HK1262992A1

HK1262992A1 - Fgfr4 inhibitor and preparation method and use thereof

Info

Publication number: HK1262992A1
Application number: HK19122952.5A
Authority: HK
Inventors: 高鹏; 孙广俊; 谭松良; 刘磊; 包如迪
Original assignee: 江苏豪森药业集团有限公司; 上海翰森生物医药科技有限公司
Priority date: 2016-08-12
Filing date: 2017-08-11
Publication date: 2020-01-24

Description

FGFR4 inhibitor and preparation method and application thereof

Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to an FGFR4 inhibitor, and a preparation method and application thereof.

Background

Fibroblast Growth Factor Receptors (FGFRs) belong to receptor tyrosine kinase transmembrane receptors, including 4 receptor subtypes, FGFR1, FGFR2, FGFR3 and FGFR 4. FGFR regulates many functions such as cell proliferation, survival, differentiation and migration, and plays an important role in human development and various functions of adult organisms. FGFR is characterized by abnormal expression in various human tumors, including gene amplification, mutation and overexpression, and is an important target for tumor targeted therapy research.

FGFR4 is a member of the FGFR receptor family, and forms dimers on the cell membrane by binding to fibroblast growth factor 19(FGF19), a ligand of these dimers, which causes phosphorylation of key tyrosine residues within the FGFR4 itself, thereby activating multiple downstream signaling pathways within the cell that play important roles in cell proliferation, survival, and anti-apoptosis. FGFR4 is overexpressed in many cancers and is a predictor of malignant tumor invasion. Decreasing and decreasing FGFR4 expression reduces cell proliferation and promotes apoptosis. Recent studies have shown that about one-third of the FGF19/FGFR4 signaling pathways in liver cancer patients are continuously activated and are the main carcinogenic factor in liver cancer development in this subset of patients. Meanwhile, the expression or high expression of the FGFR4 is closely related to other tumors, such as gastric cancer, prostatic cancer, skin cancer, ovarian cancer, lung cancer, breast cancer, colon cancer and the like.

The incidence of liver cancer is the first of our country to live in the world, and the number of new onset and death patients accounts for about half of the total number of liver cancers in the world every year. At present, the incidence rate of liver cancer in China is about 28.7/10 ten thousands, 394770 new cases exist in 2012, and the liver cancer becomes the third most malignant tumor with the mortality rate second to that of stomach cancer and lung cancer. The primary liver cancer is a complex process of multiple factors and multiple steps, and has strong invasiveness and poor prognosis. Surgical treatments such as hepatectomy and liver transplantation can improve survival in some patients, but only a limited number of patients can undergo surgical treatment and the majority of patients after surgery have a poor prognosis due to relapse and metastasis. Sorafenib is the only liver cancer treatment drug approved in the market at present, the overall life cycle can be prolonged only by about 3 months clinically, and the treatment effect is not ideal, so that the development of a liver cancer system treatment drug targeting new molecules is urgently needed. FGFR4 is used as a main carcinogenic factor of a part of liver cancer, and the development of small molecule inhibitors thereof has great clinical application potential.

At present, a plurality of FGFR inhibitors are used as antitumor drugs to enter a clinical research stage, but the FGFR inhibitors are mainly inhibitors aiming at FGFR1, 2 and 3, the activity inhibition on FGFR4 is weak, and the inhibition on FGFR1-3 has target related side effects such as hyperphosphatemia and the like. The FGFR4 high-selectivity inhibitor can effectively treat cancer diseases caused by the abnormal FGFR4 signal channel, can avoid the related side effects of hyperphosphatemia and the like caused by the inhibition of FGFR1-3, and has great application prospect in the field of tumor targeted therapy by aiming at the high-selectivity small molecule inhibitor of FGFR 4.

Disclosure of Invention

The inventor discovers an FGFR4 inhibitor with a structure shown in a formula (I) in the research process, the series of compounds have strong inhibition effect on the activity of FGFR4 kinase, have very high selectivity, can be widely applied to preparation of medicines for treating cancers, particularly liver cancer, gastric cancer, prostatic cancer, skin cancer, ovarian cancer, lung cancer, breast cancer or colon cancer, and are expected to be developed into a new generation of FGFR4 inhibitor medicines.

In a first aspect, the present invention provides a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

wherein the content of the first and second substances,

R₁selected from hydrogen, deuterium, halogen, hydroxyl, sulfydryl, cyano, nitro, azido and C_1-8Alkyl, halo-substituted C_1-8Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, -C_0-8-S(O)_rR₉、-C_0-8-O-R₁₀、-C_0-8-C(O)OR₁₀、-C_0-8-C(O)R₁₁、-C_0-8-O-C(O)R₁₁、-C_0-8-NR₁₂R₁₃、-C_0-8-C(O)NR₁₂R₁₃、-N(R₁₂)-C(O)R₁₁or-N (R)₁₂)-C(O)OR₁₀；

R₂Selected from hydrogen, deuterium, halogen, hydroxyl, sulfydryl, cyano, nitro, azido and C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, -C_0-8-S(O)_rR₉、-C_0-8-O-R₁₀、-C_0-8-C(O)OR₁₀、-C_0-8-C(O)R₁₁、-C_0-8-O-C(O)R₁₁、-C_0-8-NR₁₂R₁₃、-C_0-8-C(O)NR₁₂R₁₃、-N(R₁₂)-C(O)R₁₁or-N (R)₁₂)-C(O)OR₁₀，

Optionally further substituted C with one or more groups selected from halogen, hydroxy, alkyl, halo_1-8Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, -C_0-8-S(O)_rR₉、-C_0-8-O-R₁₀、-C_0-8-C(O)OR₁₀、-C_0-8-C(O)R₁₁、-C_0-8-O-C(O)R₁₁、-C_0-8-NR₁₂R₁₃、-C_0-8-C(O)NR₁₂R₁₃、-N(R₁₂)-C(O)R₁₁or-N (R)₁₂)-C(O)OR₁₀Substituted with the substituent(s);

or, R₁And R₂Together with the directly attached carbon atom form a 5-7 membered cyclic or 5-7 membered heterocyclic group, optionally further substituted by one or more groups selected from halogen, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, halo-substituted C_1-8Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10An arylthio group,_5-10Heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)_rR₉、-C_0-8-O-R₁₀、-C_0-8-C(O)OR₁₀、-C_0-8-C(O)R₁₁、-C_0-8-O-C(O)R₁₁、-C_0-8-NR₁₂R₁₃、-C_0-8-C(O)NR₁₂R₁₃、-N(R₁₂)-C(O)R₁₁or-N (R)₁₂)-C(O)OR₁₀Substituted with the substituent(s);

R₃selected from hydrogen, deuterium, halogen, hydroxy, mercapto, cyano, thiocyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_1-8Alkyloxy, C_3-8Cycloalkoxy or 3-to 8-membered heterocyclyloxy,

optionally further substituted with one or more groups selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, halo-substituted C_1-8Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)_rR₉、-C_0-8-O-R₁₀、-C_0-8-C(O)OR₁₀、-C_0-8-C(O)R₁₁、-C_0-8-O-C(O)R₁₁、-C_0-8-NR₁₂R₁₃、-C_0-8-C(O)NR₁₂R₁₃、-N(R₁₂)-C(O)R₁₁or-N (R)₁₂)-C(O)OR₁₀Substituted with the substituent(s);

R₄selected from hydrogen, deuterium, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, -C_0-8-C(O)R₁₁、C_3-8Cycloalkyl or 3-8 membered heterocyclyl, optionally further substituted with one or more groups selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, halo-substituted C_1-8Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)_rR₉、-C_0-8-O-R₁₀、-C_0-8-C(O)OR₁₀、-C_0-8-C(O)R₁₁、-C_0-8-O-C(O)R₁₁、-C_0-8-NR₁₂R₁₃、-C_0-8-C(O)NR₁₂R₁₃、-N(R₁₂)-C(O)R₁₁or-N (R)₁₂)-C(O)OR₁₀Substituted with the substituent(s);

R₅selected from hydrogen, C_1-8Alkyl or 3-8 membered heterocyclyl, optionally further substituted with one or more groups selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, halo-substituted C_1-8Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10An arylthio group, a 5-10 membered heteroaryl group, a 5-10 membered heteroaryloxy group,_5-10A heteroarylthio group, -C_0-8-S(O)_rR₉、-C_0-8-O-R₁₀、-C_0-8-C(O)OR₁₀、-C_0-8-C(O)R₁₁、-C_0-8-O-C(O)R₁₁、-C_0-8-NR₁₂R₁₃、-C_0-8-C(O)NR₁₂R₁₃、-N(R₁₂)-C(O)R₁₁or-N (R)₁₂)-C(O)OR₁₀Substituted with the substituent(s);

alternatively, the first and second electrodes may be,

R₄and R₅Together with the directly attached amide group to form a 5-7 membered lactam-containing heterocyclic group, optionally further substituted with one or more groups selected from halogen, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, halo-substituted C_1-8Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10An arylthio group,_5-10Heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)_rR₉、-C_0-8-O-R₁₀、-C_0-8-C(O)OR₁₀、-C_0-8-C(O)R₁₁、-C_0-8-O-C(O)R₁₁、-C_0-8-NR₁₂R₁₃、-C_0-8-C(O)NR₁₂R₁₃、-N(R₁₂)-C(O)R₁₁or-N (R)₁₂)-C(O)OR₁₀Provided that said substituent is not hydroxy, acetyl, C_1-3Alkyl or di-C_1-3An alkylamino group;

R₆、R₇、R₈each independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, nitro, azido, C_1-8Alkyl, halo-substituted C_1-8Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, -C_0-8-S(O)_rR₉、-C_0-8-O-R₁₀、-C_0-8-C(O)OR₁₀、-C_0-8-C(O)R₁₁、-C_0-8-O-C(O)R₁₁、-C_0-8-NR₁₂R₁₃、-C_0-8-C(O)NR₁₂R₁₃、-N(R₁₂)-C(O)R₁₁or-N (R)₁₂)-C(O)OR₁₀；

R₉Selected from hydrogen, deuterium, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_1-8Alkyl radical C_1-8Alkoxy radical, C_3-8Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, halogen substituted C_1-8Alkyl, phenyl, p-methylphenyl, amino, mono C_1-8Alkylamino, di-C_1-8Alkylamino or C_1-8An alkanoylamino group;

R₁₀selected from hydrogen, deuterium, C_1-8Alkyl radical, C_3-8Cycloalkyl radical, C_1-8Alkyl radical C_1-8Alkoxy radical, C_5-10Aryl, halo-substituted C_1-8Alkyl or hydroxy substituted C_1-8An alkyl group;

R₁₁selected from hydrogen, deuterium, C_1-8Alkyl radical, C_1-8Alkoxy radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkoxy, halo-substituted C_1-8Alkyl, halo-substituted C_1-8Alkoxy, hydroxy substituted C_1-8Alkyl or hydroxy substituted C_1-8An alkoxy group;

R₁₂、R₁₃each independently selected from hydrogen, deuterium and C_1-8Alkyl radical, C_1-8Alkyl radical C_1-8Alkoxy radical, C_1-8Alkoxy radical C_1-8Alkyl radical, C_3-8Cycloalkyl radical C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C_5-10Aryl, substituted or unsubstituted_5-10A hetero-aryl radical or C_1-8An alkanoyl group;

y is selected from O or S;

r is 0, 1 or 2.

As a preferred embodiment, the compound according to formula (I), which is a compound represented by general formula (I-a), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: :

wherein:

a is a 5-6 membered heterocyclyl or heteroaryl;

ra is selected from hydrogen, deuterium, halogen, mercapto, cyano, nitro, azido, C_2-8Alkenyl radical, C_2-8Alkynyl, halo-substituted C_1-8Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10An arylthio group,_5-10A heteroaromatic group,_5-10A hetero-heteroaryloxy group,_5-10A heteroarylthio group, -C_0-8-S(O)_rR₉、-C_0-8-O-R₁₀、-C_0-8-C(O)OR₁₀、-C_0-8-C(O)R₁₁、-C_0-8-O-C(O)R₁₁、-C_0-8-NR₁₂R₁₃、-C_0-8-C(O)NR₁₂R₁₃、-N(R₁₂)-C(O)R₁₁or-N (R)₁₂)-C(O)OR₁₀Provided that the substituent is not hydroxy, acetyl or di-C_1-3An alkylamino group; and is

x is 0, 1, 2 or 3.

As a preferred embodiment, the compound according to formula (I), which is a compound represented by general formula (I-a), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

wherein:

b is 5-6 membered heterocyclyl, aryl and heteroaryl;

R_bselected from hydrogen, deuterium, halogen, mercapto, cyano, nitro, azido, C_2-8An alkenyl group,C_2-8Alkynyl, halo-substituted C_1-8Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)_rR₉、-C_0-8-O-R₁₀、-C_0-8-C(O)OR₁₀、-C_0-8-C(O)R₁₁、-C_0-8-O-C(O)R₁₁、-C_0-8-NR₁₂R₁₃、-C_0-8-C(O)NR₁₂R₁₃、-N(R₁₂)-C(O)R₁₁or-N (R)₁₂)-C(O)OR₁₀Provided that the substituent is not hydroxy, acetyl or di-C_1-3An alkylamino group; and is

y is 0, 1, 2 or 3.

As a still further preferred embodiment, said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from compounds of formula (II a), (II b), (II c), (II d), (II e) or (II f) (II g), (II h), (II I), (II j) or (II k) as follows:

R₁₄、R₁₅each independently selected from hydrogen, halogen, hydroxyl, sulfhydryl, cyano, nitro, azido and C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, halo-substituted C_1-8Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)_rR₉、-C_0-8-O-R₁₀、-C_0-8-C(O)OR₁₀、-C_0-8-C(O)R₁₁、-C_0-8-O-C(O)R₁₁、-C_0-8-NR₁₂R₁₃、-C_0-8-C(O)NR₁₂R₁₃、-N(R₁₂)-C(O)R₁₁or-N (R)₁₂)-C(O)OR₁₀Substituted with the substituent(s);

R₄selected from hydrogen, deuterium, C_1-8Alkyl, halo C_1-8Alkyl, -C_0-8-C(O)R₁₁、C_1-8Alkoxy C_1-8Alkyl, amino C_1-8Alkyl, hydroxy C_1-8Alkyl radical, C_3-8Cycloalkyl radical C_1-8Alkyl, 3-8 membered heterocyclyl C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl or 3-8 membered heterocyclyl.

As still further preferred embodiments, wherein said R is₁Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, nitro, azido, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, 3-oxetanyl, methoxy, ethoxy, isopropoxy, acetoxy, amino or acetylamino;

R₂selected from the group consisting of 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, -C_0-8-S(O)_rR₉、-C_0-8-O-R₁₀or-C_0-8-NR₁₂R₁₃，

Wherein said 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, and 3-8 membered heterocyclylthio are optionally further substituted with one or more groups selected from hydrogen, halogen, hydroxy, C_1-8Alkyl radical, C_1-8Alkoxy, halogen substituted C_1-8Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, -C_0-8-S(O)_rR₉、-C_0-8-O-R₁₀、-C_0-8-C(O)OR₁₀、-C_0-8-C(O)R₁₁、-C_0-8-O-C(O)R₁₁、-C_0-8-NR₁₂R₁₃、-C_0-8-C(O)NR₁₂R₁₃、-N(R₁₂)-C(O)R₁₁or-N (R)₁₂)-C(O)OR₁₀Substituted with the substituent(s);

R₉selected from hydrogen, deuterium, C_1-8Alkyl radical, C_1-8Alkoxy and 3-8 membered heterocyclic group, wherein said C_1-8Alkyl radical, C_1-8Alkoxy and 3-8 membered heterocyclyl is optionally further substituted with one or more groups selected from hydrogen, halogen, C_1-8Alkyl or C_1-8Substituted by a substituent of alkoxy;

R₁₀selected from hydrogen, deuterium, C_1-8Alkyl radical, C_1-8Alkoxy radical, C_3-8Cycloalkyl and 3-8 membered heterocyclyl, wherein said C is_1-8Alkyl radical, C_1-8Alkoxy radical, C_3-8Cycloalkyl and 3-8 membered heterocyclyl are optionally further substituted by one or more groups selected from hydrogen, halogen, C_1-8Alkyl or C_1-8Substituted by a substituent of alkoxy;

R₁₂、R₁₃each independently selected from hydrogen, deuterium and C_1-8Alkyl radical, C_1-8Alkoxy radical, C_3-8Cycloalkyl and 3-8 membered heterocyclyl, wherein said C is_1-8Alkyl radical, C_1-8Alkoxy radical, C_3-8Cycloalkyl and 3-8 membered heterocyclyl are optionally further substituted by one or more groups selected from hydrogen, halogen, C_1-8Alkyl or C_1-8Substituted by a substituent of alkoxy;

or, R₁And R₂Together with the carbon atom to which it is directly attached form a 5-7 membered cyclic group or a 5-7 membered heterocyclic group, said 5-7 membered heterocyclic group being selected from the following structures:

optionally further substituted with one or more groups selected from halogen, mercaptoRadical, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, halo-substituted C_1-8Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10An arylthio group,_5-10Heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)_rR₉、-C_0-8-O-R₁₀、-C_0-8-C(O)OR₁₀、-C_0-8-C(O)R₁₁、-C_0-8-O-C(O)R₁₁、-C_0-8-NR₁₂R₁₃、-C_0-8-C(O)NR₁₂R₁₃、-N(R₁₂)-C(O)R₁₁or-N (R)₁₂)-C(O)OR₁₀Substituted with the substituent(s);

R₄selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, ethoxyethyl, methoxymethyl, aminomethyl, hydroxymethyl, hydroxyethyl, aldehyde, methylacetyl, cyclopropyl, cyclopropylmethyl, allyl, ethynyl or 3-oxetanyl.

As a most preferred embodiment, the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, includes, but is not limited to, the following compounds:

as a preferred embodiment, the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of compounds of the following formula (III):

R₁₆selected from hydrogen, deuterium, halogen, mercapto, cyano, C_1-8Alkyl radical, C_1-8Alkoxy, nitro, azido, C_2-8Alkenyl radical, C_2-8Alkynyl, halo-substituted C_1-8Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)_rR₉、-C_0-8-O-R₁₀、-C_0-8-C(O)OR₁₀、-C_0-8-C(O)R₁₁、-C_0-8-O-C(O)R₁₁、-C_0-8-NR₁₂R₁₃、-C_0-8-C(O)NR₁₂R₁₃、-N(R₁₂)-C(O)R₁₁or-N (R)₁₂)-C(O)OR₁₀Provided that the substituent is not hydroxy, acetyl or di-C_1-3An alkylamino group.

m is selected from 0, 1, 2 or 3.

As a further preferred embodiment, wherein R is₁₆Selected from the group consisting of halogen, mercapto, cyano, nitro, azido, allyl, alkynyl, trifluoromethyl, cyclopropyl, 3-oxetanyl, methoxy, ethoxy, isopropoxy, acetoxy, acetylamino, amino, dimethylamino, or ethoxycarbonyl.

As a preferred embodiment, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of the compounds of the following formulae (III-a), (III-b) and (III-c):

wherein:

g is selected from NH, O and S;

w ring is selected from C_3-8Cycloalkyl and 3-8 membered heterocyclyl, wherein said C is_3-8Cycloalkyl and 3-8 membered heterocyclyl are optionally further substituted by one or more groups selected from hydrogen, halogen, C_1-8Alkyl, -C_0-8-NR₁₂R₁₃Or C_1-8Substituted by a substituent of alkoxy;

R_cand R_dEach independently selected from hydrogen, C_1-8Alkyl radical, C_1-8Alkoxy, halogen;

R_eselected from hydrogen, halogen, C_1-8Alkyl radical, C_1-8Alkoxy, -C_0-8-NR₁₂R₁₃(ii) a And is

q is selected from 0, 1, 2 and 3;

R₁₆m is as defined in claim 7.

As a most preferred embodiment, the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof include, but are not limited to, the following compounds:

as a preferred embodiment, wherein R is₄Selected from hydrogen, deuterium, C_1-8Alkyl, halo C_1-8Alkyl radical, C_1-8Alkoxy C_1-8Alkyl, amino C_1-8Alkyl, hydroxy C_1-8Alkyl radical, C_3-8Cycloalkyl radical C_1-8Alkyl, 3-8 membered heterocyclyl C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl or 3-8 membered heterocyclyl;

R₅selected from hydrogen, C_1-8Alkyl radical, C_1-8Alkoxy C_1-8Alkyl, halo C_1-8Alkyl radical, C_3-8Cycloalkyl radical C_1-8Alkyl, 3-8 membered heterocyclyl C_1-8Alkyl, hydroxy C_1-8An alkyl group.

As a further preferred embodiment, wherein R is₄Selected from the group consisting of hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, aminomethyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrofuranylmethyl, tetrahydrothienylmethyl, tetrahydropyrrolylmethyl, tetrahydroimidazolylmethyl;

R₅selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl.

in a second aspect, the present invention provides a process for the preparation of a compound of formula (I) as defined above, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the steps of:

alternatively, the first and second electrodes may be,

wherein: r₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈、R₉、R₁₀、R₁₁、R₁₂、R₁₃Y, r is as defined in claim 1;

Pg₁、Pg₂for the protection of hydroxyl groups, each independently is preferably selected from benzyl, 2-tetrahydrofuran, methoxymethyl, ethoxyethyl, C_1-8Alkyl, allyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl, or, Pg₁、Pg₂Together are selected from ethylene or propylene, each independently is more preferably selected from methyl, ethyl or benzyl, or, Pg₁、Pg₂Together are selected from ethylene;

Pg₃as the amino-protecting group, it is preferably selected from tert-butoxycarbonyl, allylcarbonyl, fluorenyl-methoxycarbonyl, ethoxycarbonyl, trimethylsilethoxycarbonyl or benzyloxycarbonyl, more preferably from tert-butyloxycarbonyl.

Another aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of each formula or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The invention also relates to a method for preparing the composition, which comprises mixing the compound shown in the general formula or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture form thereof, or the pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier, a diluent or an excipient.

In a third aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In a fourth aspect, the present invention provides a use of a compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating FGFR4 inhibitor.

The present invention also relates to a method for the treatment and/or prophylaxis of diseases having a pathological profile mediated by an FGFR4 inhibitor, which comprises administering to a patient a therapeutically effective dose of a compound of the general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

In a fifth aspect, the invention provides an application of the compound shown in formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition in preparing a medicament for treating cancer.

Another aspect of the present invention relates to a method for treating cancer, which comprises administering to a patient a therapeutically effective amount of a compound of formula (I) of the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof. The method shows outstanding therapeutic effects and fewer side effects, wherein the cancer may be selected from breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, glioma, rhabdomyosarcoma, glioblastoma, hepatocellular carcinoma, papillary renal tumor, head and neck tumor, leukemia, lymphoma, myeloma, and non-small cell lung cancer; preferably, the cancer may be liver cancer, stomach cancer, prostate cancer, skin cancer, ovarian cancer, lung cancer, breast cancer, colon cancer, glioma or rhabdomyosarcoma.

Detailed Description

Detailed description: unless stated to the contrary, the following terms used in the specification and claims have the following meanings.

“C_1-8Alkyl "refers to straight and branched alkyl groups comprising 1 to 8 carbon atoms, alkyl refers to a saturated aliphatic hydrocarbon group, preferably alkyl of 1 to 6 carbon atoms, more preferably alkyl of 1 to 3 carbon atoms; for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 2-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branched isomers thereof, and the like.

"cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, "C_3-8Cycloalkyl "refers to cycloalkyl groups comprising 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms; more preferably 4 to 6 carbon atoms; for example:

non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. "spirocycloalkyl" refers to polycyclic groups that share a single carbon atom (called a spiro atom) between single rings, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Spirocycloalkyl groups are classified according to the number of spiro atoms shared between rings into mono-, di-or multi-spirocycloalkyl groups, non-limiting examples of which include:

"fused cyclic alkyl" refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. And may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused ring alkyl groups depending on the number of constituent rings, non-limiting examples of fused ring alkyl groups including:

"bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings share two carbon atoms not directly connected, and these may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Depending on the number of constituent rings, may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl groups, non-limiting examples of which include:

the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like.

Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, individuallySelected from halogen, hydroxy, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)_rR₉、-C_0-8-O-R₁₀、-C_0-8-C(O)OR₁₀、-C_0-8-C(O)R₁₁、-C_0-8-O-C(O)R₁₁、-C_0-8-NR₁₂R₁₃、-C_0-8-C(O)NR₁₂R₁₃、-N(R₁₂)-C(O)R₁₁or-N (R)₁₂)-C(O)OR₁₀Substituted with the substituent(s).

"Heterocyclyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen, or S (O)_r(wherein r is an integer 0, 1, 2) but does not include the ring moiety of-O-O-, -O-S-or-S-S-, the remaining ring atoms being carbon. "5-10 membered heterocyclic group" means a cyclic group containing 5 to 10 ring atoms, and "3-8 membered heterocyclic group" means a cyclic group containing 3 to 8 ring atoms, preferably a 5-6 membered heterocyclic group.

Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydrofuranyl, piperidinyl, pyranyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like, with pyrrolidinyl, tetrahydrofuranyl, and pyranyl being preferred.

Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups. "Spiroheterocyclyl" refers to polycyclic heterocyclic groups in which one atom (referred to as a spiro atom) is shared between monocyclic rings, and in which one or more ring atoms are selected from nitrogen, oxygen, or S (O)_r(wherein r is an integer of 0, 1, 2) and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Spirocycloalkyl groups are classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group, or a multiple spiroheterocyclyl group according to the number of spiro atoms shared between rings. Non-limiting examples of spirocycloalkyl groupsThe embodiment comprises the following steps:

"fused heterocyclyl" refers to polycyclic heterocyclic groups in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system, wherein one or more ring atoms are selected from nitrogen, oxygen, or S (O)_r(wherein r is an integer of 0, 1, 2) and the remaining ring atoms are carbon. And may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocycloalkyl depending on the number of rings comprising, non-limiting examples of fused heterocyclic groups include:

"bridged heterocyclyl" means polycyclic heterocyclic groups in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system in which one or more ring atoms are selected from nitrogen, oxygen, or S (O)_r(wherein r is an integer of 0, 1, 2) and the remaining ring atoms are carbon. Depending on the number of constituent rings, may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl groups, non-limiting examples of which include:

the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:

the heterocyclic group may be optionalSubstituted or unsubstituted, when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)_rR₉、-C_0-8-O-R₁₀、-C_0-8-C(O)OR₁₀、-C_0-8-C(O)R₁₁、-C_0-8-O-C(O)R₁₁、-C_0-8-NR₁₂R₁₃、-C_0-8-C(O)NR₁₂R₁₃、-N(R₁₂)-C(O)R₁₁or-N (R)₁₂)-C(O)OR₁₀Substituted with the substituent(s).

"aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group, a polycyclic (i.e., rings which carry adjacent pairs of carbon atoms) group having a conjugated pi-electron system, and a "C" group_5-10Aryl "means an all-carbon aryl group having 5 to 10 carbons," 5-10 membered aryl "means an all-carbon aryl group having 5 to 10 carbons, preferably a 5-8 membered aryl group, more preferably a 5-6 membered aryl group; such as phenyl and naphthyl. 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, non-limiting examples of which include:

aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)_rR₉、-C_0-8-O-R₁₀、-C_0-8-C(O)OR₁₀、-C_0-8-C(O)R₁₁、-C_0-8-O-C(O)R₁₁、-C_0-8-NR₁₂R₁₃、-C_0-8-C(O)NR₁₂R₁₃、-N(R₁₂)-C(O)R₁₁or-N (R)₁₂)-C(O)OR₁₀Substituted with the substituent(s).

"heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms including nitrogen, oxygen and s (o) r (where r is an integer 0, 1, 2), 5-7 membered heteroaryl refers to a heteroaromatic system containing 5-7 ring atoms, 5-10 membered heteroaryl refers to a heteroaromatic system containing 5-10 ring atoms, preferably 5-6 membered heteroaryl; such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:

heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)_rR₉、-C_0-8-O-R₁₀、-C_0-8-C(O)OR₁₀、-C_0-8-C(O)R₁₁、-C_0-8-O-C(O)R₁₁、-C_0-8-NR₁₂R₁₃、-C_0-8-C(O)NR₁₂R₁₃、-N(R₁₂)-C(O)R₁₁or-N (R)₁₂)-C(O)OR₁₀Substituted with the substituent(s).

"alkenyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, C_2-8Alkenyl means a straight or branched chain alkenyl group containing 2 to 8 carbons. Such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like.

The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)_rR₉、-C_0-8-O-R₁₀、-C_0-8-C(O)OR₁₀、-C_0-8-C(O)R₁₁、-C_0-8-O-C(O)R₁₁、-C_0-8-NR₁₂R₁₃、-C_0-8-C(O)NR₁₂R₁₃、-N(R₁₂)-C(O)R₁₁or-N (R)₁₂)-C(O)OR₁₀Substituted with the substituent(s).

"alkynyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, C_2-8Alkynyl refers to straight or branched chain alkynyl groups containing 2-8 carbons. For example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-or 3-butynyl and the like.

Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)_rR₉、-C_0-8-O-R₁₀、-C_0-8-C(O)OR₁₀、-C_0-8-C(O)R₁₁、-C_0-8-O-C(O)R₁₁、-C_0-8-NR₁₂R₁₃、-C_0-8-C(O)NR₁₂R₁₃、-N(R₁₂)-C(O)R₁₁or-N (R)₁₂)-C(O)OR₁₀Substituted with the substituent(s).

"alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above. "C_1-8Alkoxy "means containing_1-8Carbon alkyloxy, preferably 1-6 carbon alkyloxy, more preferably 1-3 carbon alkyloxy, non-limiting examples of which include methoxy, ethoxy, propoxy, butoxy and the like.

Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C_5-10Aryl radical, C_5-10Aryloxy radical, C_5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C_0-8-S(O)_rR₉、-C_0-8-O-R₁₀、-C_0-8-C(O)OR₁₀、-C_0-8-C(O)R₁₁、-C_0-8-O-C(O)R₁₁、-C_0-8-NR₁₂R₁₃、-C_0-8-C(O)NR₁₂R₁₃、-N(R₁₂)-C(O)R₁₁or-N (R)₁₂)-C(O)OR₁₀Substituted with the substituent(s).

"Cycloalkoxy" means a radical of and-O- (unsubstituted cycloalkane)And (iv) wherein cycloalkyl is as defined above. "C_3-8Cycloalkoxy "means a cycloalkyloxy group having 3 to 8 carbons, and non-limiting examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

"halogen-substituted C_1-8Alkyl "means that the hydrogen on the alkyl is optionally substituted by fluorine, chlorine, bromine or iodine atoms_1-8A carbon alkyl group such as difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.

"halogen-substituted C_1-8Alkoxy "a 1-8 carbon alkoxy group wherein the hydrogen on the alkyl group is optionally substituted with fluorine, chlorine, bromine, or iodine atoms. For example, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy and the like.

"halogen" means fluorine, chlorine, bromine or iodine.

"THF" refers to tetrahydrofuran.

"EtOAc" refers to ethyl acetate.

"MeOH" refers to methanol.

"DMF" refers to N, N-dimethylformamide.

"DIPEA" refers to diisopropylethylamine.

"TFA" refers to trifluoroacetic acid.

"MeCN" refers to acetonitrile.

"DMA" refers to N, N-dimethylacetamide.

“Et₂O "means diethyl ether.

"DCE" refers to 1, 2 dichloroethane.

"DIPEA" refers to N, N-diisopropylethylamine.

"NBS" refers to N-bromosuccinimide.

"NIS" refers to N-iodosuccinimide.

"Cbz-Cl" refers to benzyl chloroformate.

“Pd₂(dba)₃"refers to tris (dibenzylideneacetone) dipalladium.

"Dppf" refers to 1, 1' -bisdiphenylphosphinoferrocene.

"HATU" refers to 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate.

"KHMDS" refers to potassium hexamethyldisilazide.

"LiHMDS" refers to lithium bistrimethylsilyl amide.

"MeLi" refers to methyllithium.

"n-BuLi" refers to n-butyllithium.

“NaBH(OAc)₃"refers to sodium triacetoxyborohydride.

“NaBH(CN)₃"refers to sodium tricyano borohydride.

Different terms such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" and the like all express the same meaning, that is, X can be any one or more of A, B, C.

"stereoisomerism" encompasses geometric isomerism (cis-trans isomerism), optical isomerism, conformational isomerism, and the like.

All hydrogen atoms described in the present invention can be replaced by deuterium, which is an isotope thereof, and any hydrogen atom in the compound of the embodiment related to the present invention can also be replaced by a deuterium atom.

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

"substituted" means that one or more hydrogen atoms in a group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated bonds (e.g., olefins).

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

The present invention will be described more fully with reference to the following examples, but the present invention is not limited thereto, and the present invention is not limited to the examples.

The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated methanol (CD)₃OD) and deuterated chloroform (CDCl)₃) Internal standard is Tetramethylsilane (TMS).

LC-MS was measured using an Agilent 1200 Infinity Series Mass spectrometer. HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150X 4.6mm column).

The thin layer chromatography silica gel plate adopts a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.

The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to methods known in the art.

All reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, without specific indication, the solvent is a dry solvent, and the reaction temperature is given in degrees celsius.

Preparation of intermediates

Intermediate 1: preparation of 6-amino-4-fluoronicotinonitrile

The first step is as follows: preparation of 4-fluoro-5-iodopyridin-2-amine

4-Fluoropyridin-2-amine (9g, 80mmol), NIS (19.8g, 88mmol), TFA (3.65g, 32mmol) were mixed in MeCN (290mL) and reacted overnight at room temperature. Dilute with ethyl acetate (300mL), saturated Na₂SO₃The aqueous solution (150 mL. times.2) was washed, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound, 4-fluoro-5-iodopyridin-2-amine (15.8g, 83%).

MS m/z(ESI)：238.9[M+H]⁺.

The second step is that: preparation of 6-amino-4-fluoronicotinonitrile

4-fluoro-5-iodopyridin-2-amine (15.8g, 66.4mmol), Zn (CN)₂(8.2g, 69.8mmol) and Zn (0.87g, 13.3mmol) were mixed in DMA (55mL), and Pd was added under a nitrogen atmosphere₂(dba)₃(2.4g, 2.62mmol) and dppf (7.4g, 13.35mmol), the mixture was purged with nitrogen 3 times, and the temperature was raised to 110 ℃ under a nitrogen atmosphere to react for 3 hours. The reaction was cooled to room temperature, diluted with ethyl acetate (100mL) and saturated NaHCO was added₃The aqueous solution (200mL) was separated, the aqueous phase was extracted with ethyl acetate (150mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound 6-amino-4-fluoro nicotinonitrile (7.3g, 80%).

MS m/z(ESI)：138.1[M+H]⁺.

Intermediate 2: preparation of 6-amino-4- ((2-methoxyethyl) amino) nicotinonitrile

6-amino-4-fluoronicotinonitrile (4.11g, 30mmol), 2-methoxyethan-1-amine (4.5g, 60mmol), DIPEA (1.16g, 90mmol) were mixed in DMF (120mL) and reacted at 60 ℃ overnight. The reaction was concentrated, the residue dissolved in dichloromethane (100mL), saturated NaHCO was added₃(100mL) of the aqueous solution was separated, the organic phase was washed with saturated aqueous NaCl solution (50 mL. times.2), dried over anhydrous sodium sulfate, concentrated and column chromatographed to give the title compound 6-amino-4- ((2-methoxyethyl) amino) nicotinonitrile (3.84g, 67%).

1H NMR(400MHz，DMSO)δ7.93(s，1H)，6.39(s，2H)，6.14(t，J＝5.6Hz，1H)，5.62(s，1H)，3.47(t，J＝6.0Hz，2H)，3.29-3.22(m，5H)；

MS m/z(ESI)：193.1[M+H]⁺.

Intermediate 3: preparation of 6-amino-4- (dimethylamino) nicotinonitrile

Preparation of 6-amino-4- (dimethylamino) nicotinonitrile reference is made to intermediate 2.

MS m/z(ESI)：163.2[M+H]⁺.

Intermediate 4: preparation of 6-amino-4- (2-methoxyethoxy) nicotinonitrile

Preparation of 6-amino-4- (2-methoxyethoxy) nicotinonitrile reference is made to intermediate 2.

MS m/z(ESI)：194.2[M+H]⁺.

Intermediate 5: preparation of (R) -6-amino-4- ((1-methoxypropan-2-yl) oxo) nicotinonitrile

Preparation of (R) -6-amino-4- ((1-methoxypropan-2-yl) oxo) nicotinonitrile reference intermediate 2.

MS m/z(ESI)：208.2[M+H]⁺.

Intermediate 6: preparation of 6-amino-4- ((2-methoxyethyl) thio) nicotinonitrile

Preparation of 6-amino-4- ((2-methoxyethyl) thio) nicotinonitrile reference intermediate 2.

MS m/z(ESI)：210.3[M+H]⁺.

Intermediate 7: preparation of (S) -6-amino-4- (3-methoxypyrrolidin-1-yl) nicotinonitrile

Preparation of (S) -6-amino-4- (3-methoxypyrrolidin-1-yl) nicotinonitrile reference intermediate 2.

MS m/z(ESI)：219.3[M+H]⁺.

Intermediate 8: preparation of (S) -6-amino-4- ((tetrahydrofuran-3-yl) thio) nicotinonitrile

Preparation of (S) -6-amino-4- ((tetrahydrofuran-3-yl) thio) nicotinonitrile reference intermediate 2.

MS m/z(ESI)：222.3[M+H]⁺.

Intermediate 9: preparation of (S) -6-amino-4- (3- (dimethylamino) pyrrolidin-1-yl) nicotinonitrile

Preparation of (S) -6-amino-4- (3- (dimethylamino) pyrrolidin-1-yl) nicotinonitrile reference intermediate 2.

MS m/z(ESI)：232.3[M+H]⁺.

Intermediate 10: preparation of 6-amino-4- (3-methoxyazetidin-1-yl) nicotinonitrile

Preparation of 6-amino-4- (3-methoxyazetidin-1-yl) nicotinonitrile reference intermediate 2.

MS m/z(ESI)：205.2[M+H]⁺.

Intermediate 11: preparation of 6-amino-4- (((3S, 4R) -4-methoxytetrahydrofuran-3-yl) amino) nicotinonitrile

Preparation of 6-amino-4- (((3S, 4R) -4-methoxytetrahydrofuran-3-yl) amino) nicotinonitrile reference intermediate 2.

MS m/z(ESI)：235.3[M+H]⁺.

Intermediate 12: preparation of 6-amino-4- (((3S, 4S) -4-methoxytetrahydrofuran-3-yl) oxo) nicotinonitrile

Preparation of 6-amino-4- (((3S, 4S) -4-methoxytetrahydrofuran-3-yl) oxo) nicotinonitrile reference intermediate 2.

MS m/z(ESI)：236.2[M+H]⁺.

Intermediate 13: preparation of 6-amino-4- (((3S, 4S) -3-methoxytetrahydro-2H-pyran-4-yl) oxo) nicotinonitrile

Preparation of 6-amino-4- (((3S, 4S) -3-methoxytetrahydro-2H-pyran-4-yl) oxo) nicotinonitrile reference intermediate 2.

MS m/z(ESI)：250.3[M+H]⁺.

Intermediate 14: preparation of 6-amino-4- (((3S, 4S) -4-methoxytetrahydro-2H-pyran-3-yl) oxo) nicotinonitrile

Preparation of 6-amino-4- (((3S, 4S) -4-methoxytetrahydro-2H-pyran-3-yl) oxo) nicotinonitrile reference intermediate 2.

MS m/z(ESI)：250.3[M+H]⁺.

Intermediate 15: preparation of 6-amino-4- (((3S, 4S) -4-methoxytetrahydro-2H-pyran-3-yl) amino) nicotinonitrile

Preparation of 6-amino-4- (((3S, 4S) -4-methoxytetrahydro-2H-pyran-3-yl) amino) nicotinonitrile reference intermediate 2.

MS m/z(ESI)：249.2[M+H]⁺.

Intermediate 16: preparation of 6-amino-4- ((1R, 2R) -2-methoxycyclobutoxy) nicotinonitrile

Preparation of 6-amino-4- ((1R, 2R) -2-methoxycyclobutoxy) nicotinonitrile reference intermediate 2.

MS m/z(ESI)：220.2[M+H]⁺.

Intermediate 17: preparation of 6-amino-4- ((1R, 2S) -2-methoxycyclobutoxy) nicotinonitrile

Preparation of 6-amino-4- ((1R, 2S) -2-methoxycyclobutoxy) nicotinonitrile reference intermediate 2. MS (Mass Spectrometry)

m/z(ESI)：220.2[M+H]⁺.

Intermediate 18: preparation of 6-amino-4- (((1R, 2R) -2-methoxycyclobutyl) amino) nicotinonitrile

Preparation of 6-amino-4- (((1R, 2R) -2-methoxycyclobutyl) amino) nicotinonitrile reference intermediate 2.

MS m/z(ESI)：219.2[M+H]⁺.

Intermediate 19: preparation of 6-amino-4- (((1R, 2S) -2-methoxycyclobutyl) amino) nicotinonitrile

Preparation of 6-amino-4- (((1R, 2S) -2-methoxycyclobutyl) amino) nicotinonitrile reference intermediate 2.

MS m/z(ESI)：219.2[M+H]⁺.

Intermediate 20: preparation of 2- (dimethoxymethyl) -5, 6, 7, 8-tetrahydro-1, 8-naphthyridine-3-carbaldehyde

The first step is as follows: preparation of 2- (dimethoxymethyl) -1, 8-naphthyridine

2-Aminonicotinaldehyde (25.0g, 205mmol), 1, 1-dimethoxypropan-2-one (31.4g, 266mmol) were mixed and dissolved in a mixed solvent of ethanol (500mL) and water (50mL), and aqueous NaOH solution (3M, 88.7mL, 266mmol) was added dropwise, followed by stirring at room temperature for 3 hours. The reaction solution was concentrated, and the residue was dissolved in EtOAc, washed twice with saturated brine, dried over anhydrous sodium sulfate and concentrated to give the title compound, 2- (dimethoxymethyl) -1, 8-naphthyridine (42.3g), which was used directly in the next reaction.

The second step is that: preparation of 7- (dimethoxymethyl) -1, 2, 3, 4-tetrahydro-1, 8-naphthyridine

To a solution of 2- (dimethoxymethyl) -1, 8-naphthyridine (42.3g, 205mmol) in ethanol (600mL) was added PtO₂(1.25g), after reacting under hydrogen atmosphere at ordinary temperature and pressure for 36 hours, the catalyst was filtered off with celite. The filtrate was concentrated to give the title compound 7- (dimethoxymethyl) -1, 2, 3, 4-tetrahydro-1, 8-naphthyridine (42.7g) which was used directly in the next reaction.

The third step: preparation of 6-bromo-7- (dimethoxymethyl) -1, 2, 3, 4-tetrahydro-1, 8-naphthyridine

NBS (38.3g, 215mmol) was added portionwise to a solution of 7- (dimethoxymethyl) -1, 2, 3, 4-tetrahydro-1, 8-naphthyridine (42.7g, 205mmol) in MeCN (1L) at room temperature, followed by stirring for an additional 1 hour. The reaction mixture was concentrated, and the residue was treated with CH₂Cl₂After dissolution, the reaction mixture was washed with 1M aqueous NaOH solution and saturated brine in this order, dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography to give the title compound, 6-bromo-7- (dimethoxymethyl) -1, 2, 3, 4-tetrahydro-1, 8-naphthyridine (47.5g, 81% in three steps).

¹H NMR(400MHz，CDCl₃)：δ7.27(s，1H)，5.55(s，1H)，5.39(br s，1H)，3.45(s，6H)，3.38(m，2H)，2.70(t，J＝6.0Hz，2H)，1.88(m，2H)；

MS m/z(ESI)：287.0[M+H]⁺.

The fourth step: preparation of 2- (dimethoxymethyl) -5, 6, 7, 8-tetrahydro-1, 8-naphthyridine-3-carbaldehyde

To a solution of 6-bromo-7- (dimethoxymethyl) -1, 2, 3, 4-tetrahydro-1, 8-naphthyridine (114mg, 0.397mmol) in THF (3mL) at-78 deg.C was added MeLi (1.6M in THF, 0.30mL, 0.48mmol) dropwise. After the reaction was stirred at this temperature for 5 minutes, n-BuLi (1.6M THF solution, 0.50mL, 0.80mmol) was added dropwise and stirring continued at this temperature for 15 minutes. Dry DMF (0.12mL, 1.6mmol) was added slowly dropwise. The reaction was slowly warmed to room temperature and stirred for an additional 30 minutes. Adding saturated NH to the reaction solution₄Aqueous Cl solution, stirred for 5 minutes and then added with CH₂Cl₂Extraction was performed twice, and organic phases were combined, dried over anhydrous magnesium sulfate, concentrated, and subjected to column chromatography to give the title compound, 2- (dimethoxymethyl) -5, 6, 7, 8-tetrahydro-1, 8-naphthyridine-3-carbaldehyde (73mg, 78%).

¹H NMR(400MHz，CDCl₃)：δ10.32(s，1H)，7.75(s，1H)，5.93(br s，1H)，5.44(s，1H)，3.49(m，8H)，2.76(t，J＝6.0Hz，2H)，1.91(m，2H)；

MS m/z(ESI)：237.1[M+H]⁺.

Intermediate 21: preparation of 1- ((2- (dimethoxymethyl) -5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-3-yl) methyl) -3-methoxypyrrolidin-2-one

The first step is as follows: preparation of 4- ((tert-butoxycarbonyl) amino) -2-hydroxybutyric acid

4-amino-2-hydroxybutyric acid (10g, 84mmol), K was added to the mixture in an ice-water bath₂CO₃(34.8g, 252mmol) of H₂To a solution of O (80mL), Boc was slowly added dropwise₂O (20g, 84mmol) in 1, 4-dioxane (30mL) was reacted overnight at room temperature. Et for reaction solution₂O (30 mL. times.2) was washed, the aqueous phase was adjusted to pH 4-5 with hydrochloric acid (2N), extracted with EtOAc (100 mL. times.3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound, 4- ((tert-butoxycarbonyl) amino) -2-hydroxybutyric acid (12.2g, 66%).

MS m/z(ESI)：220.2[M+H]⁺.

The second step is that: preparation of methyl 4- ((tert-butoxycarbonyl) amino) -2-methoxybutyrate

To 4- ((tert-butoxycarbonyl) amino) -2-hydroxybutyric acid (1g, 4.6mmol), Ag was added under ice-water bath₂O (4.23g, 18.3mmol) in anhydrous DMF (10mL) was slowly added dropwise MeI (6.5g, 45.6mmol) over an ice-water bathThe reaction was kept away from light overnight. The reaction was diluted with ethyl acetate (500mL), and the organic phase was washed with saturated brine (50mL × 5), dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography to give the title compound, methyl 4- ((tert-butoxycarbonyl) amino) -2-methoxybutyrate (0.33g, 29%).

MS m/z(ESI)：248.3[M+H]⁺.

The third step: preparation of methyl 4-amino-2-methoxybutyrate hydrochloride

To methyl 4- ((tert-butoxycarbonyl) amino) -2-methoxybutyrate (0.33g, 1.33mmol) in CH with ice-water bath₂Cl₂(2mL) to the solution was added dioxane hydrochloride (5mL), the mixture was slowly warmed to room temperature, stirred for 2 hours, and the reaction was concentrated to give the title compound, methyl 4-amino-2-methoxybutyrate hydrochloride, which was used directly in the next reaction.

MS m/z(ESI)：148.2[M+H]⁺.

The fourth step: preparation of 1- ((2- (dimethoxymethyl) -5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-3-yl) methyl) -3-methoxypyrrolidin-2-one

2- (Dimethoxymethyl) -5, 6, 7, 8-tetrahydro-1, 8-naphthyridine-3-carbaldehyde (130mg, 0.55mmol) and 4-amino-2-methoxybutyrate hydrochloride (121mg, 0.66mmol) were dissolved in a 1, 2-dichloroethane (5mL) at room temperature. Triethylamine (73mg, 0.72mmol) was then added, followed by anhydrous acetic acid (6.6mg, 0.11mmol) and sodium triacetoxyborohydride (175mg, 0.83 mmol). Then, the reaction mixture was stirred at room temperature overnight, and the next day reaction mixture was concentrated and subjected to column chromatography to give the title compound, 1- ((2- (dimethoxymethyl) -5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-3-yl) methyl) -3-methoxypyrrolidin-2-one (91mg, 49%).

¹H NMR(400MHz，CDCl₃)δ7.38(s，1H)，5.42(s，1H)，5.31(s，1H)，4.68(d，J＝14.8Hz，1H)，4.63(d，J＝14.8Hz，1H)，4.11(t，J＝7.4Hz，1H)，3.70(s，3H)，3.55(s，3H)，3.54(s，3H)，3.53-3.50(m，1H)，3.39-3.35(m，1H)，3.26-3.20(m，1H)，2.81(t，J＝6.2Hz，2H)，2.57-2.32(m，1H)，2.21(s，1H)，2.06-1.88(m，3H)；

MS m/z(ESI)：336.2[M+H]⁺.

Intermediate 22: preparation of (R) -6-amino-4- ((1-methoxypropan-2-yl) amino) nicotinonitrile

6-amino-4-fluoronicotinonitrile (1.5g, 10.9mmol), (R) -1-methoxypropan-2-amine (1.2g, 13mmol) was dissolved in DMA (10mL) at room temperature, DIPEA (4.2g, 33mmol) was added and the temperature was raised to 130 ℃. The reaction mixture was stirred at this temperature for 12 hours, concentrated and subjected to column chromatography to give the compound (R) -6-amino-4- ((1-methoxypropan-2-yl) amino) nicotinonitrile (2g, 89%).

MS m/z(ESI)：207.1[M+H]⁺.

Intermediate 23: preparation of (R) -1- ((2- (dimethoxymethyl) -5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-3-yl) methyl) -3-methoxypyrrolidin-2-one

Synthesis of methyl (R) -4- ((tert-butoxycarbonyl) amino) -2-methoxybutyrate in the first step

Methyl (R) -4- ((tert-butoxycarbonyl) amino) -2-hydroxybutyrate (6.0g, 25.7mmol) was dissolved in dry DMF (200mL), cooled to 8 deg.C and Ag was added portionwise under nitrogen₂O (23.8g, 102.9mmol), MeI (36.5) was added dropwiseg, 257.2 mmol). The reaction was stirred at 8 ℃ for 18 h in the dark, then diluted with EtOAc (200mL), filtered through celite, concentrated and column chromatographed to give the compound methyl (R) -4- ((tert-butoxycarbonyl) amino) -2-methoxybutyrate (3.9g, 61%).

¹H NMR(400MHz，CDCl₃)δ4.80(s，1H)，3.86-3.83(m，1H)，3.77(s，3H)，3.41(s，3H)，3.34-3.28(m，1H)，3.21-3.17(m，1H)，1.99-1.85(m，2H)，1.44(s，9H).

Second step synthesis of methyl (R) -4-amino-2-methoxybutyrate

Methyl (R) -4- ((tert-butoxycarbonyl) amino) -2-methoxybutyrate (1.5g, 6.1mmol) was dissolved in CH₂Cl₂(5mL), cooled to 5 ℃, dioxane hydrochloride (8mL) was added under nitrogen, the temperature was gradually raised to room temperature and stirred at the temperature for 2.5 hours, and the reaction was concentrated to give the hydrochloride of methyl (R) -4- ((tert-butoxycarbonyl) amino) -2-methoxybutyrate, which was used directly in the next reaction.

MS m/z(ESI)：148.1[M+H]⁺.

The third step is the synthesis of (R) -1- ((2- (dimethoxymethyl) -5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-3-yl) methyl) -3-methoxypyrrolidin-2-one

2- (Dimethoxymethyl) -5, 6, 7, 8-tetrahydro-1, 8-naphthyridine-3-carbaldehyde (1.0g, 4.2mmol), methyl (R) -4- ((tert-butoxycarbonyl) amino) -2-methoxybutyrate hydrochloride (0.75g, 5.1mmol) were dissolved in DCE (15mL), triethylamine (0.56g, 5.5mmol) was added, then anhydrous acetic acid (63.5mg, 1.06mmol) was added, the reaction was stirred at room temperature for 12 hours, and then CH was used₂Cl₂Diluted (100mL), the organic phase was washed successively with water (10mL) and saturated brine (15mL) and washed with brineDrying over sodium sulfate, concentration and column chromatography gave compound (R) -1- ((2- (dimethoxymethyl) -5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-3-yl) methyl) -3-methoxypyrrolidin-2-one (1.1g, 77%).

MS m/z(ESI)：336.2[M+H]⁺.

Intermediate 24: preparation of (S) -6-amino-4- ((tetrahydrofuran-3-yl) amino) nicotinonitrile

6-amino-4-fluoronicotinonitrile (2.54g, 20mmol), (S) -tetrahydrofuran-3-amine hydrochloride (4.94g, 40mmol), DIPEA (0.77g, 60mmol) were mixed in DMF (60mL) and reacted at 110 ℃ overnight. The reaction was concentrated, the residue dissolved in dichloromethane (100mL), saturated NaHCO was added₃(100mL) of the aqueous solution was separated, the organic phase was washed with saturated aqueous NaCl solution (50 mL. times.2), dried over anhydrous sodium sulfate, concentrated and column chromatographed to give the title compound (S) -6-amino-4- ((tetrahydrofuran-3-yl) amino) nicotinonitrile (2.85g, 70%).

MS m/z(ESI)：205.1[M+H]⁺.

Intermediate 25: preparation of (R) -6-amino-4- ((tetrahydrofuran-3-yl) amino) nicotinonitrile

6-amino-4-fluoronicotinonitrile (2.54g, 20mmol), (R) -tetrahydrofuran-3-amine hydrochloride (4.94g, 40mmol), DIPEA (0.77g, 60mmol) were mixed in DMF (60mL) and reacted at 110 ℃ overnight. Concentrating the reaction solutionThe residue was dissolved in dichloromethane (100mL) and saturated NaHCO was added₃(100mL) of the aqueous solution, the organic phase was washed with saturated aqueous NaCl solution (50 mL. times.2), dried over anhydrous sodium sulfate, concentrated and column chromatographed to give the title compound (R) -6-amino-4- ((tetrahydrofuran-3-yl) amino) nicotinonitrile (2.68g, 66%).

MS m/z(ESI)：205.1[M+H]⁺.

Preparation of examples

Example 1

(R) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N-methyltetrahydrofuran-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

The first step is as follows: preparation of 1- (2- (dimethoxymethyl) -5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-3-yl) -N-methylmethanamine

To a solution of 2- (dimethoxymethyl) -5, 6, 7, 8-tetrahydro-1, 8-naphthyridine-3-carbaldehyde (2.00g, 8.44mmol), methylamine hydrochloride (5.60g, 84.4mmol) in MeOH (60mL) was added NaBH in one portion₃CN (1.32g, 21.1 mmol). Then, the mixture was stirred at room temperature overnight, and the reaction mixture was concentrated under reduced pressure and then treated with CH₂Cl₂Dissolving, washing with 1M KOH aqueous solution and saturated brine in sequence, drying the organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product which is directly used for the next reaction. MS m/z (ESI): 252.2[ M + H ]]⁺.

The second step is that: preparation of tert-butyl ((2- (dimethoxymethyl) -5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-3-yl) methyl) (methyl) carbamate

Add 1- (2- (Dimethoxymethyl) -5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-3-yl) -N-methylmethanamine (crude from previous step, ca. 8.44mmol), DIPEA (2.36mL, 14.3mmol) to CH in ice-water bath₂Cl₂Boc was added dropwise to the solution (50mL)₂O (2.20mL, 9.55mmol), stirred at room temperature overnight, concentrated, and column chromatographed to give the title compound tert-butyl ((2- (dimethoxymethyl) -5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-3-yl) methyl) (methyl) carbamate (2.20g, 74% yield over two steps).

¹H NMR(400MHz，CDCl₃)：δ7.03(s，1H)，5.24(m，1H)，4.89(s，1H)，4.49(s，2H)，3.40(m，8H)，2.70(m，5H)，1.90(m，2H)，1.26(s，9H)；

MS m/z(ESI)：252.1[M+H]⁺.

The third step: preparation of phenyl 6- (((tert-butoxycarbonyl) (methyl) amino) methyl) -7- (dimethoxymethyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxylate

A THF solution of LiHMDS (1M, 6.01mL, 6.01mmol) was added dropwise to a THF solution (40mL) of tert-butyl ((2- (dimethoxymethyl) -5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-3-yl) methyl) (methyl) carbamate (1.92g, 5.46mmol) and diphenyl carbonate (1.40g, 6.56mmol) in THF under a dry ice-acetone bath, and after the addition, the temperature was slowly raised to room temperature and stirred for 30 minutes. After quenching the reaction with saturated aqueous ammonium chloride, CH was added₂Cl₂Extraction, organic phase washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and column chromatographed to give phenyl 6- (((tert-butoxycarbonyl) (methyl) amino) methyl) -7- (dimethoxymethyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxylate (1.80g, 70%). MS m/z (ESI): 472.2[ M + H]⁺.

The fourth step: preparation of tert-butyl ((8- ((5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) carbamoyl) -2- (dimethoxymethyl) -5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-3-yl) methyl) (methyl) carbamate

To a solution of phenyl 6- (((tert-butoxycarbonyl) (methyl) amino) methyl) -7- (dimethoxymethyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxylate (1.80g, 3.82mmol), 6-amino-4- ((2-methoxyethyl) amino) nicotinonitrile (1.00g, 5.00mmol) in THF was added LiHMDS (1M, 6.11mL, 6.11mmol) dropwise with a dry ice-acetone bath, slowly warmed to room temperature and stirred overnight. Quenching with saturated aqueous ammonium chloride solution and then with CH₂Cl₂Extraction and washing of the organic phase with brine, drying over anhydrous sodium sulfate, concentration and column chromatography gave tert-butyl ((8- ((5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) carbamoyl) -2- (dimethoxymethyl) -5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-3-yl) methyl) (methyl) carbamate (1.95g, 90%).

¹H NMR(400MHz，CDCl₃)：δ13.72(br s，1H)，8.20(s，1H)，7.58(s，1H)，7.37(br s，1H)，5.42(m，1H)，5.23(m，1H)，4.64(s，2H)，4.03(m，2H)，3.63(m，2H)，3.47(m，8H)，3.38(s，3H)，2.81(m，5H)，2.00(m，2H)，1.50(m，9H)；

MS m/z(ESI)：570.2[M+H]⁺.

The fifth step: preparation of N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7- (dimethoxymethyl) -6- ((methylamino) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Tert-butyl ((8- ((5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) carbamoyl) -2- (dimethoxymethyl) -5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-3-yl) methyl) (methyl) carbamate (2.00g, 3.51mmol) was dissolved in 0.3M in a solution of methanol hydrochloride, and stirred at room temperature for 4 days. Under the ice-water bath, triethylamine is added dropwise until the reaction solution is alkaline. After the reaction solution was concentrated, the residue was treated with CH₂Cl₂The resulting product was dissolved, washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography to give N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7- (dimethoxymethyl) -6- ((methylamino) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide (1.00g, 61%).

¹H NMR(400MHz，CDCl₃)：δ13.55(s，1H)，8.18(s，1H)，7.87(s，1H)，7.56(s，1H)，5.40(s，1H)，5.27(m，1H)，4.23(s，2H)，4.03(m，2H)，3.63(t，J＝5.2Hz，2H)，3.58(s，6H)，3.49(t，J＝5.2Hz，2H)，3.41(s，3H)，2.88(t，J＝6.0Hz，2H)，2.66(s，3H)，1.99(m，2H)；

MS m/z(ESI)：470.2[M+H]⁺.

And a sixth step: preparation of (R) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N-methyltetrahydrofuran-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7- (dimethoxymethyl) -6- ((methylamino) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide (270mg, 0.575mmol), (R) -tetrahydrofuran-2-carboxylic acid (80mg, 0.690mmol), DIPEA (0.190mL, 1.15mmol), HATU (284mg, 0.748mmol) in CH₂Cl₂The solution (5mL) was stirred at room temperature for one hour, washed with a saturated aqueous sodium bicarbonate solution and a saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated. The crude product was dissolved in THF (11mL), then water (4mL), concentrated HCl (1.5mL) were added in that order. Stirred at room temperature for one hour. A saturated aqueous sodium bicarbonate solution was carefully added dropwise to the reaction solution until no bubbling occurred and a large amount of insoluble matter appeared. By CH₂Cl₂Extracting twice, combining organic phases. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography to give (R) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N-methyltetrahydrofuran-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide (226mg, 75%).

¹H NMR(400MHz，CDCl₃)：δ13.60(m，1H)，10.27(m，1H)，8.18(m，1H)，7.50(m，2H)，5.40(m，1H)，5.20(m，2H)，4.70(m，1H)，4.00(m，4H)，3.65(m，2H)，3.50(m，2H)，3.42(s，3H)，3.10(s，2H)，2.90(m，3H)，2.00(m，6H)；

MS m/z(ESI)：522.2[M+H]⁺.

Example 2

(S) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N-methyltetrahydrofuran-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of (S) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N-methyltetrahydrofuran-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure was referred to example 1.

¹H NMR(400MHz，CDCl₃)：δ13.64(m，1H)，10.28(m，1H)，8.19(m，1H)，7.56(m，2H)，5.44(m，1H)，5.10(m，2H)，4.73(m，1H)，4.00(m，4H)，3.65(m，2H)，3.50(m，2H)，3.42(s，3H)，3.09(s，2H)，2.92(m，3H)，2.00(m，6H)；

MS m/z(ESI)：522.2[M+H]⁺.

Example 3

N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N-methyloxetanyl-3-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N-methyloxetanyl-3-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure was referenced to example 1.

¹H NMR(400MHz，CDCl₃)：δ13.60(m，1H)，10.23(m，1H)，8.17(m，1H)，7.57(m，2H)，5.35(m，1H)，5.07(s，1H)，4.85(m，4H)，4.08(m，2H)，3.85(m，1H)，3.64(m，2H)，3.50(m，3H)，3.41(s，3H)，3.02(s，1H)，2.93(m，2H)，2.82(s，2H)，2.05(m，2H)；

MS m/z(ESI)：508.2[M+H]⁺.

Example 4

N- (5-cyano-4- (dimethylamino) pyridin-2-yl) -7-formyl-6- ((N-methyltetrahydrofuran-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (dimethylamino) pyridin-2-yl) -7-formyl-6- ((N-methyltetrahydrofuran-2-carbapimelamide) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 1.

¹H NMR(400MHz，CDCl₃)：δ13.57(m，1H)，10.25(m，1H)，8.23(m，1H)，7.55(m，2H)，5.00(m，3H)，4.00(m，4H)，3.27(s，6H)，3.09(s，2H)，2.90(m，3H)，2.04(m，6H)；

MS m/z(ESI)：492.2[M+H]⁺

Example 5

N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N-methyltetrahydrofuran-3-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N-methyltetrahydrofuran-3-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 1.

¹H NMR(400MHz，CDCl₃)：δ13.61(m，1H)，10.28(m，1H)，8.19(m，1H)，7.55(m，2H)，5.50(m，1H)，5.07(m，2H)，4.08(m，3H)，3.93(m，3H)，3.65(m，2H)，3.50(m，2H)，3.42(s，3H)，3.35(m，1H)，3.04(m，3H)，2.90(m，2H)，2.00(m，4H)；

MS m/z(ESI)：522.2[M+H]⁺.

Example 6

(S) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N-methyltetrahydrofuran-3-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of (S) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N-methyltetrahydrofuran-3-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure was referred to example 1.

¹H NMR(400MHz，CDCl₃)：δ13.59(m，1H)，10.25(m，1H)，8.17(m，1H)，7.52(m，2H)，5.30(m，1H)，5.06(m，2H)，4.00(m，6H)，3.65(m，2H)，3.49(m，2H)，3.41(s，3H)，3.30(m，1H)，3.00(m，5H)，2.05(m，4H)；

MS m/z(ESI)：522.2[M+H]⁺.

Example 7

(R) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N-methyltetrahydrofuran-3-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of (R) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N-methyltetrahydrofuran-3-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure was referred to example 1.

¹H NMR(400MHz，CDCl₃)：δ13.60(m，1H)，10.24(m，1H)，8.17(m，1H)，7.52(m，2H)，5.30(m，1H)，5.07(m，2H)，4.09(m，3H)，3.91(m，3H)，3.60(m，5H)，3.41(s，3H)，3.00(m，5H)，2.08(m，4H)；

MS m/z(ESI)：522.2[M+H]⁺.

Example 8

(R) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N-methylpyrrolidine-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of (R) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N-methylpyrrolidine-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to the preparation method

Example 1.

MS m/z(ESI)：521.2[M+H]⁺.

Example 9

(R) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -6- ((N, 1-dimethylpyrrolidine-2-carboxaldo amido) methyl) -7-formyl-3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of (R) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -6- ((N, 1-dimethylpyrrolidin-2-carbacholamido) methyl) -7-formyl-3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure was referred to in example 1.

¹H NMR(400MHz，CDCl₃)：δ13.61(m，1H)，10.25(m，1H)，8.18(m，1H)，7.56(m，2H)，5.31(m，1H)，5.08(m，2H)，4.10(m，2H)，3.64(m，2H)，3.50(m，2H)，3.41(s，3H)，3.25(m，1H)，3.00(m，5H)，2.20(m，11H)；

MS m/z(ESI)：535.2[M+H]⁺.

Example 10

(R) -6- ((1-acetyl-N-methylpyrrolidine-2-carbapimelamide) methyl) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of (R) -6- ((1-acetyl-N-methylpyrrolidine-2-carbapimelamide) methyl) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure was referred to example 1.

¹H NMR(400MHz，CDCl₃)：δ13.40(m，1H)，10.25(m，1H)，8.17(m，1H)，7.79(m，1H)，7.57(s，1H)，5.39(m，4H)，4.11(m，2H)，3.48(m，6H)，3.18(s，3H)，2.98(m，5H)，2.04(m，9H)；

MS m/z(ESI)：563.3[M+H]⁺.

Example 11

(R) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((tetrahydrofuran-2-carboxaldehyde amido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of (R) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((tetrahydrofuran-2-carbon weevilamino) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure was referred to example 1.

MS m/z(ESI)：508.2[M+H]⁺.

Example 12

(S) -N- (5-cyano-4- (2-methoxyethoxy) pyridin-2-yl) -7-formyl-6- ((N-methyltetrahydrofuran-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of (S) -N- (5-cyano-4- (2-methoxyethoxy) pyridin-2-yl) -7-formyl-6- ((N-methyltetrahydrofuran-2-carboxaldo amido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 1.

MS m/z(ESI)：523.2[M+H]⁺.

Example 13

(R) -N- (5-cyano-4- (2-methoxyethoxy) pyridin-2-yl) -7-formyl-6- ((N-methyltetrahydrofuran-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of (R) -N- (5-cyano-4- (2-methoxyethoxy) pyridin-2-yl) -7-formyl-6- ((N-methyltetrahydrofuran-2-carboxaldo amido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure was referenced to example 1.

MS m/z(ESI)：523.2[M+H]⁺.

Example 14

N- (5-cyano-4- (((R) -1-methoxypropan-2-yl) oxo) pyridin-2-yl) -7-formyl-6- (((S) -N-methyltetrahydrofuran-2-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((R) -1-methoxypropan-2-yl) oxo) pyridin-2-yl) -7-formyl-6- (((S) -N-methyltetrahydrofuran-2-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure was as in example 1.

MS m/z(ESI)：536.2[M+H]⁺.

Example 15

N- (5-cyano-4- (((R) -1-methoxypropan-2-yl) oxo) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((R) -1-methoxypropan-2-yl) oxo) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure was as in example 1.

¹H NMR(400MHz，CDCl₃)：δ14.20-13.80(m，1H)，10.50-10.30(m，1H)，8.50-8.35(m，2H)，7.65-7.45(m，1H)，5.28-4.88(m，2H)，4.78-4.45(m，1H)，4.17-3.84(m，4H)，3.71-3.55(m，3H)，3.42(s，3H)，3.16-3.06(m，2H)，2.95(s，3H)，2.65-1.80(m，6H)，1.47(s，3H)；

MS m/z(ESI)：537.2[M+H]⁺.

Example 16

(R) -N- (5-cyano-4- ((2-methoxyethyl) thio) pyridin-2-yl) -7-formyl-6- ((N-methyltetrahydrofuran-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of (R) -N- (5-cyano-4- ((2-methoxyethyl) thio) pyridin-2-yl) -7-formyl-6- ((N-methyltetrahydrofuran-2-carboxaldo amido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure was referenced to example 1.

¹H NMR(400MHz，CDCl₃)：δ14.20-13.80(m，1H)，10.50-10.25(m，1H)，8.50-8.35(m，2H)，7.65-7.45(m，1H)，5.25-4.85(m，2H)，4.77-4.45(m，1H)，4.15-3.83(m，4H)，3.77(m，2H)，3.45(s，3H)，3.35(m，2H)，3.15-2.78(m，5H)，2.55-1.70(m，6H)；

MS m/z(ESI)：539.2[M+H]⁺.

Example 17

N- (5-cyano-4- ((S) -3-methoxypyrrolidin-1-yl) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- ((S) -3-methoxypyrrolidin-1-yl) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure was referenced to example 1.

¹H NMR(400MHz，CDCl₃)：δ14.20-13.80(m，1H)，10.50-10.25(m，1H)，8.50-8.35(m，2H)，7.65-7.45(m，1H)，5.25-4.85(m，2H)，4.77-4.45(m，1H)，4.20-3.74(m，9H)，3.38(s，3H)，3.15-2.78(m，5H)，2.55-1.70(m，8H)；

MS m/z(ESI)：548.2[M+H]⁺.

Example 18

N- (5-cyano-4- ((R) -3-methoxypyrrolidin-1-yl) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- ((R) -3-methoxypyrrolidin-1-yl) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure was referenced to example 1.

¹H NMR(400MHz，CDCl₃)：δδ14.20-13.80(m，1H)，10.50-10.25(m，1H)，8.50-8.35(m，2H)，7.65-7.45(m，1H)，5.25-4.85(m，2H)，4.77-4.45(m，1H)，4.20-3.74(m，9H)，3.38(s，3H)，3.15-2.78(m，5H)，2.55-1.70(m，8H)；

MS m/z(ESI)：548.2[M+H]⁺.

Example 19

N- (5-cyano-4- (((S) -tetrahydrofuran-3-yl) thio) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((S) -tetrahydrofuran-3-yl) thio) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbaruditamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 1.

¹H NMR(400MHz，CDCl₃)：δ14.20-13.80(m，1H)，10.50-10.25(m，1H)，8.50-8.35(m，2H)，7.65-7.45(m，1H)，5.25-4.85(m，2H)，4.77-4.45(m，1H)，4.45-4.33(m，1H)，4.20-3.74(m，8H)，3.15-2.78(m，5H)，2.55-1.70(m，8H)；

MS m/z(ESI)：551.2[M+H]⁺.

Example 20

N- (5-cyano-4- (((R) -tetrahydrofuran-3-yl) thio) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((R) -tetrahydrofuran-3-yl) thio) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbaruditamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure is as in example 1.

MS m/z(ESI)：551.2[M+H]⁺.

Example 21

N- (5-cyano-4- ((S) -3- (dimethylamino) pyrrolidin-1-yl) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- ((S) -3- (dimethylamino) pyrrolidin-1-yl) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure was as in example 1.

MS m/z(ESI)：561.3[M+H]⁺.

Example 22

N- (5-cyano-4- ((R) -3- (dimethylamino) pyrrolidin-1-yl) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- ((R) -3- (dimethylamino) pyrrolidin-1-yl) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure was as in example 1.

MS m/z(ESI)：561.3[M+H]⁺.

Example 23

(R) -N- (5-cyano-4- (3-methoxyazetidin-1-yl) pyridin-2-yl) -7-formyl-6- ((N-methyltetrahydrofuran-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of (R) -N- (5-cyano-4- (3-methoxyazetidin-1-yl) pyridin-2-yl) -7-formyl-6- ((N-methyltetrahydrofuran-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide preparation is described in reference to example 1.

MS m/z(ESI)：534.2[M+H]⁺.

Example 24

N- (5-cyano-4- (((3S, 4R) -4-methoxytetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((3S, 4R) -4-methoxytetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbazamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 1.

MS m/z(ESI)：564.2[M+H]⁺.

Example 25

N- (5-cyano-4- (((3R, 4S) -4-methoxytetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((3R, 4S) -4-methoxytetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbazamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 1.

MS m/z(ESI)：564.2[M+H]⁺.

Example 26

N- (5-cyano-4- (((3S, 4S) -4-methoxytetrahydrofuran-3-yl) oxo) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((3S, 4S) -4-methoxytetrahydrofuran-3-yl) oxo) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbazamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 1.

MS m/z(ESI)：565.2[M+H]⁺.

Example 27

N- (5-cyano-4- (((3R, 4R) -4-methoxytetrahydrofuran-3-yl) oxo) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((3R, 4R) -4-methoxytetrahydrofuran-3-yl) oxo) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbazamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 1.

MS m/z(ESI)：565.2[M+H]⁺.

Example 28

N- (5-cyano-4- (((3R, 4R) -3-methoxytetrahydro-2H-pyran-4-yl) oxo) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((3R, 4R) -3-methoxytetrahydro-2H-pyran-4-yl) oxo) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbaruditamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 1.

MS m/z(ESI)：579.2[M+H]⁺.

Example 29

N- (5-cyano-4- (((3S, 4S) -4-methoxytetrahydro-2H-pyran-3-yl) oxo) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((3S, 4S) -4-methoxytetrahydro-2H-pyran-3-yl) oxo) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbaruditamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 1.

MS m/z(ESI)：579.2[M+H]⁺.

Example 30

N- (5-cyano-4- (((3R, 4R) -4-methoxytetrahydro-2H-pyran-3-yl) oxo) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((3R, 4R) -4-methoxytetrahydro-2H-pyran-3-yl) oxo) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbaruditamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 1.

MS m/z(ESI)：579.2[M+H]⁺.

Example 31

N- (5-cyano-4- (((3S, 4S) -4-methoxytetrahydro-2H-pyran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbacholamido) amino) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((3S, 4S) -4-methoxytetrahydro-2H-pyran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbaruditamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 1.

MS m/z(ESI)：578.2[M+H]⁺.

Example 32

N- (5-cyano-4- (((3R, 4R) -4-methoxytetrahydro-2H-pyran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbacholamido) amino) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((3R, 4R) -4-methoxytetrahydro-2H-pyran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbaruditamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 1.

MS m/z(ESI)：578.2[M+H]⁺.

Example 33

N- (5-cyano-4- ((1R, 2R) -2-methoxycyclobutoxy) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- ((1R, 2R) -2-methoxycyclobutoxy) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure was referred to example 1.

MS m/z(ESI)：549.2[M+H]⁺.

Example 34

N- (5-cyano-4- ((1S, 2S) -2-methoxycyclobutoxy) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- ((1S, 2S) -2-methoxycyclobutoxy) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure was referenced to example 1.

MS m/z(ESI)：549.2[M+H]⁺.

Example 35

N- (5-cyano-4- ((1R, 2S) -2-methoxycyclobutoxy) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- ((1R, 2S) -2-methoxycyclobutoxy) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure was referenced to example 1.

MS m/z(ESI)：549.2[M+H]⁺.

Example 36

N- (5-cyano-4- ((1S, 2R) -2-methoxycyclobutoxy) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- ((1S, 2R) -2-methoxycyclobutoxy) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure was referenced to example 1.

MS m/z(ESI)：549.2[M+H]⁺.

Example 37

N- (5-cyano-4- (((1R, 2R) -2-methoxycyclobutyl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((1R, 2R) -2-methoxycyclobutyl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carboxypimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure is as in example 1.

MS m/z(ESI)：548.2[M+H]⁺.

Example 38

N- (5-cyano-4- (((1S, 2S) -2-methoxycyclobutyl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((1S, 2S) -2-methoxycyclobutyl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carboxypimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 1.

MS m/z(ESI)：548.2[M+H]⁺.

Example 39

N- (5-cyano-4- (((1R, 2S) -2-methoxycyclobutyl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((1R, 2S) -2-methoxycyclobutyl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carboxypimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 1.

MS m/z(ESI)：548.2[M+H]⁺.

Example 40

N- (5-cyano-4- (((1S, 2R) -2-methoxycyclobutyl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((1S, 2R) -2-methoxycyclobutyl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carboxypimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure is as in example 1.

MS m/z(ESI)：548.2[M+H]⁺.

EXAMPLE 41

(R) -N- (5-cyano-3-fluoro-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N-methyltetrahydrofuran-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of (R) -N- (5-cyano-3-fluoro-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N-methyltetrahydrofuran-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure was referred to example 1.

MS m/z(ESI)：540.2[M+H]⁺.

Example 42

N- ((R) -7-cyano-2- (methoxymethyl) -2, 3-dihydrofuro [3, 2-c ] pyridin-4-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- ((R) -7-cyano-2- (methoxymethyl) -2, 3-dihydrofuro [3, 2-c ] pyridin-4-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 1.

MS m/z(ESI)：535.2[M+H]⁺.

Example 43

N- ((S) -7-cyano-2- (methoxymethyl) -2, 3-dihydrofuro [3, 2-c ] pyridin-4-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- ((S) -7-cyano-2- (methoxymethyl) -2, 3-dihydrofuro [3, 2-c ] pyridin-4-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 1.

MS m/z(ESI)：535.2[M+H]⁺.

Example 44

N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

The first step is as follows: preparation of phenyl 7- (dimethoxymethyl) -6- ((3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxylate

1- ((2- (Dimethoxymethyl) -5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-3-yl) methyl) -3-methoxypyrrolidin-2-one (91mg, 0.27mmol), Diphenyl carbonate (70mg, 0.33mmol) was mixed in THF (5mL), N₂Under the atmosphere, the mixture was cooled to-78 ℃ and a THF solution of LiHMDS (0.54mL, 0.54mmol) was added dropwise thereto, followed by warming to room temperature naturally and reacting overnight. Adding saturated NH₄Aqueous Cl (2mL), EtOAc (50mL × 2) extraction, organic phase washed with brine, dried over anhydrous sodium sulfate, concentrated and column chromatographed to afford title compound phenyl 7- (dimethoxymethyl) -6- ((3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxylate (61mg, 49%).

¹H NMR(400MHz，CDCl₃)δ7.37(s，1H)，7.34-7.22(m，2H)，7.17-7.04(m，3H)，5.22(s，2H)，5.14(s，1H)，4.65(q，J＝15.2Hz，2H)，3.94(t，J＝7.3Hz，1H)，3.86(m，2H)，3.52(s，3H)，3.31(d，J＝3.9Hz，6H)，3.19-3.00(m，1H)，2.74(t，J＝6.6Hz，2H)，2.25(m，1H)，2.03-1.89(m，2H)；

MS m/z(ESI)：456.1[M+H]⁺.

The second step is that: preparation of N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7- (dimethoxymethyl) -6- ((3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

6-amino-4- ((2-methoxyethyl) amino) nicotinonitrile (34mg, 0.18mmol), phenyl 7- (dimethoxymethyl) -6- ((3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxylate (68mg, 0.15mmol) were mixed in THF (5mL), N₂Under the atmosphere, the mixture was cooled to-78 ℃ and a solution of LiHMDS in THF (0.33mL, 0.33mmol) was added dropwise thereto, followed by warming to room temperature naturally and reacting overnight. Adding saturated NH₄Aqueous Cl (50mL), EtOAc (50mL × 2) extraction, organic phase washed with brine, dried over anhydrous sodium sulfate, concentrated and column chromatographed to afford the title compound N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7- (dimethoxymethyl) -6- ((3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide (51mg, 46%).

¹H NMR(400MHz，CDCl₃)δ13.63(s，1H)，8.13(s，1H)，7.49(s，1H)，7.41(s，1H)，5.36(s，1H)，5.18(dd，J＝12.5，7.5Hz，1H)，4.61(m，2H)，4.03-3.87(m，3H)，3.56(t，J＝5.1Hz，2H)，3.52(s，3H)，3.42(t，J＝5.3Hz，8H)，3.34(s，3H)，3.24(m，1H)，3.10(dm，1H)，2.74(t，J＝6.2Hz，2H)，2.26(m，1H)，1.90(m，2H)，1.88-1.83(m，1H)；

MS m/z(ESI)：554.2[M+H]⁺.

The third step: preparation of N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7- (dimethoxymethyl) -6- ((3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide (51mg, 0.09mmol) was dissolved in THF/water (volume ratio: 11/4, 1.5mL), concentrated HCl (0.15mL, 1.8mmol) was added and reacted at room temperature for 2H. Adding saturated NaHCO₃Aqueous solution (5mL), ethyl acetate (50mL × 2) and the organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated and column chromatographed to give the title compound N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide (15mg, 32%).

¹H NMR(400MHz，CDCl₃)δ13.58(s，1H)，10.24(s，1H)，8.18(s，1H)，7.63(s，1H)，7.58(s，1H)，5.34(s，1H)，4.97(d，J＝15.4Hz，1H)，4.90(d，J＝15.4Hz，1H)，4.13-4.04(m，2H)，4.04-3.93(m，1H)，3.64(t，J＝5.1Hz，2H)，3.59(s，3H)，3.51-3.47(m，2H)，3.42(s，3H)，3.41-3.35(m，1H)，3.34-3.22(m，1H)，2.92(t，J＝6.3Hz，2H)，2.39-2.35(m，1H)，2.06-2.02(m，2H)，1.98-1.88(m，1H)；

MS m/z(ESI)：508.2[M+H]⁺.

Example 45

(R) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

The first step is as follows: synthesis of (R) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7- (dimethoxymethyl) -6- ((3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

A solution of 6-amino-4- ((2-methoxyethyl) amino) nicotinonitrile (358mg, 1.9mmol) in DMF (2.5mL) was added slowly dropwise to a solution of N, N' -carbonylbis (1, 2, 4-triazole) (306mg, 1.9mmol) in DMF (2mL) at 5 ℃ and stirred for 1h at 5 ℃. Then slowly brought to room temperature and stirred for a further 1.5h, a solution of (R) -1- ((2- (dimethoxymethyl) -5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-3-yl) methyl) -3-methoxypyrrolidin-2-one (250mg, 0.75mmol) in DMF (2mL) is added dropwise and stirred at room temperature overnight. Water (20mL) was then added dropwise, and the solid precipitated from the reaction mixture was filtered and dried to give (R) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7- (dimethoxymethyl) -6- ((3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide (0.28g, 67%).

MS m/z(ESI)：554.2[M+H]⁺.

The second step is that: synthesis of (R) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of (R) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the third step of example 44 was referred to.

MS m/z(ESI)：508.2[M+H]⁺.

Example 46

(S) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of (S) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：508.2[M+H]⁺.

Example 47

(R) -N- (5-cyano-4- (2-methoxyethoxy) pyridin-2-yl) -7-formyl-6- ((3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of (R) -N- (5-cyano-4- (2-methoxyethoxy) pyridin-2-yl) -7-formyl-6- ((3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：509.1[M+H]⁺.

Example 48

(S) -N- (5-cyano-4- (2-methoxyethoxy) pyridin-2-yl) -7-formyl-6- ((3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of (S) -N- (5-cyano-4- (2-methoxyethoxy) pyridin-2-yl) -7-formyl-6- ((3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：509.1[M+H]⁺.

Example 49

N- (5-cyano-4- (((R) -1-methoxypropan-2-yl) oxo) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((R) -1-methoxypropan-2-yl) oxo) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference example 44.

MS m/z(ESI)：523.1[M+H]⁺.

Example 50

N- (5-cyano-4- (((R) -1-methoxypropan-2-yl) oxo) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((R) -1-methoxypropan-2-yl) oxo) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference example 44.

¹H NMR(400MHz，CDCl3)δ13.82(s，1H)，10.24(s，1H)，8.35(s，1H)，8.02(s，1H)，7.64(s，1H)，4.97(d，J＝15.4Hz，1H)，4.90(d，J＝15.4Hz，1H)，4.88-4.82(m，1H)，4.14-4.05(m，2H)，4.01(dd，J＝13.5，6.3Hz，1H)，3.66(dd，J＝10.7，6.6Hz，1H)，3.62-3.54(m，4H)，3.46-3.36(m，4H)，3.28(m，1H)，2.93(t，J＝6.0Hz，2H)，2.43-2.32(m，1H)，2.09-2.00(m，2H)，1.95(m，1H)，1.41(d，J＝6.3Hz，3H)；

MS m/z(ESI)：523.2[M+H]⁺.

Example 51

N- (5-cyano-4- ((S) -3-methoxypyrrolidin-1-yl) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- ((S) -3-methoxypyrrolidin-1-yl) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：534.1[M+H]⁺.

Example 52

N- (5-cyano-4- ((R) -3-methoxypyrrolidin-1-yl) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- ((R) -3-methoxypyrrolidin-1-yl) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：534.1[M+H]⁺.

Example 53

N- (5-cyano-4- ((S) -3-methoxypyrrolidin-1-yl) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- ((S) -3-methoxypyrrolidin-1-yl) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

¹H NMR(400MHz，CDCl₃)δ13.50(s，1H)，10.22(s，1H)，8.19(s，1H)，7.62(s，1H)，7.46(s，1H)，4.97(d，J＝15.4Hz，1H)，4.90(d，J＝15.4Hz，1H)，4.11-4.05(m，3H)，4.03-3.98(m，1H)，3.86-3.78(m，4H)，3.58(s，3H)，3.40-3.36(m，4H)，3.31-3.26(m，1H)，2.92(t，J＝6.2Hz，2H)，2.42-2.33(m，1H)，2.25-2.19(m，1H)，2.05-1.92(m，4H)；

MS m/z(ESI)：534.2[M+H]⁺.

Example 54

N- (5-cyano-4- ((R) -3-methoxypyrrolidin-1-yl) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- ((R) -3-methoxypyrrolidin-1-yl) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

¹H NMR(400MHz，CDCl₃)δ13.50(s，1H)，10.22(s，1H)，8.20(s，1H)，7.62(s，1H)，7.47(s，1H)，4.97(d，J＝15.4Hz，1H)，4.90(d，J＝15.4Hz，1H)，4.13-4.06(m，3H)，4.03-3.98(m，1H)，3.86-3.78(m，4H)，3.58(s，3H)，3.44-3.34(m，4H)，3.31-3.26(m，1H)，2.92(t，J＝6.2Hz，2H)，2.41-2.34(m，1H)，2.25-2.20(m，1H)，2.05-1.93(m，4H)；

MS m/z(ESI)：534.2[M+H]⁺.

Example 55

N- (5-cyano-4- (((R) -tetrahydrofuran-3-yl) thio) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((R) -tetrahydrofuran-3-yl) thio) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：537.1[M+H]⁺.

Example 56

N- (5-cyano-4- (((S) -tetrahydrofuran-3-yl) thio) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((S) -tetrahydrofuran-3-yl) thio) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：537.1[M+H]⁺.

Example 57

N- (5-cyano-4- (((R) -tetrahydrofuran-3-yl) thio) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((R) -tetrahydrofuran-3-yl) thio) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：537.1[M+H]⁺.

Example 58

N- (5-cyano-4- (((S) -tetrahydrofuran-3-yl) thio) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((S) -tetrahydrofuran-3-yl) thio) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：537.1[M+H]⁺.

Example 59

N- (5-cyano-4- (((3S, 4R) -4-methoxytetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((3S, 4R) -4-methoxytetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：550.1[M+H]⁺.

Example 60

N- (5-cyano-4- (((3R, 4S) -4-methoxytetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((3R, 4S) -4-methoxytetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：550.1[M+H]⁺.

Example 61

N- (5-cyano-4- (((3S, 4S) -4-methoxytetrahydrofuran-3-yl) oxo) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((3S, 4S) -4-methoxytetrahydrofuran-3-yl) oxo) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：551.1[M+H]⁺.

Example 62

N- (5-cyano-4- (((3R, 4R) -4-methoxytetrahydrofuran-3-yl) oxo) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((3R, 4R) -4-methoxytetrahydrofuran-3-yl) oxo) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：551.1[M+H]⁺.

Example 63

N- (5-cyano-4- (((3S, 4R) -4-methoxytetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((3S, 4R) -4-methoxytetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：550.1[M+H]⁺.

Example 64

N- (5-cyano-4- (((3R, 4S) -4-methoxytetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((3R, 4S) -4-methoxytetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：550.1[M+H]⁺.

Example 65

N- (5-cyano-4- (((3S, 4S) -4-methoxytetrahydrofuran-3-yl) oxo) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((3S, 4S) -4-methoxytetrahydrofuran-3-yl) oxo) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：551.1[M+H]⁺.

Example 66

N- (5-cyano-4- (((3R, 4R) -4-methoxytetrahydrofuran-3-yl) oxo) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((3R, 4R) -4-methoxytetrahydrofuran-3-yl) oxo) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：551.1[M+H]⁺.

Example 67

N- (5-cyano-4- (((1S, 2S) -2-methoxycyclobutyl) amino) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((1S, 2S) -2-methoxycyclobutyl) amino) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：534.1[M+H]⁺.

Example 68

N- (5-cyano-4- (((1R, 2R) -2-methoxycyclobutyl) amino) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((1R, 2R) -2-methoxycyclobutyl) amino) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：534.1[M+H]⁺.

Example 69

N- (5-cyano-4- ((1S, 2S) -2-methoxycyclobutoxy) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- ((1S, 2S) -2-methoxycyclobutoxy) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：535.1[M+H]⁺.

Example 70

N- (5-cyano-4- ((1R, 2R) -2-methoxycyclobutoxy) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- ((1R, 2R) -2-methoxycyclobutoxy) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：535.1[M+H]⁺.

Example 71

N- (5-cyano-4- (((1S, 2S) -2-methoxycyclobutyl) amino) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((1S, 2S) -2-methoxycyclobutyl) amino) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：534.1[M+H]⁺.

Example 72

N- (5-cyano-4- (((1R, 2R) -2-methoxycyclobutyl) amino) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((1R, 2R) -2-methoxycyclobutyl) amino) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：534.1[M+H]⁺.

Example 73

N- (5-cyano-4- ((1S, 2S) -2-methoxycyclobutoxy) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- ((1S, 2S) -2-methoxycyclobutoxy) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：534.1[M+H]⁺.

Example 74

N- (5-cyano-4- ((1R, 2R) -2-methoxycyclobutoxy) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- ((1R, 2R) -2-methoxycyclobutoxy) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：535.1[M+H]⁺.

Example 75

N- (5-cyano-4- (((1S, 2R) -2-methoxycyclobutyl) amino) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((1S, 2R) -2-methoxycyclobutyl) amino) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：534.1[M+H]⁺.

Example 76

N- (5-cyano-4- (((1R, 2S) -2-methoxycyclobutyl) amino) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((1R, 2S) -2-methoxycyclobutyl) amino) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：534.1[M+H]⁺.

Example 77

N- (5-cyano-4- ((1S, 2R) -2-methoxycyclobutoxy) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- ((1S, 2R) -2-methoxycyclobutoxy) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：535.1[M+H]⁺.

Example 78

N- (5-cyano-4- (((1S, 2R) -2-methoxycyclobutyl) amino) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((1S, 2R) -2-methoxycyclobutyl) amino) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：535.1[M+H]⁺.

Example 79

MS m/z(ESI)：534.1[M+H]⁺.

Example 80

N- (5-cyano-4- (((1R, 2S) -2-methoxycyclobutyl) amino) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((1R, 2S) -2-methoxycyclobutyl) amino) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：534.1[M+H]⁺.

Example 81

N- (5-cyano-4- ((1S, 2R) -2-methoxycyclobutoxy) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- ((1S, 2R) -2-methoxycyclobutoxy) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：535.1[M+H]⁺.

Example 82

N- (5-cyano-4- ((1R, 2S) -2-methoxycyclobutoxy) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- ((1R, 2S) -2-methoxycyclobutoxy) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：535.1[M+H]⁺.

Example 83

(S) -N- (5-cyano-4- (oxetan-3-ylamino) pyridin-2-yl) -7-formyl-6- ((3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of (S) -N- (5-cyano-4- (oxetan-3-ylamino) pyridin-2-yl) -7-formyl-6- ((3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference example 44.

¹H NMR(400MHz，CDCl₃)：δ13.66(s，1H)，10.22(s，1H)，8.23(s，1H)，7.63(s，1H)，7.36(s，1H)，5.40(d，J＝5.7Hz，1H)，5.08(t，J＝6.8Hz，2H)，4.97(d，J＝14.8Hz1H)，4.89(d，J＝14.8Hz1H)，4.87-4.81(m，1H)，4.63(t，J＝6.2Hz，2H)，4.13-4.03(m，2H)，3.99(t，J＝7.2Hz，1H)，3.58(s，3H)，3.42-3.37(m，1H)，3.31-3.25(m，1H)，2.92(t，J＝6.1Hz，2H)，2.39-2.35(m，1H)，2.08-2.01(m，2H)，1.98-1.91(m，1H)；

MS m/z(ESI)：506.2[M+H]⁺.

Example 84

N- (5-cyano-4- (((S) -tetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((S) -tetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

¹H NMR(400MHz，CDCl₃)：δ13.64(s，1H)，10.24(s，1H)，8.20(s，1H)，7.63(d，J＝6.1Hz，2H)，5.09(s，1H)，4.97(d，J＝14.8Hz1H)，4.90(d，J＝14.8Hz，1H)，4.34-4.25(m，1H)，4.11-3.97(m，5H)，3.91-3.86(m，1H)，3.80(dd，J＝9.6，2.8Hz，1H)，3.58(s，3H)，3.42-3.37(m，1H)，3.32-3.26(m，1H)，2.92(t，J＝6.2Hz，2H)，2.48-2.33(m，2H)，2.07-2.01(m，2H)，1.99-1.89(m，2H).

MS m/z(ESI)：520.2[M+H]⁺.

Example 85

N- (5-cyano-4- (((R) -tetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((R) -tetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

¹H NMR(400MHz，CDCl₃)：δ13.64(s，1H)，10.25(s，1H)，8.20(s，1H)，7.64(d，J＝4.4Hz，2H)，5.13(s，1H)，4.97(d，J＝14.8Hz 1H)，4.90(d，J＝14.8Hz，1H)，4.34-4.25(m，1H)，4.11-3.97(m，5H)，3.91-3.86(m，1H)，3.81(dd，J＝9.6，2.8Hz，1H)，3.58(s，3H)，3.44-3.36(m，1H)，3.32-3.26(m，1H)，2.92(t，J＝6.2Hz，2H)，2.50-2.32(m，2H)，2.01-2.07(m，2H)，1.99-1.91(m，2H)；

MS m/z(ESI)：520.2[M+H]⁺.

Example 86

N- (5-cyano-4- (((trans) -4-methoxytetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((trans) -4-methoxytetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference example 44.

¹H NMR(400MHz，CDCl₃)δ13.65(s，1H)，10.23(s，1H)，8.21(s，1H)，7.77(s，1H)，7.63(s，1H)，5.02-4.88(m，3H)，4.16-4.06(m，5H)，4.00(t，J＝7.2Hz，1H)，3.92-3.88(m，1H)，3.85-3.80(m，2H)，3.58(s，3H)，3.54(s，3H)，3.42-3.36(m，1H)，3.32-3.25(m，1H)，2.92(t，J＝6.3Hz，2H)，2.43-2.35(m，1H)，2.05-1.93(m，3H)；

MS m/z(ESI)：550.2[M+H]⁺.

Example 87

N- (5-cyano-4- (((R) -tetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((R) -tetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

¹H NMR(400MHz，CDCl₃)δ13.63(s，1H)，10.22(s，1H)，8.19(s，1H)，7.63(s，1H)，7.60(s，1H)，5.11(d，J＝6.5Hz，1H)，4.96(d，J＝15.2Hz，1H)，4.88(d，J＝15.2Hz，1H)，4.42-4.20(m，1H)，4.12-4.06(m，2H)，4.06-3.96(m，3H)，3.91-3.88(m，1H)，3.82-3.79(m，1H)，3.58(s，3H)，3.47-3.34(m，1H)，3.32-3.26(m，1H)，2.93(t，J＝6.2Hz，2H)，2.45-2.36(m，2H)，2.15-1.88(m，4H)；

MS m/z(ESI)：520.2[M+H]⁺.

Example 88

N- (5-cyano-4- (((S) -tetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((S) -tetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 44.

MS m/z(ESI)：520.2[M+H]⁺.

Example 89

N- (5-cyano-4- (((R) -1-methoxypropan-2-yl) amino) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((R) -1-methoxypropan-2-yl) amino) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference example 44.

¹H NMR(400MHz，CDCl₃)δ13.55(s，1H)，10.22(s，1H)，8.17(s，1H)，7.63(s，1H)，7.60(s，1H)，5.20-5.14(m，1H)，4.97(d，J＝15.4Hz，1H)，4.90(d，J＝15.4Hz，1H)，4.10-4.05(m，2H)，4.02-3.98(m，1H)，3.96-3.90(m，1H)，3.58(s，3H)，3.53-3.48(m，1H)，3.47-3.43(m，1H)，3.41-3.36(m，4H)，3.31-3.26(m，1H)，2.92(t，J＝6.3Hz，2H)，2.41-2.32(m，1H)，2.06-1.93(m，3H)，1.32(d，J＝6.6Hz，3H)；

MS m/z(ESI)：522.2[M+H]⁺.

Example 90

N- (5-cyano-4- (((S) -1-methoxypropan-2-yl) amino) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((S) -1-methoxypropan-2-yl) amino) pyridin-2-yl) -7-formyl-6- (((S) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference example 44.

¹H NMR(400MHz，CDCl₃)δ13.55(s，1H)，10.21(s，1H)，8.15(s，1H)，7.61(s，1H)，7.59(s，1H)，5.18(d，J＝7.8Hz，1H)，4.90(d，J＝15.6Hz，1H)，4.88(d，J＝15.6Hz，1H)，4.16-3.87(m，4H)，3.58(s，3H)，3.49-3.43(m，2H)，3.39(s，3H)，3.34-3.21(m，2H)，2.91(t，J＝6.2Hz，2H)，2.45-2.36(m，1H)，2.20-1.86(m，3H)，1.32-1.30(d，J＝6.8Hz，3H)；

MS m/z(ESI)：522.2[M+H]⁺.

Example 91

Preparation of N- (5-cyano-4- (((R) -1-methoxypropan-2-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

The first step is as follows: synthesis of diphenyl (R) - (5-cyano-4- ((1-methoxypropan-2-yl) amino) pyridin-2-yl) aminodicarboxylate

(R) -6-amino-4- ((1-methoxypropan-2-yl) amino) nicotinonitrile (1g, 4.9mmol) was dissolved in CH at room temperature₂Cl₂(10mL) in sequencePyridine (1.92g, 24mmol) and phenyl chloroformate (1.9g, 12mmol) were added and stirred at room temperature for 5 hours, and then the reaction mixture was reacted with CH₂Cl₂(100mL), the organic phase was washed successively with water (10mL) and saturated brine (15mL), dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography to give the compound diphenyl (R) - (5-cyano-4- ((1-methoxypropan-2-yl) amino) pyridin-2-yl) carbamate (1.56g, 72%).

MS m/z(ESI)：447.2[M+H]⁺.

The second step is that: synthesis of N- (5-cyano-4- (((R) -1-methoxypropan-2-yl) amino) pyridin-2-yl) -7- (dimethoxymethyl) -6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

(R) -1- ((2- (dimethoxymethyl) -5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-3-yl) methyl) -3-methoxypyrrolidin-2-one (0.3g, 0.9mmol), diphenyl (R) - (5-cyano-4- ((1-methoxypropan-2-yl) amino) pyridin-2-yl) aminodiformate (0.64g, 1.3mmol) were dissolved in toluene (10mL) at room temperature, warmed to 105 ℃, stirred at this temperature for 8 hours, and then the reaction was cooled to room temperature. By CH₂Cl₂(100mL), the organic phase was washed with water (10mL) and brine (15mL) successively, dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography to give the compound N- (5-cyano-4- (((R) -1-methoxypropan-2-yl) amino) pyridin-2-yl) -7- (dimethoxymethyl) -6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide (0.23g, 45%).

¹H NMR(400MHz，CDCl₃)δ13.70(s，1H)，8.23(s，1H)，7.61(s，1H)，7.47(s，1H)，5.43(s，1H)，5.12(m，1H)，4.73(d，J＝15.2Hz，1H)，4.64(d，J＝15.2Hz，1H)，4.01-3.99(m，3H)，3.96-3.91(m，1H)，3.59(s，3H)，3.53-3.51(m，1H)，3.50(s，3H)，3.49(s，3H)，3.46-3.42(m，1H)，3.40(s，3H)，3.34-3.28(m，1H)，3.21-3.14(m，1H)，2.82(t，J＝6.2Hz，2H)，2.37-2.12(m，1H)，2.05-1.87(m，3H)，1.30(d，J＝6.6Hz，3H)；

MS m/z(ESI)：568.2[M+H]⁺.

The third step: synthesis of N- (5-cyano-4- (((R) -1-methoxypropan-2-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((R) -1-methoxypropan-2-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -3-methoxy-2-carbonylpyrrolidin-1-yl) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide proceeds as in the third step of EXAMPLE 44.

MS m/z(ESI)：522.2[M+H]⁺.

Example 92

N- (5-cyano-4- (((S) -1-methoxypropan-2-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((S) -1-methoxypropan-2-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure was as in example 1.

¹H NMR(400MHz，CDCl₃)：δ14.20-13.80(m，1H)，10.50-10.30(m，1H)，8.50-8.35(m，2H)，7.65-7.45(m，1H)，5.18-4.80(m，2H)，4.70-4.40(m，1H)，4.10-3.80(m，4H)，3.45-3.25(m，6H)，3.05-2.75(m，5H)，2.35-1.70(m，6H)，1.25(d，J＝6.4Hz，3H)；

MS m/z(ESI)：536.2[M+H]⁺.

Example 93

N- (5-cyano-4- (((R) -1-methoxypropan-2-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((R) -1-methoxypropan-2-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure was as in example 1.

¹H NMR(400MHz，CDCl₃)：δ14.20-13.80(m，1H)，10.50-10.30(m，1H)，8.50-8.35(m，2H)，7.65-7.45(m，1H)，5.18-4.80(m，2H)，4.70-4.40(m，1H)，4.10-3.80(m，4H)，3.45-3.25(m，6H)，3.05-2.75(m，5H)，2.3-1.705(m，6H)，1.25(d，J＝6.4Hz，3H)；

MS m/z(ESI)：536.2[M+H]⁺.

Example 94

N- (5-cyano-4- (((S) -tetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((S) -tetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 1.

¹H NMR(400MHz，CDCl₃)：δ13.61(m，1H)，10.25(m，1H)，8.20(s，1H)，7.55(m，2H)，4.75(m，4H)，4.30(m，1H)，4.00(m，8H)，3.00(m，5H)，2.04(m，8H)；

MS m/z(ESI)：534.2[M+H]⁺.

Example 95

N- (5-cyano-4- (((R) -tetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((R) -tetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure is as in example 1.

¹H NMR(400MHz，CDCl₃)：δ13.60(m，1H)，10.25(s，1H)，8.21(s，1H)，7.59(m，2H)，5.10(m，3H)，4.80(m，1H)，4.30(m，1H)，4.00(m，9H)，3.00(m，6H)，2.10(m，6H)；

MS m/z(ESI)：534.2[M+H]⁺.

Example 96

N- (5-cyano-4- (((trans) -4-methoxytetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((trans) -4-methoxytetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-2-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure is as in example 1.

¹H NMR(400MHz，CDCl₃)δ13.70-13.58(m，1H)，10.27-10.22(m，1H)，8.21(s，1H)，7.77(s，1H)，7.63-7.45(m，1H)，5.22-5.09(m，1H)，5.02-4.85(m，2H)，4.76-4.71(m，1H)，4.17-4.06(m，5H)，4.03-3.97(m，1H)，3.94-3.88(m，2H)，3.85-3.80(m，2H)，3.54(s，3H)，3.10(s，2H)，2.96-2.88(m，3H)，2.35-2.20(m，1H)，2.17-1.96(m，5H)；

MS m/z(ESI)：564.2[M+H]⁺.

Example 97

(R) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -6- ((1-ethyl-N-methylpyrrolidine-2-carbacholamido) methyl) -7-formyl-3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of (R) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -6- ((1-ethyl-N-methylpyrrolidine-2-carbacholamido) methyl) -7-formyl-3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure was referred to example 1.

¹H NMR(400MHz，CDCl₃)：δ13.50(m，1H)，10.25(m，1H)，8.17(s，1H)，7.56(m，2H)，5.31(m，1H)，5.07(m，2H)，4.08(m，2H)，3.64(m，3H)，3.49(m，3H)，3.41(s，3H)，2.94(m，7H)，2.46(m，1H)，2.03(m，6H)，1.28(m，3H)；

MS m/z(ESI)：549.3[M+H]⁺.

Example 98

N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N-methyltetrahydro-2H-pyran-4-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N-methyltetrahydro-2H-pyran-4-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 1.

¹H NMR(400MHz，CDCl₃)：δ13.64(m，1H)，10.30(s，1H)，8.20(s，1H)，7.54(m，2H)，5.50(m，1H)，5.04(m，2H)，4.05(m，4H)，3.65(m，2H)，3.50(m，7H)，3.00(m，3H)，2.90(m，3H)，2.03(m，4H)，1.65(m，2H)；

MS m/z(ESI)：536.2[M+H]⁺.

Example 99

(S) -N- (5-cyano-4- ((tetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- ((N-methyltetrahydro-2H-pyran-4-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of (S) -N- (5-cyano-4- ((tetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- ((N-methyltetrahydro-2H-pyran-4-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure was referred to example 1.

¹H NMR(400MHz，CDCl₃)：δ13.68(m，1H)，10.27(m，1H)，8.21(m，1H)，7.53(m，2H)，5.15(m，1H)，5.03(m，2H)，4.30(m，1H)，4.00(m，8H)，3.48(m，2H)，3.08(m，3H)，2.90(m，3H)，2.03(m，8H)；

MS m/z(ESI)：548.2[M+H]⁺.

Example 100

N- (5-cyano-4- (((R) -1-methoxypropan-2-yl) amino) pyridin-2-yl) -7-formyl-6- (((S) -N-methyltetrahydrofuran-3-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((R) -1-methoxypropan-2-yl) amino) pyridin-2-yl) -7-formyl-6- (((S) -N-methyltetrahydrofuran-3-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure was as in example 1.

MS m/z(ESI)：536.2[M+H]⁺.

Example 101

N- (5-cyano-4- (((R) -1-methoxypropan-2-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-3-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((R) -1-methoxypropan-2-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-3-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure was as in example 1.

MS m/z(ESI)：536.2[M+H]+.

Example 102

N- (5-cyano-4- (((S) -tetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((S) -N-methyltetrahydrofuran-3-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((S) -tetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((S) -N-methyltetrahydrofuran-3-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure is as in example 1.

MS m/z(ESI)：534.2[M+H]+.

Example 103

N- (5-cyano-4- (((R) -tetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((S) -N-methyltetrahydrofuran-3-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((R) -tetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((S) -N-methyltetrahydrofuran-3-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure is as in example 1.

MS m/z(ESI)：534.2[M+H]+.

Example 104

N- (5-cyano-4- (((S) -tetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-3-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((S) -tetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-3-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 1.

MS m/z(ESI)：534.2[M+H]+.

Example 105

N- (5-cyano-4- (((R) -tetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-3-carbacholamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((R) -tetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- (((R) -N-methyltetrahydrofuran-3-carbapimelamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide the procedure is as in example 1.

MS m/z(ESI)：534.2[M+H]+.

Example 106

(S) -N- (5-cyano-4- (3-methoxypyrrolidin-1-yl) pyridin-2-yl) -7-formyl-6- ((2-methoxy-N-methylacetamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of (S) -N- (5-cyano-4- (3-methoxypyrrolidin-1-yl) pyridin-2-yl) -7-formyl-6- ((2-methoxy-N-methylacetamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 1.

¹H NMR(400MHz，CDCl₃)δ13.54-13.40(m，1H)，10.26-10.22(m，1H)，8.20(s，1H)，7.63-7.40(m，2H)，5.08-4.96(m，2H)，4.18(s，1H)，4.11-4.05(m，4H)，3.84-3.77(m，4H)，3.49(s，2H)，3.39-3.35(m，4H)，3.01-2.96(m，3H)，2.95-2.87(m，2H)，2.26-2.19(m，1H)，2.08-1.99(m，3H)；

MS m/z(ESI)：522.2[M+H]⁺.

Example 107

(R) -N- (5-cyano-4- (3-methoxypyrrolidin-1-yl) pyridin-2-yl) -7-formyl-6- ((2-methoxy-N-methylacetamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of (R) -N- (5-cyano-4- (3-methoxypyrrolidin-1-yl) pyridin-2-yl) -7-formyl-6- ((2-methoxy-N-methylacetamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 1.

¹H NMR(400MHz，CDCl₃)δ13.54-13.40(m，1H)，10.26-10.22(m，1H)，8.20(s，1H)，7.63-7.40(m，2H)，5.08-4.96(m，2H)，4.18(s，1H)，4.11-4.05(m，4H)，3.84-3.77(m，4H)，3.49(s，2H)，3.39-3.35(m，4H)，3.01-2.96(m，3H)，2.95-2.87(m，2H)，2.25-2.19(m，1H)，2.08-1.99(m，3H)；

MS m/z(ESI)：522.2[M+H]⁺.

Example 108

N- (5-cyano-4- (((trans) -4-methoxytetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- ((2-methoxy-N-methylacetamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of N- (5-cyano-4- (((trans) -4-methoxytetrahydrofuran-3-yl) amino) pyridin-2-yl) -7-formyl-6- ((2-methoxy-N-methylacetamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 1.

¹H NMR(400MHz，CDCl₃)δ13.70-13.56(m，1H)，10.26-10.22(m，1H)，8.21(s，1H)，7.77(s，1H)，7.63-7.41(m，1H)，5.07(d，J＝2.6Hz，1H)，5.03-4.96(m，2H)，4.19-4.07(m，7H)，3.92-3.89(m，1H)，3.86-3.81(m，2H)，3.55-3.53(m，3H)，3.49(s，2H)，3.36(s，1H)，3.02-2.97(m，3H)，2.95-2.89(m，2H)，2.08-2.00(m，2H)；

MS m/z(ESI)：538.2[M+H]⁺.

Example 109

(R) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N- ((tetrahydrofuran-2-yl) methyl) acetamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

The first step is as follows: preparation of (R) -1- (2- (dimethoxymethyl) -5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-3-yl) -N- ((tetrahydrofuran-2-yl) methyl) methylamine

In a 100mL single neck flask 2- (dimethoxymethyl) -5, 6, 7, 8-tetrahydro-1, 8-naphthyridine-3-carbaldehyde (1.0g, 4.2mmol) and (R) - (tetrahydrofuran-2-yl) methylamine (0.6g, 5.9mmol) were dissolved in methanol (35mL), and sodium cyanoborohydride (0.68g, 10.8mmol) was added and stirred at room temperature overnight. LC-MS monitored complete conversion of starting material, stopped reaction, concentrated under reduced pressure and chromatographed to give (R) -1- (2- (dimethoxymethyl) -5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-3-yl) -N- ((tetrahydrofuran-2-yl) methyl) methylamine (0.75g, 55%).

MS m/z(ESI)：322.0[M+H]⁺.

The second step is that: preparation of (R) -N- ((2- (dimethoxymethyl) -5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-3-yl) methyl) -N- ((tetrahydrofuran-2-yl) methyl) acetamide

(R) -N- ((2- (dimethoxymethyl) -5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-3-yl) methyl) -N- ((tetrahydrofuran-2-yl) methyl) acetamide (150mg, 0.47mmol) was dissolved in dichloromethane (15mL) in a 100mL single-necked flask, and acetic anhydride (57mg, 0.56mmol) and DIPEA (0.3mL) were added and stirred at room temperature overnight. The reaction was stopped, water (50mL) was added to quench the reaction, extraction was performed with ethyl acetate (50mL × 2), the combined organic phases were washed with saturated sodium chloride (50mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and subjected to column chromatography to give (R) -N- ((2- (dimethoxymethyl) -5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-3-yl) methyl) -N- ((tetrahydrofuran-2-yl) methyl) acetamide (90mg, 53%).

MS m/z(ESI)：364.2[M+H]⁺.

The third step: preparation of (R) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N- ((tetrahydrofuran-2-yl) methyl) acetamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

6-amino-4- ((2-methoxyethyl) amino) nicotinonitrile (90mg, 0.47mmol) was dissolved in anhydrous DMF (1mL) in a 100mL single-necked flask, cooled to 0 ℃ with an ice bath and bis (1H-1, 2, 4-triazol-1-yl) methanone (80mg, 0.48mol) was dissolved in DMF (1mL) and added dropwise to the solution after 10 minutes, stirring was continued at 0 ℃ for 45 minutes and then at room temperature for 90 minutes, and (R) -N- ((2- (dimethoxymethyl) -5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-3-yl) methyl) -N- ((tetrahydrofuran-2-yl) methyl) acetamide (70mg, 0.19mmol) was dissolved in DMF (1.5mL) and added to the reaction, stir at room temperature overnight. The reaction was stopped, quenched by the addition of water (40mL), extracted with ethyl acetate (40mL × 2), the combined organic phases washed with saturated sodium chloride (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give (R) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N- ((tetrahydrofuran-2-yl) methyl) acetylamino) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide (32mg, 31%).

MS m/z(ESI)：582.2[M+H]⁺.

The fourth step: preparation of (R) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N- ((tetrahydrofuran-2-yl) methyl) acetamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

(R) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N- ((tetrahydrofuran-2-yl) methyl) acetamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide (36.0mg, 0.06mmol) was dissolved in tetrahydrofuran (5mL) in a 100mL single vial, 4mol/L hydrochloric acid (1.5mL) was added and stirred at room temperature for 4H. The reaction was stopped, saturated sodium bicarbonate solution (30mL) was added, extraction was performed with ethyl acetate (30mL × 2), the combined organic phases were washed with saturated sodium chloride (30mL), dried over anhydrous sodium sulfate, filtered, concentrated and separated with preparative thin layer to give (R) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N- ((tetrahydrofuran-2-yl) methyl) acetylamino) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide (26.0mg, 78%).

¹H NMR(400MHz，CDCl₃)δ13.55(d，J＝34.0Hz，1H)，10.25(d，J＝34.0Hz，1H)，8.18(d，J＝2.8Hz，1H)，7.58(t，2H)，5.33(s，1H)，5.17-5.00(m，2H)，4.14-4.04(m，3H)，3.88-3.62(m，4H)，3.51-3.43(m，3H)，3.41(s，3H)，3.25(m，1H)，3.93(m，2H)，2.25(s，2H)，2.05(m，4H)，1.97(m，2H)，1.47(m，1H)；

MS m/z(ESI)：536.2[M+H]⁺.

Example 110

(R) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N- ((tetrahydrofuran-2-yl) methyl) carboxamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of (R) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N- ((tetrahydrofuran-2-yl) methyl) carboxamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 109.

¹H NMR(400MHz，CDCl₃)δ13.61-13.52(m，1H)，10.24(s，1H)，8.28(s，1H)，8.18(s，1H)，7.66-7.59(m，2H)，5.32(s，1H)，5.14-5.00(m，2H)，4.11-3.62(m，7H)，3.51-3.47(m，2H)，3.41(s，3H)，3.28-3.23(m，2H)，2.96-2.83(m，2H)，2.06-1.95(m，5H)，1.57-1.41(m，1H)；

MS m/z(ESI)：522.2[M+H]⁺.

Example 111

(S) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N- ((tetrahydrofuran-2-yl) methyl) acetamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of (S) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N- ((tetrahydrofuran-2-yl) methyl) acetamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference example 109.

¹H NMR(400MHz，CDCl₃)δ13.65-13.5(m，1H)，10.25(d，J＝34.0Hz，1H)，8.18(d，J＝2.8Hz，1H)，7.65-7.46(m，2H)，5.33(s，1H)，5.17-5.00(m，2H)，4.14-4.04(m，3H)，3.88-3.62(m，4H)，3.51-3.43(m，3H)，3.41(s，3H)，3.29-3.25(m，1H)，2.95-2.89(m，2H)，2.25(s，2H)，2.07-1.99(m，4H)，1.95-1.85(m，2H)，1.53-1.43(m，1H)；

MS m/z(ESI)：536.2[M+H]⁺.

Example 112

(S) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N- ((tetrahydrofuran-2-yl) methyl) carboxamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of (S) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N- ((tetrahydrofuran-2-yl) methyl) carboxamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 109.

¹H NMR(400MHz，CDCl₃)δ13.60-13.52(m，1H)，10.24(s，1H)，8.28(s，1H)，8.18(s，1H)，7.66-7.50(m，2H)，5.32(s，1H)，5.14-5.00(m，2H)，4.11-3.62(m，7H)，3.51-3.47(m，2H)，3.41(s，3H)，3.30-3.25(m，2H)，2.96-2.89(m，2H)，2.06-1.95(m，5H)，1.53-1.43(m，1H)；

MS m/z(ESI)：522.2[M+H]⁺.

Example 113

(R) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N- (tetrahydrofuran-3-yl) acetylamino) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of (R) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N- (tetrahydrofuran-3-yl) acetylamino) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 109.

¹H NMR(400MHz，DMSO-d₆)：δ13.57-13.45(m，1H)，10.28(s，1H)，8.22(s，1H)，7.57(s，1H)，7.46(s，1H)，6.84(s，1H)，5.32(m，2H)，4.95(m，2H)，4.09(m，2H)，3.95(m，1H)，3.60-3.78(m，4H)，3.57(m，2H)，3.07(s，3H)，2.93(m，2H)，2.35(s，3H)，2.04(m，2H)，1.70(m，2H)；

MS m/z(ESI)：522.2[M+H]⁺.

Example 114

(S) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N- (tetrahydrofuran-3-yl) carboxamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide

Preparation of (S) -N- (5-cyano-4- ((2-methoxyethyl) amino) pyridin-2-yl) -7-formyl-6- ((N- (tetrahydrofuran-3-yl) carboxamido) methyl) -3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxamide reference is made to example 109.

¹H NMR(400MHz，DMSO-d₆)：δ13.57-13.46(m，1H)，10.27(s，1H)，8.43(s，1H)，8.19(s，1H)，7.60(s，1H)，7.52(s，1H)，5.40(s，1H)，5.05(s，2H)，4.33-4.28(m，2H)，4.11-4.06(m，2H)，4.02-3.92(m，1H)，3.60-3.75(m，6H)，3.52-3.49(m，2H)，3.42(s，3H)，2.96-2.89(m，2H)，2.08-2.01(m，2H)；

MS m/z(ESI)：508.2[M+H]⁺.

Biological test evaluation

FGFR4 enzymological assay

The experiment adopts a fluorescence resonance energy transfer (TR-FRET) method to test the inhibition effect of the compound on the activity of FGFR4 kinase, and obtains the half inhibition concentration IC of the compound on the activity of FGFR4 kinase₅₀。

1) Adding 1-5 uL FGFR4 enzyme solution into a 384-well plate, wherein the final enzyme concentration is 0.1-5 nM.

2) And adding 1-5 uL of the compound solution diluted in a gradient manner.

3) Adding 1-5 uL substrate mixed liquor containing 5-50 nM of substrate polypeptide and 10-200 uM of ATP final concentration.

4) And incubating for 0.5-3 hours at room temperature.

5) 10uL of EDTA and a detection solution containing a labeled antibody were added, and the mixture was incubated at room temperature for 1 hour.

6) The microplate reader measures the 665nm fluorescence signal value of each plate hole.

7) The inhibition rate was calculated from the fluorescence signal value.

8) Obtaining the IC of the compound by curve fitting according to the inhibition rates of different concentrations₅₀The enzymatic activities of the specific examples are shown in Table 1.

FGFR1 enzymological assay

The experiment adopts a fluorescence resonance energy transfer (TR-FRET) method to test the inhibition effect of the compound on the activity of FGFR1 kinase, and obtains the half inhibition concentration IC of the compound on the activity of FGFR1 kinase₅₀。

1) Adding 1-5 uL FGFR1 enzyme solution into a 384-well plate, wherein the final enzyme concentration is 0.1-5 nM.

2) And adding 1-5 uL of the compound solution diluted in a gradient manner.

4) And incubating for 0.5-3 hours at room temperature.

7) The inhibition rate was calculated from the fluorescence signal value.

Obtaining the IC of the compound by curve fitting according to the inhibition rates of different concentrations₅₀The enzymatic activities of the specific examples are shown in Table 1.

TABLE 1

From the enzymatic activity data of the compounds of the specific examples, the series of compounds have strong inhibition effect on the activity of FGFR4 kinase, but have almost no inhibition effect on the activity of FGFR1 kinase. Therefore, the compounds of the series of the invention have very high selectivity on the activity of FGFR4 kinase.

Hep 3B cell proliferation inhibition assay

The experiment adopts a CellTiter-Glo method to test the inhibition effect of the compound on the proliferation of Hep 3B cells and obtains the half inhibition concentration IC of the compound for inhibiting the cell proliferation activity₅₀。

1) Inoculating 50-100 uL of Hep 3B cell suspension into a 96-well cell culture plate, wherein the density is 1-5 multiplied by 10⁴cells/mL, the plates were incubated in an incubator for 16-24 hours (37 ℃ C., 5% CO)₂)。

2) Adding gradient diluted test compound solutions with different concentrations into cells of the culture plate, and culturing the culture plateIncubate in incubator for 72 hours (37 ℃, 5% CO)₂)。

3) And adding 50-100 uL CellTiter-Glo reagent into each hole, and oscillating or standing for 5-30 minutes at room temperature.

4) The microplate reader measures the chemiluminescence signal value of each plate.

5) The inhibition rate was calculated from the chemiluminescence signal value.

6) Obtaining the IC of the compound by curve fitting according to the inhibition rates of different concentrations₅₀The cell activities of the specific examples are shown in Table 2.

HuH-7 cell proliferation inhibition assay

The experiment adopts the CellTiter-Glo method to test the inhibition effect of the compound on HuH-7 cell proliferation, and obtains the half inhibition concentration IC of the compound for inhibiting the cell proliferation activity₅₀。

1) Inoculating 50-100 uL of HuH-7 cell suspension into a 96-well cell culture plate, wherein the density is 1-5 multiplied by 10⁴cells/mL, the plates were incubated in an incubator for 16-24 hours (37 ℃ C., 5% CO)₂)。

2) To the cells of the plate, solutions of the test compounds at different concentrations were added in a gradient and the plate was incubated in an incubator for 72 hours (37 ℃ C., 5% CO)₂)。

5) The inhibition rate was calculated from the chemiluminescence signal value.

SK-HEP-1 cell proliferation inhibition assay

The experiment adopts the CellTiter-Glo method to test the inhibition effect of the compound on SK-HEP-1 cell proliferation, and obtains the half inhibition concentration IC of the compound for inhibiting the cell proliferation activity₅₀。

1) Inoculating 50-100 uL SK-HEP-1 cell suspension in a 96-hole cell culture plate, wherein the density is 1-5 multiplied by 10⁴cells/mL, the plates were incubated in an incubator for 16-24 hours (37 ℃ C., 5% CO)₂)。

5) The inhibition rate was calculated from the chemiluminescence signal value.

Obtaining the IC of the compound by curve fitting according to the inhibition rates of different concentrations₅₀The cell activities of the specific examples are shown in Table 2.

TABLE 2

From the cell activity data of the compounds of specific examples, the series of compounds have strong inhibition effect on the cell proliferation activity of Hep 3B and HuH-7 with high expression of FGF19 and FGFR4, have no inhibition effect on the cell proliferation of SK-HEP-1 with low expression of FGF19 and FGFR4, and show good cell activity and selectivity.

6. PK analysis in rats

The rat pharmacokinetic experiments of the preferred embodiment of the present invention were performed using SD rats (shanghai jestie laboratory animals ltd).

The administration mode comprises the following steps: single administration by intragastric administration.

Administration dose: 5 mg/10 ml/kg.

The preparation prescription is as follows: 0.5% CMC and 1% Tween 80, sonicated.

Sampling points are as follows: 0.5, 1, 2, 4, 6, 8 and 24 hours after administration.

Sample treatment:

1. collecting 1.0mL of blood by vein, placing the blood in a K2EDTA test tube, centrifuging at 1000-3000 Xg for 5-20 min at room temperature to separate blood plasma, and storing at-80 ℃.

2. Adding 160uL acetonitrile into 40uL of the plasma sample for precipitation, mixing, and then centrifuging for 5-20 minutes at 500-2000 Xg.

3. Taking 100uL of the treated solution for LC/MS/MS analysis to analyze the concentration of the compound to be detected, and an LC/MS/MS analysis instrument: AB Sciex API 4000.

Liquid phase analysis:

liquid phase conditions: shimadzu LC-20AD pump

A chromatographic column: phenomenex Gemiu 5um C1850 x 4.6mm

Mobile phase: the solution A is 0.1% formic acid water solution, and the solution B is acetonitrile

Flow rate: 0.8mL/min

Elution time: 0-3.5 min, the eluent is as follows:

time/minute	Solution A	Liquid B
			0.01	80％	20％
0.5	80％	20％
			1.2	10％	90％
2.6	10％	90％
			2.7	80％	20％
3.8	80％	20％

Mass spectrometry analysis:

the mass spectrometer setting conditions are as follows: positive ion electrospray ionization (ESI) mode.

The main parameters were calculated by WinNonlin 6.1, and the results of the rat pharmacokinetic experiments are shown in Table 3 below

TABLE 3

As can be seen from the results of the rat pharmacokinetic experiments in the table: the compounds of the examples of the invention show good metabolic properties, exposure AUC and maximum blood concentration C_maxAll performed well.

FGFR4 pharmacodynamic test procedure and test results

7.1 reagents and materials

The Hep 3B2.1-7 cell line was from the cell bank of Chinese academy of sciences, MEM cell culture medium, fetal bovine serum, trypsin were purchased from Life Technologies, cell culture flasks were purchased from Corning, disposable cell counting plates were purchased from Eppendorf, and Trypan blue solution was purchased from Sigma. Disposable sterile syringes were purchased from the national pharmacy group, disposable mouse gavage needles from fucchigai corporation, and ophthalmic surgical scissors and forceps from the national pharmacy group. BALB/cA-nude mice, 5-7 weeks old, purchased from Shanghai Spirol-bikai laboratory animals, Inc.

7.2 cell culture and cell suspension preparation

a, taking a Hep 3B cell from a cell bank, using MEM (MEM + 10% FBS + 1% Glu + 1% SP) to recover the cell, placing the recovered cell in a cell culture flask (marking the cell type, date, name of cultured person and the like on the flask wall) and placing in CO₂Culturing in incubator (incubator temperature 37 deg.C, CO)₂Concentration 5%).

b, after the cells are paved at 80-90% of the bottom of the culture flask, carrying out passage, and continuously placing the cells in CO after passage₂Culturing in an incubator. This process is repeated until the number of cells meets the in vivo pharmacodynamic requirements.

c, collecting cultured cells, counting by using a full-automatic cell counting instrument, and re-suspending the cells by using PBS according to the counting result to prepare cell suspension (the density is 7 multiplied by 10)⁷mL), and placing in an ice box for standby.

7.3 cell inoculation, quantification of tumors:

1. cells were mixed well before inoculation, 0.5mL of cell suspension was withdrawn with a 1mL syringe, air bubbles were removed, and the syringe was placed on an ice bag for use.

2. The nude mice were left-handed, the right dorsal skin of the nude mice was disinfected with 75% alcohol, and the inoculation was started 30 seconds later.

3. When in inoculation, a 1mL syringe is held by the right hand, and 0.1mL cell suspension is subcutaneously inoculated at the position close to the right shoulder on the back of the right side of the nude mouse; at the inoculation gap, the syringe was placed on an ice bag. Test nude mice were sequentially inoculated.

4. Tumors were measured on days 14-16 after inoculation and tumor size was calculated, depending on tumor growth.

Calculating the tumor volume: tumor volume (mm)³) Length (mm) × width (mm)/2

5. Grouping is performed by a random grouping method according to the size of the tumor.

6. Tumors were dosed and weighed twice a week after the start of treatment drug administration.

7. The data were processed with software such as Excel.

7.4 administration:

1. the nude mice are numbered and weighed by the core before administration, a 1mL syringe is taken out, the needle head is removed, a No. 8 mouse gastric lavage needle is replaced, and then the drugs with corresponding volume are extracted and the air is removed for standby.

2. Left hand fixing the nude mouse, right hand holding the injector to lavage, and sequentially performing lavage on the test nude mouse.

3. The administration frequency is as follows: 2 times per day.

Vehicle: 0.5% CMC/1% Tween 80.

7.5 test results are shown in Table 4 below

TABLE 4

7.6 results

From the above results, it can be seen that the tumor inhibition rate of the above examples is significant, and some of the compounds of the examples can reduce the size of the tumor and even eliminate the tumor within a certain period of time.

Claims

1. A compound of formula (III-a), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

g is selected from NH, O or S;

R_cand R_dEach independently selected from hydrogen, C_1-8Alkyl radical, C_1-8Alkoxy or halogen;

R₁₆is C_1-8An alkoxy group; and is

m is 1.

2. The compound of formula (III-a), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R is₁₆Selected from methoxy, ethoxy or isopropoxy.

3. The compound of formula (III-a), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein it is selected from the following compounds:

4. a process for the preparation of a compound of formula (III-a), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, comprising the steps of:

wherein: r₂Is composed of

R_c、R_d、R₁₆M is as defined in claim 1;

Pg₁、Pg₂is a hydroxyl protecting group.

5. The method according to claim 4, wherein Pg is₁、Pg₂Each independently selected from benzyl, 2-tetrahydrofuryl, methoxymethyl, ethoxyethyl, C_1-8Alkyl, allyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butylDimethylsilyl or tert-butyldiphenylsilyl, or, Pg₁、Pg₂Together are selected from ethylene or propylene.

6. The method according to claim 5, wherein Pg is₁、Pg₂Each independently selected from methyl, ethyl or benzyl, or, Pg₁、Pg₂Are collectively selected from ethylene.

7. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (III-a), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 3, in association with a pharmaceutically acceptable carrier.

8. Use of a compound of formula (III-a), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3, or a pharmaceutical composition as claimed in claim 7, in the manufacture of a medicament for an FGFR4 inhibitor.

9. Use of a compound of formula (III-a), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, or a pharmaceutical composition according to claim 7, for the manufacture of a medicament for the treatment of cancer.

10. The use of claim 9, wherein the cancer is liver cancer, stomach cancer, prostate cancer, skin cancer, ovarian cancer, lung cancer, breast cancer, colon cancer, glioma or rhabdomyosarcoma.