H), 5.67( d, J=12.5Hz, 1H), 5.32(d, J=12.0Hz, 1H), 5.22(d, J=7.0Hz, 1H), 4.68(d, J=14.2Hz, 1H), 4.38-4.31( m, 1H), 2.89(s, 3H), 1.48(d, J=6.3Hz, 3H).

Example 31: N-methyl-2 ⁷ H-6-oxyl-3-aza-1(6,3)-quinoline-2(5,4)-pyrrole[2,3-d]pyrimidine- Preparation of 5(1,3)-Phenencyclononane-2 ² -Amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method as in Example 28 above.

MS (ESI) m/z (M+H) ⁺ = 423.0.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.26(s, 1H), 8.71(d, J=2.8Hz, 1H), 8.45(s, 1H), 8.05(s, 1H), 7.88(d, J=8.8Hz, 1H), 7.75(d, J=8.6Hz, 1H), 7.41(s, 1H), 7.14-7.02(m, 2H), 6.75(dd, J=13.5, 8.1Hz, 2H), 6.24(s, 1H), 4.85(s, 1H), 4.33(d, J=8.0Hz, 4H), 3.15(d, J=5.9Hz, 2H), 2.83(t, J=3.5Hz, 3H).

Example 32: N,8-Dimethyl-2 ⁷ H-3,6,9-trioxa-1(6,3)-quinoline-2(5,4)-pyrrolo[2,3- d] Preparation of pyrimidine-5(3,5)-pyridine heterocyclic nonapheno-2 ² -amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a preparation method similar to that of Example 6 above.

MS (ESI) m/z (M+H) ⁺ = 455.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.61(s, 1H), 8.62(d, J=2.8Hz, 1H), 8.57-8.48(m, 1H), 8.36(d, J=2.0Hz, 1H), 8.16-8.04(m, 1H), 7.87-7.75(m, 2H), 7.54(t, J=2.3Hz, 1H), 7.43-7.34(m, 1H), 7.32-7.22(m, 1H) , 6.73(q, J=4.7Hz, 1H), 5.91-5.63(m, 1H), 5.36-5.08(m, 2H), 4.96-4.60(m, 1H), 4.40-4.26(m, 1H), 2.89 (d, J=4.8Hz, 3H), 1.49(d, J=6.4Hz, 3H).

Example 33: N-Methyl-2 ⁷ H-3,6,9-trioxy-1(6,3)-quinoline-2(5,4)-pyrrole[2,3-d]pyrimidine- Preparation of 5(4,2)-pyridine heterocyclic nonapheno-1 ² ,2 ² -amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a preparation method similar to that of Example 6 above.

MS (ESI) m/z (M+H) ⁺ = 456.2.

Example 34: 1 ² -Methoxy-N-methyl-2 ⁷ H-3,6,9-trioxa-1(6,3)-quinoline-2(5,4)-pyrrolo[ Preparation of 2,3-d]pyrimidine-5(3,5)-pyridine heterocyclic nonapheno-2 ² -amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a preparation method similar to that of Example 6 above.

MS (ESI) m/z (M+H) ⁺ = 471.1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.52(s, 1H), 8.57(d, J=2.7Hz, 1H), 8.33(s, 1H), 8.02(s, 1H), 7.81-7.52( m, 3H), 7.36-7.16(m, 2H), 6.69(d, J=5.3Hz, 1H), 5.47(s, 2H), 4.69(d, J=5.2Hz, 2H), 4.55(d, J =5.1Hz, 2H), 4.01(s, 3H), 2.88(d, J=4.7Hz, 3H).

Example 35: 5 ⁵ -Fluoro-N-methyl-2 ⁷ H-3,6,9-trioxy-1(6,3)-quinoline-2(5,4)-pyrrole[2,3 -d] Preparation of pyrimidine-5(1,3)-phencyclononane-2 ² -amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Example 4 above.

MS (ESI) m/z (M+H) ⁺ = 458.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.62(s, 1H), 8.51(d, J=2.9Hz, 1H), 8.18(d, J=1.6Hz, 1H), 7.86-7.79(m, 2H), 7.41(d, J=3.0Hz, 1H), 7.39(d, J=2.4Hz, 1H), 7.19(dd, J=11.4, 2.4Hz, 1H), 7.08(d, J=2.2Hz, 1H), 6.95(d, J=8.9Hz, 1H), 6.70(q, J=4.7Hz, 1H), 5.43(s, 2H), 4.70-4.64(m, 2H), 4.57(d, J=5.0 Hz, 2H), 2.88 (d, J=4.7Hz, 3H).

Example 36: N-methyl-2 ⁷ H-6,9-dioxy-1(6,3)-quinoline-2(5,4)-pyrrole[2,3-d]pyrimidine-5( Preparation of 3,5)-pyridine heterocyclic nonacene-3-en-2 ² -amine

Step 1: 2-((5-(2-(5-(3-hydroxypyridin-6-yl)-2-(methylamino)-7-tosyl-7H-pyrrolo[2,3-d )]pyrimidin-4-yl)vinyl)pyridin-3-yl)oxy)ethyl methanesulfonate

2-((5-(2-(2-(methylamino)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)quinolin-6-yl)-7 -Tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)vinyl)pyridin-3-yl)oxy)methylsulfonate (0.19g) was dissolved in dichloromethane (4mL ), added trifluoroacetic acid (2 mL), and reacted at room temperature for 0.5 hours. TLC showed the reaction was complete. Concentrate to dryness under reduced pressure, add triethylamine to adjust to alkalinity, and purify by silica gel column to obtain 0.12 g of the product.

MS (ESI) m/z (M+H) ⁺ = 687.1.

Step 2: N-methyl-2 ⁷ -tosyl-2 ⁷ H-6,9-dioxy-1(6,3)-quinoline-2(5,4)-pyrrole[2,3- d] Preparation of pyrimidine-5(3,5)-pyridine heterocyclic nonacene-3-en- ^{2 2} -amine

2-((5-(2-(5-(3-hydroxypyridin-6-yl)-2-(methylamino)-7-tosyl-7H-pyrrolo[2,3-d)] Pyrimidin-4-yl)vinyl)pyridin-3-yl)oxy)ethyl methanesulfonate (0.12g, 0.17mmol) was dissolved in N,N-dimethylformamide (35mL), at room temperature Add cesium carbonate (0.17 g, 0.51 mmol) and react at room temperature for 4 hours. After TLC showed that the reaction was complete, most of the solvent was spun off, water was added to the system, extracted three times with dichloromethane, the organic phase was combined, and the organic phase was backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 70 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 591.1.

Step 3: N-methyl-2 ⁷ H-6,9-dioxy-1(6,3)-quinoline-2(5,4)-pyrrole[2,3-d]pyrimidine-5(3 , 5) Preparation of -pyridine heterocyclic nonacene-3-en-2 ² -amine

N-methyl-2 ⁷ -tosyl-2 ⁷ H-6,9-dioxy-1(6,3)-quinoline-2(5,4)-pyrrole[2,3-d] Pyrimidine-5(3,5)-pyridinecyclononan-3-en-2 ² -amine (70 mg, 0.12 mmol) was dissolved in tetrahydrofuran (8 mL), and 4M aqueous potassium hydroxide solution (8 mL) was added. The reaction was carried out under microwave at 100°C for 4 hours, and a small amount of starting material remained. The solvent was spin-dried, and the obtained crude product was purified by Prep-HPLC and freeze-dried to obtain 10.7 mg of the title compound.

MS (ESI) m/z (M+H)+ = 437.1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.73(s, 1H), 8.73(d, J=2.8Hz, 1H), 8.49(d, J=2.6Hz, 1H), 8.38(d, J= 1.7Hz, 1H), 8.02(d, J=8.6Hz, 1H), 7.96(d, J=2.8Hz, 2H), 7.83-7.79(m, 1H), 7.74(q, J=15.7, 14.4Hz, 2H), 7.48(s, 1H), 7.14(d, J=2.3Hz, 1H), 6.73(d, J=5.2Hz, 1H), 4.58(m, 4H), 2.91(d, J=4.7Hz, 3H).

Example 37: N-(2 ⁷ H-7-oxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo[2,3-d]pyrimidine-5 Preparation of (2,4)-Pyrimidine Heterocyclic Nonaden-2 ² -yl)cyclopropanecarboxamide

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Example 5 above.

MS (ESI) m/z (M+H) ⁺ = 465.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.41(s, 1H), 8.87(d, J=2.8Hz, 1H), 8.79(d, J=5.1Hz, 1H), 8.73(d, J= 2.8Hz, 1H), 8.08-8.00(m, 2H), 7.85(dd, J=8.7, 2.0Hz, 1H), 7.69(dd, J=8.9, 3.7Hz, 2H), 7.29-7.08(m, 2H ), 5.76(d, J=12.1Hz, 1H), 5.53(d, J=12.1Hz, 1H), 5.16(dd, J=14.0, 6.0Hz, 1H), 4.41(s, 1H), 2.21(ddd , J=12.1, 7.7, 4.6Hz, 1H), 1.10-0.99(m, 4H).

Example 38: N-Methyl-2 ⁷ H-3,6,9-trioxa-1(7,2)-quinoxaline-2(5,4)-pyrrolo[2,3-d] Preparation of Pyrimidine-5(3,5)-Pyridine Heterocyclic Nonapheno-2 ² -Amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a preparation method similar to that of Example 6 above.

MS (ESI) m/z (M+H) ⁺ = 442.1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.71(s, 1H), 8.57(d, J=2.8Hz, 1H), 8.49(s, 1H), 8.34(d, J=1.7Hz, 1H) , 8.08(m, 1H), 7.90(m, 2H), 7.68(t, J=2.2Hz, 1H), 7.47(d, J=2.5Hz, 1H), 6.79(d, J=5.2Hz, 1H) , 5.61(s, 2H), 4.83-4.73(m, 4H), 2.89(d, J=4.6Hz, 3H).

Example 39: N-Methyl-2 ⁷ H-6,9-Dioxy-3-aza-1(7,2)-quinoxaline-2(5,4)-pyrrole[2,3- d] Preparation of pyrimidine-5(3,5)-pyridine heterocyclic nonapheno-2 ² -amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a preparation method similar to that of Example 11 above.

MS (ESI) m/z (M+H) ⁺ = 441.1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.31(s, 1H), 8.54(s, 1H), 8.46(d, J=2.8Hz, 1H), 8.25(d, J=1.6Hz, 1H) , 7.98(d, J=8.5Hz, 1H), 7.82(dd, J=8.5, 2.0Hz, 1H), 7.44(t, J=2.3Hz, 1H), 7.20(d, J=1.9Hz, 1H) , 7.07(d, J=2.4Hz, 1H), 6.29(q, J=4.8Hz, 1H), 6.04(t, J=6.2Hz, 1H), 4.84(t, J=4.8Hz, 2H), 4.79 -4.58(m, 4H), 2.87(d, J=4.7Hz, 3H).

Example 40: N-Methyl-1 ² -(trifluoromethyl)-2 ⁷ H-7-oxa-3-aza-1(6,3)-quinoline-2(5,4)- Preparation of pyrrolo[2,3-d]pyrimidine-5(2,4)-pyrimidine heterocyclic nonaden- ^{2 2} -amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Example 5 above.

MS (ESI) m/z (M+H) ⁺ = 479.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.36(s, 1H), 8.83(s, 1H), 8.74(d, J=5.1Hz, 1H), 8.01(d, J=1.9Hz, 1H) , 7.90(d, J=8.7Hz, 1H), 7.76(dd, J=8.7, 1.9Hz, 1H), 7.55(d, J=5.1Hz, 1H), 7.23(d, J=2.4Hz, 1H) , 6.29(d, J=5.3Hz, 1H), 5.82(d, J=12.1Hz, 1H), 5.58(d, J=12.2Hz, 1H), 5.29(d, J=4.0Hz, 1H), 4.96 -4.90(m, 1H), 4.31-4.26(m, 1H), 2.83(d, J=4.8Hz, 3H).

Example 41: N-Methylpyrro[cyclopropane-1,7′-3,6,9-trioxa-1(6,3)-quinoline-2(5,4)-pyrrolo[2 , 3-d] the preparation of pyrimidine-5 (3,5)-pyridine cyclononane]-2'-amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a preparation method similar to that of Example 6 above.

MS (ESI) m/z (M+H) ⁺ = 467.1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.82(d, J=2.8Hz, 1H), 8.52(d, J=2.9Hz, 1H), 8.49(d, J=1.7Hz, 1H), 8.06 (d, J=1.8Hz, 1H), 7.91-7.79(m, 2H), 7.44(d, J=11.0Hz, 2H), 6.99(d, J=2.9Hz, 1H), 6.72(m, 1H) , 6.07(s, 1H), 5.52(s, 2H), 4.56(s, 2H), 2.89(d, J=4.7Hz, 3H), 1.35-1.16(m, 4H).

Example 42: (S)-N,8-Dimethyl-2 ⁷ H-3,6,9-trioxa-1(6,3)-quinoline-2(5,4)-pyrrolo[ Preparation of 2,3-d]pyrimidin-5(3,5)-pyridocycloalkan-2 ² -amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a preparation method similar to that of Example 6 above.

MS (ESI) m/z (M+H) ⁺ = 455.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.59(s, 1H), 8.61(d, J=2.9Hz, 1H), 8.51(d, J=2.9Hz, 1H), 8.36(s, 1H) , 8.06(s, 1H), 7.85-7.77(m, 2H), 7.54(s, 1H), 7.36-7.29(m, 2H), 6.70(d, J=5.4Hz, 1H), 5.87(d, J =12.1Hz, 1H), 5.13(d, J=12.1Hz, 1H), 4.95-4.80(m, 2H), 4.31(dd, J=12.9, 7.5Hz, 1H), 2.88(d, J=4.7Hz , 3H), 1.48(d, J=6.3Hz, 3H).

Example 43: (R)-N,8-Dimethyl-2 ⁷ H-3,6,9-trioxa-1(6,3)-quinoline-2(5,4)-pyrrolo[ Preparation of 2,3-d]pyrimidin-5(3,5)-pyridocycloalkan-2 ² -amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a preparation method similar to that of Example 6 above.

MS (ESI) m/z (M+H) ⁺ = 455.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.62(s, 1H), 8.62(s, 1H), 8.51(s, 1H), 8.36(s, 1H), 8.06(s, 1H), 7.86- 7.77(m, 2H), 7.54(s, 1H), 7.36(s, 1H), 7.29(s, 1H), 6.73(s, 1H), 5.87(d, J=12.1Hz, 1H), 5.13(d , J=12.2Hz, 1H), 4.97-4.90(m, 1H), 4.83(d, J=13.0Hz, 1H), 4.42-4.18(m, 1H), 2.89(s, 3H), 1.51-1.44( m, 3H).

Example 44: N-methyl-2 ⁷ H-4,6,9-trioxy-1(6,3)-quinoline-2(5,4)-pyrrole[2,3-d]pyrimidine- Preparation of 5(3,5)-pyridinecyclononan-2 ² -amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method as in Example 36 above.

MS (ESI) m/z (M+H)+ = 441.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.85-11.73(m, 1H), 8.56(d, J=2.8Hz, 1H), 8.13(d, J=2.2Hz, 1H), 7.91(d, J=8.6Hz, 1H), 7.84(d, J=2.4Hz, 1H), 7.60(dd, J=8.6, 1.9Hz, 1H), 7.50(d, J=1.9Hz, 1H), 7.36(d, J=2.3Hz, 1H), 7.12(d, J=2.9Hz, 1H), 6.96(s, 1H), 6.76(t, J=2.4Hz, 1H), 4.95(s, 2H), 4.72(dd, J=5.3, 2.1Hz, 2H), 4.65-4.50(m, 2H), 2.88(d, J=4.8Hz, 3H).

Example 45: N-Methylpyrro[cyclopropane-1,8'-3,6,9-trioxa-1(6,3)-quinoline-2(5,4)-pyrrolo[2 , 3-d] the preparation of pyrimidine-5 (3,5)-pyridine cyclononane]-2'-amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using the preparation methods similar to the aforementioned Preparation Example 33 and Example 6.

MS (ESI) m/z (M+H) ⁺ = 467.1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.62(s, 1H), 8.59(d, J=2.7Hz, 1H), 8.44(d, J=2.7Hz, 1H), 8.29(d, J= 1.6Hz, 1H), 8.21(d, J=1.8Hz, 1H), 7.90-7.65(m, 4H), 7.35(d, J=2.3Hz, 1H), 6.72(d, J=5.2Hz, 1H) , 5.48(s, 2H), 4.83(s, 2H), 2.88(d, J=4.7Hz, 3H), 1.32-1.07(m, 4H).

Example 46: N-Methyl-2 ⁷ H-3,6,9-trioxa-1(6,3)-quinoline-2(5,4)-pyrrolo[2,3-d]pyrimidine - Preparation of 5(5,3)-pyridazinecyclononan-2 ² -amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method as in Example 45 above.

MS (ESI) m/z (M+H) ⁺ = 442.1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.66(s, 1H), 9.12(d, J=1.7Hz, 1H), 8.55(d, J=2.9Hz, 1H), 8.01(d, J= 1.9Hz, 1H), 7.85(d, J=8.7Hz, 1H), 7.80(dd, J=8.8, 2.0Hz, 1H), 7.40(s, 1H), 7.26(d, J=1.6Hz, 1H) , 7.19(d, J=2.9Hz, 1H), 6.74(q, J=4.7Hz, 1H), 5.50(s, 2H), 5.13-5.06(m, 2H), 4.70-4.61(m, 2H), 2.89(d, J=4.7Hz, 3H).

Example 47: 2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo[2,3-d]pyrimidine-5 Preparation of (3,5)-pyridocycloalkan-2 ² -amine

Step 1: 2-((5-((2-chloro-5-(3-hydroxyquinolin-6-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-4- Base) amino) methyl) pyridin-3-yl) oxy) ethyl methylsulfonate

Weigh 2-((5-((2-chloro-5-(3-((4-methoxybenzyl)oxy)quinolin-6-yl)-7-toluenesulfonyl-7H-pyrrolo [2,3-d]Pyrimidin-4-yl)amino)methyl)pyridin-3-yl)oxy)methylsulfonate ethyl ester (1.3g, 1.6mmol) was dissolved in dichloromethane (24mL) and cooled To 0°C, add trifluoroacetic acid (5mL), and react at room temperature for 1h. TLC showed that the reaction was complete. Pour the reaction system into water (50mL), then adjust the pH to 8 with saturated sodium bicarbonate solution, and extract with dichloromethane. The organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was separated by column chromatography to obtain 1.0 g of the title compound.

MS (ESI) m/z (M+H) ⁺ = 695.2.

Step 2: ²² -Chloro- ²⁷ -tosyl- ^27H -6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrole Preparation of [2,3-d]pyrimidine-5(3,5)-pyridocyclane

Weigh 2-((5-((2-chloro-5-(3-hydroxyquinolin-6-yl)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl )amino)methyl)pyridin-3-yl)oxyl)ethyl methylsulfonate (1.0g, 1.44mmol) was dissolved in N,N-dimethylformamide (100mL), slowly added cesium carbonate ( 2.3g, 7.2mmol), the system was reacted at room temperature for 4 hours, TLC showed that the raw materials were completely consumed, the reaction system was poured into water (200mL), extracted with ethyl acetate, the organic phases were combined, backwashed once with a saturated sodium chloride solution, Dry over sodium sulfate and concentrate, and the resulting crude product is separated by column chromatography to obtain 350 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 599.2.

Step 3: N-(2 ⁷ -tosyl-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo Preparation of [2,3-d]pyrimidine-5(3,5)-pyridocycloalkan-2 ² -yl)acetamide

Weigh 2 ² -chloro-2 ⁷ -tosyl-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo [2,3-d]pyrimidine-5(3,5)-pyridocyclane (40.0 mg, 6.7% mmol), acetamide (19 mg, 0.2 mmol), tris(dibenzylideneacetone)dipalladium (12 mg , 1.3% mmol), 2-dicyclohexylphosphine-2′, 4′, 6′-triisopropylbiphenyl (13.0mg, 2.7%mmol), cesium carbonate (65mg, 0.2mmol), then seal the system with nitrogen After protection, the solvent dioxane (1 mL) was added to dissolve, and the system was ventilated three times with nitrogen, and then reacted at 90° C. for 3 hours, and LCMS monitored the complete reaction of the raw materials. It was quenched by adding water, extracted with ethyl acetate, and concentrated. The resulting crude product was separated by column chromatography to obtain 20 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 622.2.

Step 4: 2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo[2,3-d]pyrimidine-5( Preparation of 3,5)-pyridocycloalkan-2 ² -amine

N-(2 ⁷ -tosyl-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo[2,3 -d] pyrimidine-5(3,5)-pyridocycloalkan-2 ² -yl)acetamide (20 mg, 3.2% mmol) was dissolved in methanol (3 mL), and sodium hydroxide solution (3 mL, 2 mol/L), react at 100°C for 3 hours after the addition, TLC shows that the raw materials are completely consumed, the system is filtered, the obtained crude product is purified by Pre-HPLC, and lyophilized to obtain 1.2 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 426.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.14(s, 1H), 8.55(d, J=2.8Hz, 1H), 8.48(d, J=2.7Hz, 1H), 8.20(d, J= 1.6Hz, 1H), 7.90(d, J=8.6Hz, 1H), 7.72(dd, J=8.6, 1.9Hz, 1H), 7.57(d, J=1.9Hz, 1H), 7.52(t, J= 2.2Hz, 1H), 7.41(d, J=2.9Hz, 1H), 7.04(d, J=2.1Hz, 1H), 5.79(s, 2H), 5.74(t, J=5.6Hz, 1H), 4.74 -4.59(m, 6H).

Example 48: N-(2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo[2,3-d] Preparation of pyrimidine-5(3,5)-pyridinoylnonan-2 ² -yl)morpholine-4-carboxamide

Step 1: N-(2 ⁷ -tosyl-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo[ Preparation of 2,3-d]pyrimidine-5(3,5)-pyridocycloalkan-2 ² -yl)morpholine-4-carboxamide

Weigh 2 ² -chloro-2 ⁷ -tosyl-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo [2,3-d]pyrimidine-5(3,5)-pyridocyclane (40 mg, 0.067 mmol), morpholine-4-carboxamide (43.6 mg, 0.34 mmol), tris(dibenzylideneacetone) Dipalladium (24.54mg, 0.027mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (25.55mg, 0.054mmol), cesium carbonate (65.49mg, 0.20mmol), Then the system was sealed under nitrogen protection, and after the solvent dioxane (1 mL) was added to dissolve, the system was ventilated with nitrogen three times, and then reacted at 90° C. for 2 hours, and the reaction of the raw materials was monitored by LCMS. Add water to quench, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the system on a large plate to obtain 35 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 693.2.

Step 2: N-(2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo[2,3-d]pyrimidine Preparation of -5(3,5)-pyridinoylnonan-2 ² -yl)morpholine-4-carboxamide

N-(2 ⁷ -tosyl-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo[2,3 -d] pyrimidine-5(3,5)-pyridocycloalkan-2 ² -yl)morpholine-4-carboxamide (30 mg, 0.043 mmol) dissolved in methanol (5 mL) and water (0.5 mL), added Sodium hydroxide (17.2 mg, 0.43 mmol) was added and reacted at room temperature for 1 hour. TLC showed that the raw material was completely consumed. After the system was concentrated under reduced pressure to remove the solvent, DMF was added to dissolve the system, and 8.2 mg of the purified title compound was prepared by high pressure reaction.

MS (ESI) m/z (M+H) ⁺ = 539.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.64(s, 1H), 8.81(s, 1H), 8.57(d, J=2.9Hz, 1H), 8.49(d, J=2.8Hz, 1H) , 8.24(d, J=1.7Hz, 1H), 7.94(d, J=8.6Hz, 1H), 7.77(dd, J=8.6, 1.9Hz, 1H), 7.57-7.49(m, 2H), 7.40( d, J=2.9Hz, 1H), 7.30(d, J=2.3Hz, 1H), 6.04(t, J=5.7Hz, 1H), 4.77-4.57(m, 6H), 3.63(t, J=4.7 Hz, 4H), 3.46(t, J=4.7Hz, 4H).

Example 49: N-(Pyridin-3-yl)-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo Preparation of [2,3-d]pyrimidine-5(3,5)-pyridocycloalkan-2 ² -amine

Step 1: N-(pyridin-3-yl)-2 ⁷ -tosyl-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5 , 4) Preparation of-pyrrolo[2,3-d]pyrimidine-5(3,5)-pyridocycloalcane- ^{2 2} -amine

Weigh 2 ² -chloro-2 ⁷ -tosyl-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo [2,3-d]pyrimidine-5(3,5)-pyridocyclane (40.0mg, 6.7%mmol), pyridin-3-amine (19mg, 0.20mmol), tris(dibenzylideneacetone) di Palladium (12.0 mg, 1.3% mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (13.0 mg, 2.7% mmol), cesium carbonate (65 mg, 0.2 mmol), Then the system was sealed under nitrogen protection, the solvent dioxane (1 mL) was added to dissolve the system, and the system was ventilated three times with nitrogen, and then reacted at 90° C. for 3 hours, and the reaction of the raw materials was monitored by LCMS. The system was quenched with water, extracted with ethyl acetate, concentrated, and the resulting crude product was separated by column chromatography to obtain 20 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 657.2.

Step 2: N-(pyridin-3-yl)-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo[ Preparation of 2,3-d]pyrimidin-5(3,5)-pyridocycloalkan-2 ² -amine

N-(pyridin-3-yl)-2 ⁷ -tosyl-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4) -Pyrrolo[2,3-d]pyrimidine-5(3,5)-pyridocycloalkan-2 ² -amine (20 mg, 3.0% mmol) was dissolved in methanol (3 mL), and sodium hydroxide was slowly added at room temperature The solution (3mL, 2mol/L) was reacted at 60°C for 3 hours, LCMS showed that the starting material was completely consumed, and the system was filtered to obtain a black oil. The resulting crude product was purified by Pre-HPLC and lyophilized to obtain 1.26 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 503.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.57(d, J=2.4Hz, 1H), 9.19(s, 1H), 9.05(d, J=2.6Hz, 1H), 8.57(d, J= 2.8Hz, 1H), 8.50(d, J=2.7Hz, 1H), 8.37(dt, J=8.7, 1.8Hz, 1H), 8.25(d, J=1.7Hz, 1H), 8.09(dd, J= 4.5, 1.4Hz, 1H), 7.94(d, J=8.6Hz, 1H), 7.77(dd, J=8.6, 1.9Hz, 1H), 7.65-7.54(m, 2H), 7.44(d, J=2.9 Hz, 1H), 7.31(dd, J=8.4, 4.6Hz, 1H), 7.23(d, J=2.3Hz, 1H), 6.07(t, J=5.6Hz, 1H), 4.83-4.52(m, 6H ).

Example 50: N-(6-Methylpyridin-3-yl)-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4 Preparation of )-pyrrolo[2,3-d]pyrimidine-5(3,5)-pyridocycloalcane- ^{2 2} -amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method as in Example 49 above.

MS (ESI) m/z (M+H) ⁺ = 517.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.53(s, 1H), 9.04(s, 1H), 8.91(d, J=2.6Hz, 1H), 8.57(d, J=2.8Hz, 1H) , 8.50(d, J=2.8Hz, 1H), 8.28-8.19(m, 2H), 7.93(d, J=8.6Hz, 1H), 7.76(dd, J=8.6, 2.0Hz, 1H), 7.59( d, J=2.0Hz, 1H), 7.56(s, 1H), 7.43(d, J=2.9Hz, 1H), 7.21(d, J=2.4Hz, 1H), 7.17(d, J=8.5Hz, 1H), 6.04(t, J=5.6Hz, 1H), 4.80-4.58(m, 6H), 2.41(s, 3H).

Example 51: N-(6-methylpyridin-3-yl)-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4 Preparation of )-pyrrolo[2,3-d]pyrimidine-5(3,5)-pyridocycloalcane- ^{2 2} -amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method as in Example 49 above.

MS (ESI) m/z (M+H) ⁺ = 533.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.48(s, 1H), δ8.88(s, 1H), 8.67(d, J=2.7Hz, 1H), 8.56(d, J=2.9Hz, 1H), 8.50(d, J=2.7Hz, 1H), 8.24(d, J=1.7Hz, 1H), 8.18(m, 1H), 7.93(d, J=8.6Hz, 1H), 7.76(m, 1H), 7.63-7.53(m, 2H), 7.42(d, J=2.9Hz, 1H), 7.18(d, J=2.4Hz, 1H), 6.80(d, J=8.9Hz, 1H), 6.00( t, J=5.6Hz, 1H), 4.77-4.57(m, 6H), 3.83(s, 3H).

Example 52: 2 ² -(Methylamino)-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo[2 , 3-d] Preparation of pyrimidine-5(3,5)-pyridinecyclononan-1 ² -alcohol

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 11.

MS (ESI) m/z (M+H) ⁺ = 456.1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.91(s, 1H), 11.11(s, 1H), 8.43(d, J=2.7Hz, 1H), 8.19(d, J=1.7Hz, 1H) , 7.54(t, J=2.2Hz, 1H), 7.45(m, 1H), 7.35(d, J=1.9Hz, 1H), 7.25(d, J=8.4Hz, 1H), 7.12(s, 1H) , 6.81(d, J=2.3Hz, 1H), 6.21(d, J=4.9Hz, 1H), 5.45(t, J=5.5Hz, 1H), 4.70-4.43(m, 6H), 2.83(d, J=4.8Hz, 3H).

Example 53: N,1 ² -Dimethyl-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo[ Preparation of 2,3-d]pyrimidin-5(3,5)-pyridocycloalkan-2 ² -amine

Step 1: 2 ² -(Methylamino)-2 ⁷ -tosyl-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4 Preparation of )-pyrrolo[2,3-d]pyrimidine-5(3,5)-pyridocyclononan- ^{1 2} -yl trifluoromethanesulfonate

Weighing 2 ² -(methylamino)-2 ⁷ -tosyl-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4) -Pyrrolo[2,3-d]pyrimidine-5(3,5)-pyridocycloalkan-1 ² -ol (20 mg, 3.3% mmol) was dissolved in dichloromethane (3 mL), and triethyl Amine (10.0 mg, 9.8% mmol), 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (17.7 mg, 5.0% mmol). The reaction was carried out at this temperature for half an hour, TLC showed that the raw material was completely reacted, and the reaction system was poured into water (10 mL). Extracted three times with ethyl acetate, combined the organic phases, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and the obtained crude product was separated by column chromatography to obtain 15.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 742.1.

Step 2: N,1 ² -Dimethyl-2 ⁷ -tosyl-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5, 4) Preparation of -pyrrolo[2,3-d]pyrimidine-5(3,5)-pyridocycloalkan- ^{2 2} -amine

Weigh 3-fluoro-4-((-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene)1-sulfonamido)ethyl benzoate (15.0 mg, 0.02mmol), methylboronic acid (6.0mg, 0.10mmol), potassium phosphate (13.0mg, 0.06mmol), dissolved in dioxane/water (1.0mL/0.1mL), added [1,1'-bis( Diphenylphosphino)ferrocene]palladium dichloride (1.5 mg, 0.2 mmol%). The system was reacted at 100°C for 1 hour. TLC showed that the reaction of the raw materials was complete. Water (5 mL) was added, extracted with ethyl acetate, and the organic phase was backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and spin-dried. The obtained crude product was separated by column chromatography to obtain 5.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 608.2.

Step 3: N,1 ² -Dimethyl-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo[2 , 3-d] Preparation of pyrimidine-5(3,5)-pyridocycloalkan-2 ² -amine

N,1 ² -Dimethyl-2 ⁷ -tosyl-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)- Pyrrolo[2,3-d]pyrimidine-5(3,5)-pyridocycloalkan-2 ² -amine (5 mg, 0.8% mmol) was dissolved in methanol (3 mL), and sodium hydroxide solution was slowly added at room temperature (1 mL, 2 mol/L), reacted at 60°C for 3 hours after the addition, TLC showed that the raw material was completely consumed, and the system was filtered to obtain a black oily substance. The resulting crude product was purified by Pre-HPLC and lyophilized to obtain 1.8 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 454.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.23(s, 1H), 8.47(d, J=2.7Hz, 1H), 8.20(d, J=1.7Hz, 1H), 7.82(d, J= 8.6Hz, 1H), 7.67(dd, J=8.6, 2.0Hz, 1H), 7.57-7.47(m, 2H), 7.34(s, 1H), 6.99(d, J=2.0Hz, 1H), 6.24( q, J=4.8Hz, 1H), 5.68(t, J=5.6Hz, 1H), 4.66(dt, J=18.3, 5.3Hz, 6H), 2.84(d, J=4.7Hz, 3H), 2.56( s, 3H).

Example 54: (S)-N-(8-Methyl-2 ⁷ H-3,6,9-trioxa-1(6,3)-quinoline-2(5,4)-pyrrolo[ Preparation of 2,3-d]pyrimidine-5(3,5)-pyridocycloalkan-2 ² -yl)cyclopropanecarboxamide

Step 1: (S)-N-(8-Methyl-2 ⁷ -tosyl- ^{2 7} H-6,9-dioxa-3-aza-1(6,3)-quinoline-2 Preparation of (5,4)-pyrrolo[2,3-d]pyrimidine-5(3,5)-pyridocycloalkan-2 ² -yl)cyclopropanecarboxamide

(S)-2 ² -chloro-8-methyl-2 ⁷ -tosyl-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2 (5,4)-pyrrolo[2,3-d]pyrimidine-5(3,5)-pyridocycloalkane (50.0 mg, 0.08 mmol), cyclopropanecarboxamide (35.0 mg, 0.41 mmol), tris( Dibenzylideneacetone) dipalladium (4.7mg, 0.01mmol), cesium carbonate (53.4mg, 0.16mmol) and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (7.8mg , 0.02mmol) was weighed in a microwave test tube, nitrogen was replaced, nitrogen was replaced again after adding 1,4-dioxane (3 mL), and the system was heated to 90° C. for 2 hours. After TLC showed that the reaction was complete, saturated brine was added to the reaction system, extracted several times with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain 25.0 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 662.2.

Step 2: (S)-N-(8-methyl-2 ⁷ H-6,9-dioxo-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo Preparation of [2,3-d]pyrimidine-5(3,5)-pyridocycloalkan- ^{2 2} -yl)cyclopropanecarboxamide

(S)-N-(8-methyl-2 ⁷ -tosyl-2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5 ,4)-Pyrrolo[2,3-d]pyrimidine-5(3,5)-pyridocycloalkan- ^{2 2} -yl)cyclopropanecarboxamide (30.0 mg, 0.04 mmol) was dissolved in methanol (2 mL) , added dropwise an aqueous solution of sodium hydroxide (3.0 mg, 0.08 mmol), and reacted at room temperature for 2 hours after the addition was complete. After TLC showed that the reaction was complete, dilute hydrochloric acid was added to the system to adjust the system to be neutral, and concentrated under reduced pressure. The resulting crude product was purified by Prep _- HPLC and lyophilized to obtain 0.62 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 508.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.82(d, J=2.4Hz, 1H), 10.21(s, 1H), 8.57(d, J=2.8Hz, 1H), 8.52(d, J= 2.7Hz, 1H), 8.26(d, J=1.6Hz, 1H), 7.95(d, J=8.6Hz, 1H), 7.78(dd, J=8.6, 1.9Hz, 1H), 7.45(t, J= 2.1Hz, 2H), 7.36(d, J=2.4Hz, 1H), 7.30(d, J=2.8Hz, 1H), 6.17(dd, J=8.9, 2.9Hz, 1H), 5.32(dd, J= 8.5, 5.5Hz, 1H), 5.03(t, J=7.0Hz, 1H), 4.75(dd, J=12.6, 2.2Hz, 1H), 4.27(dd, J=12.8, 7.7Hz, 1H), 4.07( dd, J=14.2, 2.8Hz, 1H), 2.02-1.97(m, 1H), 1.48(d, J=6.3Hz, 3H), 0.86-0.79(m, 4H).

Example 55: (R)-N-(8-Methyl-2 ⁷ H-3,6,9-trioxa-1(6,3)-quinoline-2(5,4)-pyrrolo[ Preparation of 2,3-d]pyrimidine-5(3,5)-pyridocycloalkan-2 ² -yl)cyclopropanecarboxamide

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a preparation method similar to that of Example 54 above.

MS (ESI) m/z (M ⁺ H) ⁺ = 508.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.81(s, 1H), 10.21(s, 1H), 8.56(d, J=2.8Hz, 1H), 8.51(d, J=2.8Hz, 1H) , 8.26(s, 1H), 7.95(d, J=8.6Hz, 1H), 7.80-7.75(m, 1H), 7.45(s, 2H), 7.36(s, 1H), 7.29(d, J=2.6 Hz, 1H), 6.16(dd, J=8.9, 3.0Hz, 1H), 5.31(dd, J=14.1, 8.6Hz, 1H), 5.02(t, J=7.0Hz, 1H), 4.74(d, J =11.5Hz, 1H), 4.27(dd, J=12.8, 7.7Hz, 1H), 4.07(dd, J=14.2, 2.9Hz, 1H), 2.32(d, J=11.2Hz, 1H), 1.48(d , J=6.3Hz, 3H), 0.90-0.78(m, 4H).

Example 56: (R)-N-(8-Methyl-2 ⁷ H-3,6,9-trioxa-1(6,3)-quinoline-2(5,4)-pyrrolo[ Preparation of 2,3-d]pyrimidine-5(3,5)-pyridocycloalkan-2 ² -yl)cyclopropanecarboxamide

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method as in Example 48 above.

MS (ESI) m/z (M+H) ⁺ = 468.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.66(s, 1H), 9.57(s, 1H), 8.57(d, J=2.8Hz, 1H), 8.45(d, J=2.8Hz, 1H) , 8.24(d, J=1.7Hz, 1H), 7.95(d, J=8.7Hz, 1H), 7.76(dd, J=8.6, 1.9Hz, 1H), 7.58-7.56(m, 1H), 7.49( d, J=2.3Hz, 1H), 7.42(d, J=2.9Hz, 1H), 7.30(s, 1H), 5.95(t, J=5.6Hz, 1H), 5.56(d, J=9.3Hz, 1H), 4.72-4.61(m, 8H).

Example 57: cis-N-methyl-17H-3,5,8-trioxa-2(6,3)-quinoline-1(5,4)-pyrrolo[2,3-d] Preparation of pyrimidine-6(3,5)-pyridine-4(1,3)-cyclobutanecyclooctane-1 ² -amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Example 4 above.

MS (ESI) m/z (M ⁺ H) ⁺ = 467.1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.58(s, 1H), 8.50(d, J=2.5Hz, 1H), 8.19(d, J=3.4Hz, 2H), 8.02(s, 2H) , 7.91(d, J=2.4Hz, 1H), 7.86-7.74(m, 2H), 7.29(d, J=2.4Hz, 1H), 6.71(d, J=4.9Hz, 1H), 5.39(s, 2H), 5.20(s, 1H), 5.12(s, 1H), 2.82(m, 5H), 2.03(d, J=14.1Hz, 2H).

Example 58: trans-N-methyl- ^{1 7} H-3,5,8-trioxa-2(6,3)-quinoline-1(5,4)-pyrrolo[2,3- d] Preparation of pyrimidine-6(3,5)-pyridine-4(1,3)-cyclobutanecyclooctane- ^{1 2} -amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Example 4 above.

MS (ESI) m/z (M+H) ⁺ = 467.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.82(s, 1H), 8.65(d, J=2.7Hz, 1H), 8.34(d, J=1.9Hz, 1H), 8.15-8.08(m, 2H), 7.93(d, J=8.7Hz, 1H), 7.88(dd, J=8.8, 2.0Hz, 1H), 7.45(s, 1H), 7.27(s, 1H), 6.76(d, J=5.1 Hz, 1H), 6.07(s, 2H), 5.57(s, 2H), 5.05(t, J=7.4Hz, 1H), 2.89(d, J=4.9Hz, 3H), 2.69-2.65(m, 2H ), 2.35-2.31(m, 2H).

Example 59: N-Methyl-2 ⁷ H-7-oxa-3-aza-5(2,5)-thiazoline-1(6,3)-quinoline-2(5,4)- Preparation of pyrrolo[2,3-d]pyrimidincycloheptan-2 ² -amine

Step 1: ²² -Chloro- ²⁷ -toluenesulfonyl-27H- ⁷ -oxa-3-aza-5(2,5)-thiazoline-1(6,3)-quinoline-2 Preparation of (5,4)-pyrrolidine[2,3-d]pyrimidinecycloheptane

6-(2-chloro-4-(((5-(chloromethyl)thiazol-2-yl)methyl)amino)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine -5-yl)quinolin-3-ol (300mg, 0.49mmol) was dissolved in acetonitrile (300mL), cesium carbonate (480mg, 1.47mmol) was added, and stirred at room temperature for 6 hours. LCMS monitored a little raw material remaining in the reaction, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain 90 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 575.1.

Step 2: N-Methyl-2 ⁷ -tosyl-2 ⁷ H-7-oxa-3-aza-5(2,5)-thiazoline-1(6,3)-quinoline-2 Preparation of (5,4)-pyrrolo[2,3-d]pyrimidincycloheptan-2 ² -amine

Weigh 2 ² -chloro-2 ⁷ -toluenesulfonyl-2 ⁷ H-7-oxa-3-aza-5(2,5)-thiazoline-1(6,3)-quinoline-2( 5,4)-Pyrrolidine[2,3-d]pyrimidinecycloheptane (90mg, 0.147mmol) in a 20mL microwave tube, add 2M methylamine in tetrahydrofuran (7mL), 1,4-dioxane solution ( 7mL) was dissolved, sealed, and heated to 100°C by microwave for 2.5 hours. After TLC showed that the reaction was complete, it was concentrated to dryness and purified by column chromatography to obtain 40 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 570.1.

Step 3: N-Methyl-27H- ⁷ -oxa-3-aza-5(2,5)-thiazoline-1(6,3)-quinoline-2(5,4)-pyrrole Preparation of [2,3-d]pyrimidine cycloheptane-2 ² -amine

Weigh N-methyl-2 ⁷ -tosyl-2 ⁷ H-7-oxa-3-aza-5(2,5)-thiazoline-1(6,3)-quinoline-2( 5,4)-Pyrrolo[2,3-d]pyrimidincycloheptane-2 ² -amine (40mg, 0.07mmol) was dissolved in 1,4-dioxane solution (5mL), and 15% sodium hydroxide was added Solution (5 mL), sealed, heated to 102 ° C for 6 hours. After LCMS showed that the reaction was complete, the system was cooled and the layers were separated. The upper layer was purified by reverse-phase preparation to obtain 10 mg of the title compound.

MS (ESI) m/z (M+H) ⁺ = 416.1.

¹ H NMR (400MHz, DMSO-d6) δ11.27(s, 1H), 8.72(d, J=2.5Hz, 1H), 7.97(d, J=8.6Hz, 1H), 7.85(s, 1H), 7.74(dd, J=8.7, 2.0Hz, 1H), 7.44(d, J=2.0Hz, 1H), 7.08(d, J=2.2Hz, 1H), 6.82(s, 1H), 6.30(q, J =4.7Hz, 1H), 5.66(d, J=12.8Hz, 1H), 5.13(dd, J=13.3, 7.7Hz, 1H), 5.04(d, J=12.8Hz, 1H), 4.42-4.28(m , 1H), 4.15(d, J=13.1Hz, 1H), 2.81(d, J=4.7Hz, 3H).

Example 60: N-Methyl-2 ⁷ H-6,9-dioxa-3-aza-5(2,5)-thiazole-1(6,3)-quinoline-2(5,4 Preparation of )-pyrrolo[2,3-d]pyrimidinecyclononan-2 ² -amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Example 5 above.

MS (ESI) m/z (M ⁺ H) ⁺ = 446.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.32(s, 1H), 8.55(d, J=2.7Hz, 1H), 7.91(d, J=8.6Hz, 1H), 7.74(d, J= 8.6Hz, 1H), 7.42(d, J=4.2Hz, 2H), 7.08(s, 1H), 7.04(s, 1H), 6.36(s, 1H), 5.54(s, 1H), 4.79-4.64( m, 4H), 4.54(s, 2H), 2.83(d, J=4.5Hz, 3H).

Example 61: N-Methyl-2 ⁷ H-9-oxa-3-aza-5(2,5)-thiazoline-1(6,3)-quinoline-2(5,4)- Preparation of pyrrolo[2,3-d]pyrimidine cyclononan-2 ² -amine

The title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Example 5 above.

MS (ESI) m/z (M+H) ⁺ = 444.1.

¹ H NMR (400MHz, DMSO-d6) δ11.32(s, 1H), 8.45(d, J=2.7Hz, 1H), 7.87(d, J=8.7Hz, 1H), 7.81(d, J=8.8 Hz, 1H), 7.69(s, 1H), 7.63(s, 1H), 7.16(t, J=1.5Hz, 1H), 6.82(d, J=2.8Hz, 1H), 6.30(d, J=5.0 Hz, 1H), 6.22(t, J=5.8Hz, 1H), 4.94(d, J=5.5Hz, 2H), 4.33(t, J=7.9Hz, 2H), 2.93-2.87(m, 2H), 2.84(d, J=4.7Hz, 3H), 1.97(d, J=8.2Hz, 2H).

For the synthesis of Examples 62-65, the title compound was prepared by using the corresponding commercial reagents and the products in the aforementioned Preparation Examples as raw materials, and using a similar preparation method as in Example 48 above.

Example 62: (1R,2S)-N-(2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo[ 2,3-d]pyrimidine-5(3,5)-pyridinoylnonan-2 ² -yl)-2-fluorocyclopropane-1-carboxamide

MS (ESI) m/z (M+H) ⁺ = 512.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.84(s, 1H), 10.36(s, 1H), 8.57(s, 1H), 8.49(s, 1H), 8.22(s, 1H), 7.95( d, J=8.6Hz, 1H), 7.78(d, J=8.6Hz, 1H), 7.53(d, J=9.6Hz, 2H), 7.40(s, 1H), 7.37(s, 1H), 6.23- 6.14(m, 1H), 5.06-4.48(m, 8H), 1.56-1.52(m, 1H), 1.30-1.24(m, 1H).

Example 63: (1S,2R)-N-(2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo[ 2,3-d]pyrimidine-5(3,5)-pyridinoylnonan-2 ² -yl)-2-fluorocyclopropane-1-carboxamide

MS (ESI) m/z (M ⁺ H) ⁺ = 512.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.85(s, 1H), 10.36(s, 1H), 8.57(d, J=2.8Hz, 1H), 8.49(d, J=2.7Hz, 1H) , 8.21(s, 1H), 7.94(d, J=8.6Hz, 1H), 7.77(dd, J=8.6, 2.0Hz, 1H), 7.57-7.49(m, 2H), 7.44-7.34(m, 2H ), 6.18(t, J=5.7Hz, 1H), 4.99(s, 1H), 4.83(s, 1H), 4.73-4.59(m, 5H), 4.35(t, J=5.1Hz, 1H), 1.61 -1.42(m, 1H), 1.34-1.18(m, 1H).

Example 64: N-(2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo[2,3-d] Pyrimidin-5(3,5)-pyridocycloalkan-2 ² -yl)-2,2-difluorocyclopropane-1-carboxamide

MS (ESI) m/z (M+H) ⁺ = 530.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.47(s, 1H), 8.58(d, J=2.7Hz, 1H), 8.50(d, J=2.7Hz, 1H), 8.23(s, 1H) , 7.95(d, J=8.6Hz, 1H), 7.78(d, J=8.7Hz, 1H), 7.54(d, J=10.5Hz, 2H), 7.42-7.35(m, 2H), 6.20(d, J=5.9Hz, 2H), 4.67(dd, J=17.5, 5.1Hz, 6H), 2.12-1.91(m, 3H).

Example 65: (1S,2S)-N-(2 ⁷ H-6,9-dioxa-3-aza-1(6,3)-quinoline-2(5,4)-pyrrolo[ 2,3-d]pyrimidine-5(3,5)-pyridocycloalkan-2 ² -yl)-2-fluorocyclopropane-1-carboxamide

MS (ESI) m/z (M+H) ⁺ = 512.2.

1H NMR (400MHz, DMSO-d6) δ8.58(s, 1H), δ8.58(d, J=2.9Hz, 1H), 8.50(s, 1H), 8.24(s, 1H), 7.95(d, J=8.7Hz, 1H), 7.82-7.75(m, 1H), 7.56(d, J=8.6Hz, 2H), 7.42(s, 1H), 7.37(s, 1H), 6.15(s, 2H), 5.05(s, 1H), 4.88(s, 1H), 4.76-4.61(m, 4H), 1.69(m, 4H).

Test Example 1: Detection of CLK2 Kinase Activity

Experimental purpose: To detect the inhibitory effect of compounds on CLK2 kinase.

Experimental Materials:

experimental method:

a) preparing a working concentration of the kinase buffer;

b) transfer the compound dilution to a 384-well plate using an Echo550 pipette;

c) Seal the assay plate and centrifuge at 1000g for 1 minute;

d) Prepare twice the concentration of CLK2 in the kinase buffer of the working concentration;

e) Add 2.5 μL of CLK2 with twice the concentration to the 384-well plate;

f) Centrifuge the plate at 1000g for 30 seconds and incubate at room temperature for 10 minutes;

g) prepare a mixture of MBP and ATP at twice the concentration with a working concentration of the kinase buffer;

h) Add 2.5 μL of the mixture of MBP and ATP to the 384-well plate to start the reaction;

i) Centrifuge the plate at 1000g for 30 seconds, seal the assay plate, and incubate at room temperature for 60 minutes;

j) Add 4 μL ADP-Glo reagent and incubate at room temperature for 40 minutes;

k) Add 8 μL of kinase detection reagent and incubate at room temperature for 40 minutes;

l) Read the luminescent signal on the Envision2104 plate reader.

data analysis:

Calculate % inhibition using the following formula:

Inhibition rate%=100-(signal value of compound wells-signal value of positive control wells)/(signal value of blank control wells-average signal value of positive control wells)×100.

Calculate IC ₅₀ and draw the inhibition rate-dose curve: use GraphPad6.0 to fit the compound concentration and the corresponding inhibition rate with nonlinear regression (dose response-variable slope), and calculate the IC ₅₀ value. The formula is as follows: Y=baseline response+(maximum response-baseline response)/(1+10^((Log half inhibitory concentration-X)*slope of the curve)), where X is the log value of the compound concentration, and Y is the inhibition rate% . Experimental results:

Table 1 Compounds have inhibitory activity on CLK2 kinase

Example CLK2 IC ₅₀ (nM) Example CLK2 IC ₅₀ (nM) 1 1.5 2 4.0 3 2.9 4 1.1 5 2.1 6 1.7 7 4.2 8 2.4 9 1.7 10 2.0 11 2.4 12 2.4 13 1.1 14 1.3 15 2.4 16 1.3 17 1.0 18 0.6 19 1.1 20 3.2 twenty one 1.1 twenty two 1.2 twenty three 1.1 twenty four 1.8 25 1.9 26 1.8 27 0.8 28 2.9 29 0.7 30 0.8 31 1.6 32 1.2 33 35.2 34 2.6 35 2.4 36 2.4 37 0.72 38 0.59 39 3.7 40 48.1 41 1.5 42 1.0 43 3.0 44 2.8 45 1.0 46 1.0 47 1.3 48 1.2 49 23.1 50 1.7 51 1.6 52 - 53 6.3 54 1.6 55 7.0 56 2.2 57 2.7 58 4.0 59 8.5 60 1.5 61 1.9 62 1.5

63 1.0 64 2.1 65 2.4 the the

"-" indicates not detected

According to the biological activity data of the compounds in specific examples, the compounds of the present application have high inhibitory activity on CLK2.

Test Example 2: In Vitro Proliferation Inhibition Experiment

Experimental purpose: To evaluate the in vitro proliferation inhibitory effect of compounds on colorectal cancer cell line HCT116.

Experimental Materials:

experimental method:

a) Take HCT116 cells in the logarithmic growth phase, digest with trypsin, centrifuge at 1000rpm for 3 minutes, discard the supernatant, resuspend the medium and count, inoculate 2* ¹⁰ cells/well into a 96-well plate, store at 37°C, Cultivate for 24 hours in a 5% CO ₂ incubator;

b) The compound to be tested was dissolved in 100% DMSO, prepared as a 10 mM stock solution, and stored at 4° C. in the dark. Take 3 microliters of 10mM stock solution and add 95 microliters of medium and 2 microliters of DMSO. At this time, the concentration of the compound is 300000nM, and then three-fold dilution of 8 concentration points with the medium containing 5% DMSO; Add microliters into a 96-well plate containing cells (containing 90 microliters of medium), the final concentration of the compound is 30000nM, 10000nM, 3333nM, 1111nM, 370nM, 123nM, 41nM, 14nM and 5nM, set control wells and blank wells, all wells The DMSO content is 0.5%. Continue culturing for 72 hours at 37°C in a 5% CO ₂ incubator;

c) Take out the cell culture plate to be tested, equilibrate at room temperature for 30 minutes, add CellCounting-LiteTM2.0 equal to the volume of the cell culture to be tested, shake and mix for 5 minutes to fully lyse the cells, and use a multi-functional microplate reader after standing for 10 minutes Detect luminescent signal.

data analysis:

Calculate the cell viability% using the following calculation formula: cell viability% = (luminescence value of the compound well - luminescence value of the solvent control well) / (luminescence value of the control well - luminescence value of the solvent control well) * 100%

Calculate the IC ₅₀ and draw the inhibition rate-dose curve: take the log value of the concentration as the X-axis, and the percentage inhibition rate as the Y-axis, using the log (inhibitor) vs. response-variable slope (log (inhibitor) of the analysis software GraphPad Prism 5 vs.response-Variable slope) to fit the dose-effect curve to obtain the IC ₅₀ value of each compound on tumor cell HCT116.

The calculation formula is Y=baseline response+(maximum response-baseline response)/(1+10^((Log half inhibitory concentration-X)*slope of the curve)), where X is the log value of the compound concentration, and Y is the inhibition rate% .

Experimental results

Table 2 Compounds inhibit the proliferation of HCT116 cells in vitro

Example IC50(nM) Example IC50(nM) 1 19.8 2 201.0 3 132.0 4 23.9 5 461.0 6 154.4 8 49.8 9 247.4 10 231.4 11 379.0 12 483.0 13 360.0 14 163.0 15 69.0 16 116.9 17 74.4

19 20.9 20 284.9 twenty one 134.6 twenty two 29.9 twenty three 69.6 twenty four 50.0 25 221 26 115 27 13 28 478.4 29 52.4 30 111.9 31 191.4 32 12.1 33 - 34 - 35 139.9 36 198 37 12.4 38 129.1 39 897.1 40 - 41 96 42 98 43 164 44 - 45 30.62 46 128.3 47 41.49 48 - 49 23.58 50 37.76 51 24.42 52 - 53 - 54 40.51 55 - 56 119.4 57 655.1 58 - 59 252.9 60 27.1 61 35.17 62 91.74 63 35.48 64 283.7 65 - the the

"-" indicates not detected

According to the biological activity data of the compounds in specific examples, the compounds of the present application have high inhibitory activity on HCT116 cells.

Test Example 3: Detection of DYRK1A Kinase Activity

Experimental purpose: To detect the inhibitory effect of compounds on DYRK1A kinase.

Experimental Materials:

experimental method:

a) Prepare experimental buffer solution with working concentration

b) Use echo550 to transfer the compound solution into a 384-well assay plate (784075, Greiner)

c) Seal the experimental plate and centrifuge at 1000g for 1 minute

d) Use the working concentration of the experimental buffer to prepare a two-fold concentration of DYRK1A solution

e) Transfer 2.5 μL of twice the concentration of DYRK1A kinase buffer to the assay plate

f) Centrifuge at 1000g for 30s, react at room temperature for 10 minutes

g) Use the working concentration of the experimental buffer to prepare a mixture of DYRK1A substrate DYRK peptide and ATP at twice the concentration

h) Transfer 2.5 μL of the above mixed liquid to the experimental plate and start the reaction

i) Centrifuge at 1000g for 30s, seal the experimental plate, and react at room temperature for 120 minutes

j) Add 4 μL ADP-Glo reagent and react at room temperature for 40 minutes

k) Add 84 μL kinase detection assay and react at room temperature for 40 minutes

l) Use a multifunctional microplate reader to detect the luminescent signal

m) Calculate the inhibition rate according to the following formula: inhibition rate %=(1-(signal value of the experimental group-signal value of the positive control group)/(blank control group-positive control group))*100

data analysis:

Calculate % inhibition using the following formula:

Inhibition rate%=100-(signal value of compound wells-signal value of positive control wells)/(signal value of blank control wells-average signal value of positive control wells)×100.

Calculate IC ₅₀ and draw the inhibition rate-dose curve: use GraphPad6.0 to fit the compound concentration and the corresponding inhibition rate with nonlinear regression (dose response-variable slope), and calculate the IC ₅₀ value. The formula is as follows: Y=baseline response+(maximum response-baseline response)/(1+10^((Log half inhibitory concentration-X)*slope of the curve)), where X is the log value of the compound concentration, and Y is the inhibition rate% . Experimental results:

Table 3 Compounds have inhibitory activity on DYRK1A kinase

Example DYRK1A IC ₅₀ (nM) Example DYRK1A IC ₅₀ (nM) 1 1.23 3 1.65 4 0.43 7 25.66 8 1.17 9 1.51 15 0.78 17 0.69 19 0.59 twenty two 0.35 twenty three 0.50 the the

According to the biological activity data of the compounds in specific examples, the compounds of the present application have high inhibitory activity on DYRK1A.

Claims (34)

Compound shown in general formula (I):

Or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereoisomers or mixtures thereof, or pharmaceutically acceptable salts and deuteriums thereof , in: X ¹ and X ² are each independently CH ₂ , CH, O, NH, or S; when X ¹ and X ² are CH at the same time, X ¹ and X ² are linked by a double bond; X ⁶ is CR ⁶ , N, O, or S; R ⁶ is H, halogen, hydroxyl, amino, -C(O)NH ₂ , CN, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy, halogenated C ₁ ~C ₆ alkyl, hydroxyl substitution C ₁ ~ C ₆ alkyl; Ring A is a substituted or unsubstituted five-membered or six-membered aryl or heteroaryl group, wherein the heteroatoms are selected from N, O, and S; the substituents of the A ring are selected from halogen, hydroxyl, amino, -C (O) NH ₂ , CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogenated C ₁ -C ₆ alkyl, and hydroxy substituted C ₁ -C ₆ alkyl; X ⁷ is CR ⁶ or N; ^X8 is O or NH; R ¹ is H, C ₁ to C ₆ alkyl, C ₃ to C ₆ cycloalkyl, C ₂ to C ₆ heterocycloalkyl, -(CH ₂ ) _p C(O)R ⁷ , C ₅ to C ₁₀ Aryl, C ₂ -C ₉ heteroaryl, C ₄ -C ₁₅ fused cycloalkyl, C ₄ -C ₁₅ fused heterocycloalkyl, wherein the C ₁ -C ₆ alkyl, C ₃ -C ₆ Cycloalkyl, C ₂ ~C ₆ heterocycloalkyl, C ₅ ~C ₁₀ aryl, C ₂ ~C ₉ heteroaryl, C ₄ ~C ₁₅ fused cycloalkyl, C ₄ ~C ₁₅ fused heterocycloalkane Each group is independently and optionally substituted by one or more selected from halogen, -CF ₃ , C ₁ to C ₆ alkyl, C ₃ to C ₆ cycloalkyl, and C ₁ to C ₆ alkoxy; R ⁷ is H, amino, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogenated C ₁ -C ₆ alkyl, halogenated C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ Alkoxy, C ₂ -C ₆ heterocycloalkyl; wherein the heteroatom is selected from N, O, and S; p is 0, 1, 2, or 3; R ² , R ³ , R ⁴ , and R ⁵ are each independently H, halogen, hydroxyl, amino, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogenated C ₁ -C ₆ alkane Group, C ₁ ~ C ₆ alkyl substituted by hydroxyl, -C(O)NR ⁸ R ⁹ , or -NR ⁸ C(O)R ¹⁰ ; R ⁸ and R ⁹ are each independently hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, or halogenated C ₁ -C ₃ alkyl; R ¹⁰ is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogenated C ₁ -C ₆ alkyl, or hydroxy substituted C ₁ -C ₆ alkyl; L is -W ¹ (CR ^a R ^b ) _m1 W ² -,

-W ¹ (CR ^a R ^b ) _m3 CR ^a =CR ^a (CR ^a R ^b ) _n2 W ² -, or -W ¹ (CR ^a R ^b ) _m4 W ³ (CR ^a R ^b ) _n3 W ² -; W ¹ and W ² are each independently CR ¹² R ¹³ , O, S; R ¹² and R ¹³ are each independently H, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogenated C _{1 -C 3} alkyl, or -C(O)NH ₂ ; R ^a and R ^b are each independently H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, halogenated C ₁ -C ₆ alkyl, halogenated C ₃ -C ₆ cycloalkyl, or -C(O)NH ₂ or R ^a and R ^b form a three- to six-membered ring together with the carbon atoms connected to them; R ¹¹ is H, halogen, hydroxyl, amino, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogenated C ₁ -C ₆ alkyl, hydroxyl substituted C ₁ -C ₆ alkyl, or -C(O)NH ₂ ; W ³ is O, or S; m1, m2, m3, m4, n1, n2, and n3 are each independently 0, 1, 2, 3, or 4. The compound according to claim 1 or its tautomer, cis-trans isomer, mesoform, racemate, enantiomer, diastereoisomer or mixture thereof, or Pharmaceutically acceptable salts, deuteriums, which are compounds represented by general formula (II):

in: X ¹ and X ² are each independently CH ₂ , O, NH, or S; X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ are each independently CR ⁶ or N; R ⁶ is H, halogen, hydroxyl, amino, -C(O)NH ₂ , CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogenated C ₁ -C ₆ alkyl, or hydroxyl Substitute C ₁ ~ C ₆ alkyl; ^X8 is O or NH; R ¹ is H, C ₁ to C ₆ alkyl, C ₃ to C ₆ cycloalkyl, or -(CH ₂ ) _p C(O)R ⁷ , wherein the C ₁ to C ₆ alkyl, C ₃ Each of ~C ₆ cycloalkyl is independently and optionally selected from one of halogen, -CF ₃ , C ₁ ~C ₆ alkyl, C ₃ ~C ₆ cycloalkyl, and C ₁ ~C ₆ alkoxy, or multiple replaced; R ⁷ is H, amino, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogenated C ₁ -C ₆ alkyl, halogenated C ₃ -C ₆ cycloalkyl, or C _{1 -C 6} alkoxy; p is 0, 1, 2, or 3; R ² , R ³ , R ⁴ , and R ⁵ are each independently H, halogen, hydroxyl, amino, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogenated C ₁ -C ₆ alkane group, hydroxyl substituted C ₁ ~ C ₆ alkyl, -C(O)NR ⁸ R ⁹ , or -NR ⁸ C(O)R ¹⁰ ; R ⁸ and R ⁹ are each independently hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, or halogenated C ₁ -C ₃ alkyl; R ¹⁰ is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogenated C ₁ -C ₆ alkyl, or hydroxy substituted C ₁ -C ₆ alkyl; L is -W ¹ (CR ^a R ^b ) _m1 W ² -,

-W ¹ (CR ^a R ^b ) _m3 CR ^a =CR ^a (CR ^a R ^b ) _n2 W ² -, or -W ¹ (CR ^a R ^b ) _m4 W ³ (CR ^a R ^b ) _n3 W ² -; W ¹ and W ² are each independently CR ¹² R ¹³ , O, or S; R ¹² and R ¹³ are each independently H, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogenated C _{1 -C 3} alkyl, or -C(O)NH ₂ ; R ^a and R ^b are each independently H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, halogenated C ₁ -C ₆ alkyl, halogenated C ₃ -C ₆ cycloalkyl, or -C(O)NH ₂ or R ^a and R ^b together form a three- to six-membered ring with the carbon atoms connected to them; R ¹¹ is H, halogen, hydroxyl, amino, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogenated C ₁ -C ₆ alkyl, hydroxyl substituted C ₁ -C ₆ alkyl, or -C(O)NH ₂ ; W ³ is O, or S; m1, m2, m3, m4, n1, n2, and n3 are each independently 0, 1, 2, 3, or 4. The compound according to claim 1 or 2, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereoisomers or mixtures thereof , or pharmaceutically acceptable salts and deuterated products thereof, wherein R ² , R ³ , R ⁴ , and R ⁵ are each independently H, halogen, amino, C ₁ ~C ₃ alkyl, C ₁ ~C ₃ alkoxy , halogenated C ₁ -C ₃ alkyl, -C(O)NH ₂ , or -NHC(O)R ¹⁰ , R ¹⁰ is C ₁ -C ₃ alkyl, or halogenated C ₁ -C ₃ alkyl. The compound according to claim 2, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereoisomers or mixtures thereof, or Its pharmaceutically acceptable salts and deuteriums, wherein X ³ , X ⁴ , X ⁵ , and X ⁶ are each independently CR ⁶ or N; R ⁶ is H, halogen, amino, -C(O)NH ₂ , C ₁ ~C ₃ alkyl, C ₁ ~C ₃ alkoxy, or halogenated C ₁ ~C ₃ alkyl. The compound according to claim 1 or 2, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereomers or mixtures thereof , or its pharmaceutically acceptable salt, deuterium, wherein X ⁶ is CR ⁶ , N, S; R ⁶ is selected from H, halogen, amino, -C(O)NH ₂ , C ₁ ~C ₃ alkyl, C ₁ -C ₃ alkoxy, or halogenated C ₁ -C ₃ alkyl. The compound according to claim 1 or 2, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereomers or mixtures thereof , or a pharmaceutically acceptable salt or deuterated substance thereof, wherein X ⁷ is CH or N. The compound according to claim 1 or 2, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereoisomers or mixtures thereof , or a pharmaceutically acceptable salt or deuterated product thereof, wherein R ¹ is H, C ₁ to C ₃ alkyl, or -(CH ₂ ) _p C(O)R ⁷ , wherein the C ₁ to C ₃ alkane The group is optionally substituted by one or more substituents selected from halogen, -CF ₃ , C ₁ to C ₆ alkyl, C ₃ to C ₆ cycloalkyl, and C ₁ to C ₆ alkoxy; R7 is C ₁ -C ₃ alkyl, or C ₃ -C ₆ cycloalkyl; p is 0 or 1. The compound according to claim 1 or 2, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereomers or mixtures thereof , or its pharmaceutically acceptable salts and deuterated substances, wherein R ¹ is H, C ₁ ~C ₃ alkyl, -(CH ₂ ) _p C(O)R ⁷ , C ₅ ~C ₁₀ aryl, C ₂ ~ C ₉ heteroaryl, C ₄ -C ₁₀ fused cycloalkyl, or C ₄ -C ₁₀ fused heterocycloalkyl, wherein the C ₁ -C ₃ alkyl, C ₅ -C ₁₀ aryl, C ₂ ~C ₉ heteroaryl, C ₄ ~C ₁₀ fused cycloalkyl, C ₄ ~C ₁₀ fused heterocycloalkyl are optionally selected from halogen, -CF ₃ , C ₁ ~C ₆ alkyl, C ₃ ~ C ₆ cycloalkyl, and one or more substituents in C ₁ ~ C ₆ alkoxy; R ⁷ is C ₁ ~ C ₃ alkyl, halogenated C ₁ ~ C ₃ alkyl, C ₃ ~ C ₆ cycloalkyl, halogenated C ₃ -C ₆ cycloalkyl, or C ₂ -C ₆ heterocycloalkyl; the heteroatom is selected from N, O, and S; p is 0 to 1. According to the compound described in claim 7, or its tautomer, cis-trans isomer, mesoform, racemate, enantiomer, diastereoisomer or mixture thereof, or its pharmaceutically acceptable salts and deuterated substances, wherein R ¹ is -CH ₃ ,

According to the compound described in claim 8, or its tautomer, cis-trans isomer, mesoform, racemate, enantiomer, diastereoisomer or mixture thereof, or its pharmaceutically acceptable salts and deuterated substances, wherein R ¹ is -CH ₃ ,

The compound according to claim 1 or 2, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereomers or mixtures thereof , or a pharmaceutically acceptable salt or deuterated substance thereof, wherein X ¹ is O, NH, or S; X ² is CH ₂ , O or CH. The compound according to claim 1 or 2, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereomers or mixtures thereof , or a pharmaceutically acceptable salt or deuterated substance thereof, wherein L is -W ¹ (CR ^a R ^b ) _m1 W ² -; W ¹ and W ² are each independently CR ¹² R ¹³ , O, S; R ¹² and R ¹³ are each independently H, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogenated C _{1 -C 3} alkyl, or -C(O)NH ₂ ; R ^a and R ^b are each independently H, C ₁ to C ₃ alkyl, C ₁ to C ₃ alkoxy, or halogenated C ₁ to C ₃ alkyl, or R ^a and R ^b are jointly form three- to six-membered rings; m1 is 0, 1, 2 or 3; Further, W ¹ and W ² are preferably CH ₂ or O. The compound according to claim 1 or 2, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereomers or mixtures thereof , or its pharmaceutically acceptable salt, deuterium, wherein L is

-W ¹ (CR ^a R ^b ) _m3 CR ^a =CR ^a (CR ^a R ^b ) _n2 W ² -, or -W ¹ (CR ^a R ^b ) _m4 W ³ (CR ^a R ^b ) _n3 W ² -; Preferably, L is

CR ¹² R ¹³ , O, S, R ¹² and R ¹³ are each independently H, C ₁ to C ₃ alkyl, C ₁ to C ₃ alkoxy, halogenated C ₁ to C ₃ alkyl, or -C (O) _NH2 ; R ^a and R ^b are each independently H, C ₁ to C ₃ alkyl, C ₁ to C ₃ alkoxy, a halogenated C ₁ to C ₃ alkyl, or the carbon atom to which R ^a and R ^b are connected form three- to six-membered rings; m2, m3, m4, n1, n2, n3 are 0, 1, 2, or 3; Further, W ¹ and W ² are preferably CH ₂ or O. The compound according to claim 1 or 2, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereomers or mixtures thereof , or its pharmaceutically acceptable salt, deuterium, wherein L is

m is 2, 3, or 4; n is 1, 2, or 3. The compound according to claim 1 or 2, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereomers or mixtures thereof , or its pharmaceutically acceptable salt, deuterium, wherein L is

m is 2, 3, or 4; n is 1, 2, or 3. According to the compound described in claim 1 or 2, or its tautomer, cis-trans isomer, mesoform, racemate, enantiomer, diastereoisomer or its The mixture, or its pharmaceutically acceptable salt, deuterated substance, which is a compound represented by general formula (III):

Wherein, X ¹ , X ² , X ⁶ , X ⁸ , R ¹ , and L are as defined in any one of claims 1, 2, 4, 5, 7-15; X ³ , X ⁴ , X ⁵ are as defined in any one of claims 2 or 4. According to the compound described in claim 1 or 2, or its tautomer, cis-trans isomer, mesoform, racemate, enantiomer, diastereoisomer or its The mixture, or its pharmaceutically acceptable salt, deuterated substance, which is a compound represented by general formula (IV):

Wherein, X ¹ , X ⁶ , X ⁷ , X ⁸ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and L are as defined in any one of claims 1-3, 5-15; X ³ , X ⁴ , X ⁵ are as defined in any one of claims 2 or 4. According to the compound described in claim 1 or 2, or its tautomer, cis-trans isomer, mesoform, racemate, enantiomer, diastereoisomer or its The mixture, or its pharmaceutically acceptable salt, deuterated substance, which is a compound represented by general formula (V):

Wherein, X ¹ , X ⁶ , X ⁸ , R ¹ , and L are as defined in any one of claims 1, 2, 4, 5, 7-15; X ³ , X ⁴ , X ⁵ are as defined in any one of claims 2 or 4. According to the compound described in claim 1 or 2, or its tautomer, cis-trans isomer, mesoform, racemate, enantiomer, diastereoisomer or its The mixture, or its pharmaceutically acceptable salt, deuterated substance, which is a compound represented by general formula (VI):

Wherein, X ¹ , X ⁶ , X ⁸ , R ¹ , and L are as defined in any one of claims 1, 245, 7-15; X ³ , X ⁴ , X ⁵ are as defined in any one of claims 2 or 4. According to claim 1, the compound described in any one of 3,5-15, or its tautomer, cis-trans isomer, mesoform, racemate, enantiomer, non- Enantiomers or mixtures thereof, or pharmaceutically acceptable salts or deuterated substances thereof, which are compounds represented by general formula (VII):

Wherein, X ¹ , X ² , X ⁶ , X ⁷ , X ⁸ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and L are as defined in claim 1; X ⁹ and X ¹⁰ are each independently CR ¹⁴¹⁴ , N, O, or S; preferably, X ⁶ is S, X ⁹ is N, and X ¹⁰ is CH; R ¹⁴ is H, halogen, hydroxyl, amino, -C(O)NH ₂ , CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogenated C ₁ -C ₆ alkyl, or hydroxyl Substitute C ₁ -C ₆ alkyl. A compound according to any one of the preceding claims, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereoisomers or Its mixture, or its pharmaceutically acceptable salt, deuterated substance, has the following structure:

A pharmaceutical composition comprising the compound according to any one of claims 1 to 21, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, Diastereomers or their mixtures, or their pharmaceutically acceptable salts, deuterated substances, and pharmaceutically acceptable diluents or carriers. The compound according to any one of claims 1 to 21, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereoisomers or a mixture thereof, or a pharmaceutically acceptable salt, deuterated substance thereof, or the pharmaceutical composition described in claim 22 in the preparation of DYRK1a and/or CLK inhibitor drugs. According to the use described in claim 23, the CLK inhibitor is selected from one or more of CLK1, CLK2 and CLK4 inhibitors. The compound according to any one of claims 1 to 21, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereoisomers or its mixture, or its pharmaceutically acceptable salt, deuterated substance, or the pharmaceutical composition described in claim 22 in the preparation of medicines for the prevention and/or treatment of DYRK1a and/or CLK-related cancers; Preferably, the cancer is selected from liver cancer, colorectal cancer, breast cancer, pancreatic cancer, leukemia, lymphoma, sarcoma, ovarian cancer, lung cancer, melanoma, squamous cell carcinoma, multiple myeloma, prostate cancer, digestive tract cancer One or more of neoplasms, malignant glioma, head and neck squamous cell carcinoma, and pancreatic ductal carcinoma. The compound according to any one of claims 1 to 21, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereoisomers or its mixture, or its pharmaceutically acceptable salt, deuterium, or the pharmaceutical composition described in claim 22 in the preparation of medicines for preventing and/or treating DYRK1a and/or CLK-related bone or cartilage-related diseases use; Preferably, the bone or cartilage-related diseases are selected from the group consisting of osteoarthritis, osteochondral dysplasia, axial spondylitis, costochondritis, degenerative disc disease, degenerative spondylolisthesis, elbow dysplasia, juvenile idiopathic One or more of arthritis, osteoarthritis, osteochondritis dissecans, Panner's disease, reactive arthritis, relapsing polychondritis, rheumatoid arthritis, sacroiliac joint dysfunction, and septic arthritis kind. The compound according to any one of claims 1 to 21, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereoisomers Or its mixture, or its pharmaceutically acceptable salt, deuterium, or the purposes of the pharmaceutical composition described in claim 22 in the medicine for preventing and/or treating DYRK1a and/or CLK related fibrosis; Preferably , the fibrotic disease is selected from the group consisting of pulmonary fibrosis, skin fibrosis, scleroderma, progressive systemic fibrosis, glomerulosclerosis, glomerulonephritis, hypertrophic scarring, uterine fibrosis, renal fibrosis, liver Cirrhosis, liver fibrosis, abdominal adhesions, pelvic adhesions, spinal adhesions, tendon adhesions, chronic obstructive pulmonary disease, fibrosis after myocardial infarction, fibrosis and scarring associated with diffuse or interstitial lung disease, central nervous system fibrosis , post-stroke fibrosis, fibrosis associated with neurodegenerative diseases such as Alzheimer's or multiple sclerosis, fibrosis associated with proliferative vitreoretinopathy, restenosis, endometriosis, ischemic disease, and radiation fibrosis. The compound according to any one of claims 1 to 21, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereoisomers Or its mixture, or its pharmaceutically acceptable salt, deuterium, or the pharmaceutical composition described in claim 22 is used for preventing and/or treating DYRK1a and/or CLK-related inflammatory diseases or autoimmune diseases, Use in medicine for neurodegenerative, genetic, metabolic, infectious or other diseases; Preferably, the inflammatory disease or autoimmune disease is selected from psoriasis, systemic lupus erythematosus, hepatitis, inflammatory bowel disease, neuroinflammation, Hashimoto's thyroiditis, allergic purpura, Sjögren's syndrome, Weigl One or more of sodium granuloma; Preferably, the neurodegenerative disease is selected from one or more of Alzheimer's disease, dementia, tau disease, and Parkinson's disease; Preferably, the genetic disease is selected from the group consisting of Ehlers-Danlos syndrome, hemochromatosis, hyperimmunoglobulin D syndrome, familial Mediterranean fever, tumor necrosis factor receptor-associated periodic fever syndrome, and CDKL5 deficiency one or more; Preferably, the metabolic disease is selected from one or more of type I and type II diabetes, abnormal metabolism of folic acid and methionine, Duchenne muscular dystrophy, and gout; Preferably, the infectious disease is selected from one or more of viral infection, Lyme disease, Whipple's disease, and anemia and infection caused by unicellular parasites; Preferably, said other disease is selected from one or more of celiac disease, non-celiac gluten sensitivity, sarcoidosis, Down syndrome, Phelan-McDermid syndrome, and autism. The preparation method of compound in claim 2, comprises the following steps: The compound represented by formula (VIII) is placed in an organic solvent, and a ring-closing reaction occurs under alkaline conditions to generate the target product;

Among them, X ¹ , X ² , X ^{3 ,} X ⁴ , X 5 , X ⁶ , X ⁷ , X ⁸ , R ¹ , R 2 , R ³ , R ⁴ , ^{R 5 ,} R ^a , R ^b , W ¹ , m1 is as defined in any one of claims 2-15; W ² is O; ^Y is H, 2-(trimethylsilyl)ethoxymethyl, or 4-methylbenzenesulfonyl; Wherein, when Y ¹ is 2-(trimethylsilyl)ethoxymethyl or 4-methylbenzenesulfonyl, the step of deprotection is also included after ring closure; when Y ¹ is 2-(trimethylsilane For ethoxymethyl groups, the deprotection conditions are: dioxane hydrochloride solution followed by ammonia methanol solution, trifluoroacetic acid followed by ammonia methanol solution, tetrabutylammonium fluoride tetrahydrofuran solution followed by ammonia Methanol solution; when ^Y1 is 4-methylbenzenesulfonyl, the deprotection conditions are: lithium hydroxide/methanol/water, sodium hydroxide/methanol/water, potassium hydroxide/methanol/water, potassium carbonate/methanol / water, tetrahydrofuran solution of tetrabutylammonium fluoride, dioxane hydrochloride solution; Y ² is H, 4-methoxybenzyl, tetrahydropyranyl, or benzyl; ^Y3 is H, halogen, methylsulfonyloxy, 4-methylbenzenesulfonyloxy, or trifluoromethanesulfonyloxy; The organic solvent is selected from N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, N-methylpyrrolidone, and acetonitrile; The base is selected from cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, potassium tert-butoxide, and sodium tert-butoxide. The preparation method of compound in claim 2, comprises the following steps: The compound shown in the formula (IX) is placed in an organic solvent, and a ring-closing reaction occurs under alkaline conditions to generate the target product;

Among them, X ¹ , X ² , X ^{3 ,} X ⁴ , X 5 , X ⁶ , X ⁷ , X ⁸ , R 1 , R ² , R ³ , R ⁴ , ^{R 5 ,} R ^a , R ^b , W ² , m1 is as defined in any one of claims 2-15; W ¹ is O; ^Y is H, 2-(trimethylsilyl)ethoxymethyl, or 4-methylbenzenesulfonyl; Wherein, when Y ¹ is 2-(trimethylsilyl)ethoxymethyl or 4-methylbenzenesulfonyl, the step of deprotection is also included after ring closure; when Y ¹ is 2-(trimethylsilane For ethoxymethyl groups, the deprotection conditions are: dioxane hydrochloride solution followed by ammonia methanol solution, trifluoroacetic acid followed by ammonia methanol solution, tetrabutylammonium fluoride tetrahydrofuran solution followed by ammonia Methanol solution; when ^Y1 is 4-methylbenzenesulfonyl, the deprotection conditions are: lithium hydroxide/methanol/water, sodium hydroxide/methanol/water, potassium hydroxide/methanol/water, potassium carbonate/methanol / water, tetrahydrofuran solution of tetrabutylammonium fluoride, dioxane hydrochloride solution; Y ² is H, 4-methoxybenzyl, tetrahydropyranyl, or benzyl; ^Y3 is H, halogen, methylsulfonyloxy, 4-methylbenzenesulfonyloxy, or trifluoromethanesulfonyloxy; The organic solvent is N, N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, N-methylpyrrolidone, or acetonitrile; The base is cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, potassium tert-butoxide, or sodium tert-butoxide. The preparation method of compound in claim 2, comprises the following steps: The compound of formula (X) is placed in an organic solvent, and a ring-closing reaction occurs under alkaline conditions to generate the target product;

Among them, X ² , X ³ , X ⁴ , X ⁷ , X ⁸ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^a , R ^b , W ¹ , W ² , m1 are as claimed in claim 2- as defined in any of 15; ^X1 is NH or O; Wherein, X ⁵ or X ⁶ is N, and m1 is not 0; ^Y is H, 2-(trimethylsilyl)ethoxymethyl, or 4-methylbenzenesulfonyl; Wherein, when Y ¹ is 2-(trimethylsilyl)ethoxymethyl or 4-methylbenzenesulfonyl, the step of deprotection is also included after ring closure; when Y ¹ is 2-(trimethylsilane For ethoxymethyl groups, the deprotection conditions are: dioxane hydrochloride solution followed by ammonia methanol solution, trifluoroacetic acid followed by ammonia methanol solution, tetrabutylammonium fluoride tetrahydrofuran solution followed by ammonia Methanol solution; when ^Y1 is 4-methylbenzenesulfonyl, the deprotection conditions are: lithium hydroxide/methanol/water, sodium hydroxide/methanol/water, potassium hydroxide/methanol/water, potassium carbonate/methanol / water, tetrahydrofuran solution of tetrabutylammonium fluoride, dioxane hydrochloride solution; ^Y3 is H, halogen, methylsulfonyloxy, 4-methylbenzenesulfonyloxy, trifluoromethanesulfonyloxy, 4-nitrobenzenesulfonyloxy, trifluoroethoxy, or methyl Sulfone group; When ^X is NH, the organic solvent is selected from N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, or methyltetrahydrofuran; the base is selected from N , N-diisopropylethylamine, triethylamine, and N-methylmorpholine; when ^X is O, the organic solvent is selected from tetrahydrofuran, dichloromethane, and methyltetrahydrofuran; the base is selected from From sodium hydride, potassium tert-butoxide, and sodium tert-butoxide. Compound shown in formula (VIII):

Among them, X ¹ , X ² , X ^{3 ,} X ⁴ , X 5 , X ⁶ , X ⁷ , X ⁸ , R ¹ , R 2 , R ³ , R ⁴ , ^{R 5 ,} R ^a , R ^b , W ¹ , W ² and m1 are as defined in any one of claims 2-15; Y ^is H, 2-(trimethylsilyl)ethoxymethyl, 4-methylbenzenesulfonyl, benzoyl, pivaloyl, tert-butoxycarbonyl, or benzyloxycarbonyl; ^Y is H, 4-methoxybenzyl, tetrahydropyranyl, benzyl, tert-butyldimethylsilyl, or benzoyl; Y ³ is H, halogen, methylsulfonyloxy, 4-methylbenzenesulfonyloxy, trifluoromethanesulfonyloxy, or 4-nitrobenzenesulfonyloxy. Compound shown in formula (IX):

Among them, X ¹ , X ² , X ^{3 ,} X ⁴ , X 5 , X ⁶ , X ⁷ , X ⁸ , R ¹ , R 2 , R ³ , R ⁴ , ^{R 5 ,} R ^a , R ^b , W ¹ , W ² and m1 are as defined in any one of claims 2-15; Y ^is H, 2-(trimethylsilyl)ethoxymethyl, 4-methylbenzenesulfonyl, benzoyl, pivaloyl, tert-butoxycarbonyl, or benzyloxycarbonyl; ^Y is H, 4-methoxybenzyl, tetrahydropyranyl, benzyl, tert-butyldimethylsilyl, or benzoyl; Y ³ is H, halogen, methylsulfonyloxy, 4-methylbenzenesulfonyloxy, trifluoromethanesulfonyloxy, or 4-nitrobenzenesulfonyloxy. Compound shown in formula (X):

Among them, X ¹ , X ² , X ^{3 ,} X ⁴ , X 5 , X ⁶ , X ⁷ , X ⁸ , R ¹ , R 2 , R ³ , R ⁴ , ^{R 5 ,} R ^a , R ^b , W ¹ , W ² and m1 are as defined in any one of claims 2-15; Y ^is H, 2-(trimethylsilyl)ethoxymethyl, 4-methylbenzenesulfonyl, benzoyl, pivaloyl, tert-butoxycarbonyl, or benzyloxycarbonyl; ^Y3 is H, halogen, methylsulfonyloxy, 4-methylbenzenesulfonyloxy, trifluoromethanesulfonyloxy, 4-nitrobenzenesulfonyloxy, trifluoroethoxy, or methyl sulfone.