CN115362155A

CN115362155A - Arylamine derivatives, and preparation method and medical application thereof

Info

Publication number: CN115362155A
Application number: CN202180025028.9A
Authority: CN
Inventors: 殷惠军; 闫旭; 田卫学; 陈士柱
Original assignee: National Institutes of Pharmaceutical R&D Co Ltd
Current assignee: National Institutes of Pharmaceutical R&D Co Ltd
Priority date: 2020-07-22
Filing date: 2021-07-21
Publication date: 2022-11-18
Also published as: WO2022017408A1

Abstract

Relates to arylamine derivatives, a preparation method and medical application thereof. In particular to a compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and the application of the compound as a Toll-like receptor (TLR) agonist in treating diseases related to TLR8 activityThe use of (1). Wherein the definition of each substituent in the general formula (I) is the same as that in the specification.

Description

Arylamine derivative and preparation method and medical application thereof

Technical Field

The invention relates to arylamine derivatives, a preparation method and medical application thereof. In particular, the invention relates to a compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and an application of the compound serving as a Toll-like receptor (TLR) agonist in treating diseases related to TLR8 activity.

Background

Toll-like receptors (TLRs) are a class of pattern recognition receptors that recognize and respond to microorganisms. Members of the TLRs family play an important role in the immune system, are important elements involved in innate immunity and are also bridges connecting innate immunity and specific immunity. The receptor can specifically recognize the microorganism and initiate an immune response.

TLRs are all type I transmembrane glycoproteins, composed of an extracellular domain rich in 16-28 leucine repeats (LRR), a transmembrane domain, and a cytoplasmic Toll/IL-1 receptor (TIR) domain. X-ray crystallography analysis determined that TLR LRR domains are horseshoe-like structures. To date, 11 members have been found in humans, with TLRs 1,2, 4,5, 6, 10 and 11 located on the cell surface and TLRs 3, 7,8, 9 located on the intracellular membrane. TLR8 and TLR7 are phylogenetically close to each other and have high sequence homology and are located on adjacent X chromosomes (Xp 22). Upon binding of the LRR of TLRs to the ligand, the TIR domain conformation changes, which in turn triggers activation of the TLR signaling pathway. The TIR domain of TLRs can recruit a variety of signaling molecules, including tumor necrosis factor receptor-related factor 6 and myeloid differentiation factor 88 (MyD 88), among others. Wherein TLR8 relies on a MyD88 signal path to induce and activate the transfer of protease-1 (AP-1) and nuclear factor kappa B (NF-kappa B) into the nucleus, and to induce the expression of related genes in the nucleus, secrete chemotactic factors, inflammatory factors and the like, thereby playing a role in transcriptional regulation. In addition, TLR8 can also activate mitogen-activated protein kinase (MAPK) signaling pathways, including p38, ERK, JNK, and the like, and are mainly involved in regulation of cell proliferation, cell differentiation, cell transformation, apoptosis, and the like, and are closely related to various diseases such as inflammation and tumor (journal of immunology, 2017, 33, 813).

Hepatitis B Virus (HBV) is a granular double-stranded DNA virus. Activation of TLR8 can effectively inhibit replication of hepatitis B virus in vivo and in vitro, thus becoming a target for developing and treating chronic hepatitis B virus. Research finds that the TLR8 agonist ssRNA40 can selectively activate the congenital immune cells around the liver to generate a large amount of IFN-gamma so as to inhibit the replication of hepatitis B virus, so that the application of the SSRNA in the treatment of hepatitis virus infection is potential. Inhibition of HBV replication by stimulation of PBMCs with a TLR8 agonist and by induction of high levels of IFN- γ and TNF- α productionCurrent Opinion in Virology，2018，30，9)。

TLRs not only are expressed on immune cells, but also can be expressed in various tumor cells, participate in tumor immune surveillance, and play different roles in tumor growth. Wherein TLR8 is activated to enhance the activity of natural killer cells (NK cells), improve the antibody dependent cell mediated cytotoxicity (ADCC) and induce Th1 polarization. TLR8 agonists are potential adjuvants in cancer therapy with the aim of inducing a specific immune response against tumour cells, improving the clinical efficacy of approved monoclonal antibody therapy, especially in individuals with reduced ADCC.

In view of the important potential of TLR-8 agonists in treating various diseases, the clinical application of the novel TLR-8 agonists with strong activity and high selectivity has urgent need.

Disclosure of Invention

The inventor designs and synthesizes a series of arylamine compounds through intensive research, the arylamine compounds show excellent TLR8 agonistic activity, and can be developed into medicaments for treating diseases related to TLR8.

Accordingly, it is an object of the present invention to provide a compound of the general formula (I) or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein, the first and the second end of the pipe are connected with each other,

x is a C atom or a N atom;

ring a is cycloalkyl, heterocycle, aromatic ring or heteroaromatic ring;

l is selected from a bond, - (CH) ₂ ) _t -、-C(O)(CH ₂ ) _t -or- (CH) ₂ ) _t C(O)-；

Each R is independently selected from hydrogen, halogen, cyano, oxo, alkyl, alkenyl, alkynyl, -OR ^a 、-SR ^a 、-NR ^a R ^b Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted with one or more Q groups;

R ⁴ selected from the group consisting of hydrogen, halogen, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b (ii) a Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ⁵ and R ⁶ Each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ^a R ^b 、-C(O)R ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-S(O) _n R ^a and-S (O) _n NR ^a R ^b (ii) a Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further selected from the group consisting of halogen, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b Substituted with one or more groups of (a);

or, R ⁵ And R ⁶ Together with the nitrogen atom to which it is attached, form a nitrogen-containing heterocycle optionally further containing one OR more heteroatoms selected from N, O, S, in addition to N, said nitrogen-containing heterocycle optionally further selected from halogen, nitro, cyano, oxo, alkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b Substituted with one or more groups of (a);

or, R ⁴ And R ⁵ Or R ⁶ Together with the atoms to which they are attached form a nitrogen-containing heterocycle optionally further containing one OR more heteroatoms selected from N, O, S in addition to N, said nitrogen-containing heterocycle optionally further selected from halogen, nitro, cyano, oxo, alkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b Substituted with one or more groups of (a);

q is selected from the group consisting of halogen, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、-SR ^a 、-(CH ₂ ) _v -NR ^a R ^b 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b Wherein the alkyl and alkenyl groupsAlkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^a and R ^b Each independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, are optionally further substituted with one or more groups selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

or R ^a And R ^b Together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group optionally further containing one or more heteroatoms selected from N, O, S in addition to N, said nitrogen-containing heterocyclic group optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl;

m is 0,1, 2,3 or 4;

n is 1 or 2;

v is 1 or 2;

t is 0,1, 2,3,4, 5 or 6.

In a preferred embodiment, the compound of general formula (I) according to the present invention or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: l is selected from a bond or-C (O) -; preferably a bond.

In another preferred embodiment, the compound of formula (I) according to the invention, in the form of its stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (II), in the form of its stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof,

x is a C atom or a N atom;

ring a is cycloalkyl, heterocycle, aromatic ring or heteroaromatic ring;

R ⁴ selected from hydrogen, halogen, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b (ii) a Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ⁵ and R ⁶ Each independently selected fromHydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ^a R ^b 、-C(O)R ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-S(O) _n R ^a and-S (O) _n NR ^a R ^b (ii) a Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further selected from the group consisting of halogen, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b Substituted with one or more groups of (a);

or, R ⁵ And R ⁶ Together with the nitrogen atom to which it is attached, form a nitrogen-containing heterocycle optionally further containing one OR more heteroatoms selected from N, O, S in addition to N, said nitrogen-containing heterocycle optionally further selected from halogen, nitro, cyano, oxo, alkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b Substituted with one or more groups of (a);

or, R ⁴ And R ⁵ Or R ⁶ Together with the atoms to which they are attached formA nitrogen-containing heterocycle optionally further containing one OR more heteroatoms selected from N, O, S in addition to N, said nitrogen-containing heterocycle optionally further selected from halogen, nitro, cyano, oxo, alkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b Substituted with one or more groups;

q is selected from the group consisting of halogen, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、-SR ^a 、-(CH ₂ ) _v -NR ^a R ^b 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ^a and R ^b Each independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further selected from the group consisting ofSubstituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

or R ^a And R ^b Together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group optionally further containing one or more heteroatoms selected from N, O, S, in addition to N, said nitrogen-containing heterocyclic group optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl;

m is 0,1, 2,3 or 4;

n is 1 or 2;

v is 1 or 2.

In another preferred embodiment, the compounds of the general formula (I) according to the invention or stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof,

wherein: ring a is a 5-to 7-membered heterocyclic ring, a benzene ring, or a 5-to 6-membered heteroaromatic ring.

In another preferred embodiment, the compound of formula (I) according to the present invention, which is a compound of formula (III) or a stereoisomer, a tautomer, a meso, a racemic, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, is in the form of a stereoisomer, a tautomer, a meso, a racemic, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

x is a C atom or a N atom;

y is a C atom or a N atom;

z is a C atom or a N atom;

s is 1 or 2;

each R is independently selected from hydrogen, halogen, oxo, C ₁ -C ₆ Alkyl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ Aryl and 5 to 10 membered heteroaryl, wherein said C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ Aryl, 5-to 10-membered heteroaryl optionally further substituted with one or more Q groups;

q is selected from the group consisting of halogen, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) ₂ ) _v -NR ^a R ^b 、-C(O)R ^a Wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

or R ^a And R ^b Together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group optionally further containing one or more heteroatoms selected from N, O, S in addition to N, said nitrogen-containing heterocyclic groupThe nitrogen heterocycle is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

v is 0,1 or 2;

R ⁴ 、R ⁵ 、R ⁶ m is as defined in formula (I).

wherein:

each R is independently selected from hydrogen, halogen, oxo, C ₁ -C ₆ Alkyl radical, C ₆ -C ₁₀ Aryl and 5 to 10 membered heteroaryl, wherein said alkyl, aryl, heteroaryl are optionally further substituted by one or more Q groups;

q is selected from the group consisting of halogen, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted with one or more groups selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl.

In another preferred embodiment, the compound of formula (I) according to the present invention, which is a compound of formula (IV) or a stereoisomer, a tautomer, a meso, a racemic, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, is in the form of a stereoisomer, a tautomer, a meso, a racemic, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

x is a C atom;

y is a C atom or a N atom;

R ¹ 、R ² 、R ³ each independently selected from hydrogen, halogen, C ₁ -C ₆ Alkyl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ Aryl and 5 to 10 membered heteroaryl, wherein said C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ Aryl, 5-to 10-membered heteroaryl optionally further substituted with one or more Q groups;

or, R ⁴ And R ⁵ Or R ⁶ Together with the atoms to which they are attached form a nitrogen-containing heterocycle optionally further containing, in addition to N, one or more members selected from the group consisting of N, O, SA heteroatom, said nitrogen-containing heterocycle optionally further selected from halogen, nitro, cyano, oxo, alkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b Substituted with one or more groups of (a);

R ^a and R ^b Each independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, heteroaryl, and mixtures thereof,Alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

n is 1 or 2;

v is 1 or 2.

wherein:

R ⁵ and R ⁶ Each independently selected from hydrogen and C ₁ -C ₁₂ Alkyl radical, said C ₁ -C ₁₂ The alkyl group is optionally further selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b Substituted with one or more groups of (a);

R ^a and R ^b Each independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkylThe group, heterocyclyl, aryl, heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

or R ^a And R ^b Together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group optionally containing, in addition to N, one or more heteroatoms selected from N, O, S, said nitrogen-containing heterocyclic group optionally being further substituted by one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl;

n is 1 or 2.

wherein:

R ⁵ and R ⁶ Each independently selected from hydrogen and C ₁ -C ₁₂ Alkyl radical, said C ₁ -C ₁₂ Alkyl is optionally further selected from-OR ^a 、-SR ^a 、-NR ^a R ^b 、-NR ^a C(O)R ^b and-NR ^a S(O) _n R ^b Substituted with one or more groups of (a);

R ^a selected from hydrogen, C ₁ -C ₆ An alkyl group;

R ^b selected from hydrogen, C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl and 5 to 7 membered heterocyclyl.

In another preferred embodiment, the compound of formula (I) according to the invention, in the form of its stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (V), in the form of its stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof,

wherein:

x is a C atom;

y is a C atom or a N atom;

ring E is a nitrogen-containing heterocyclic group, preferably a 3-to 12-membered heterocyclic group, more preferably a 5-to 10-membered heterocyclic group, further preferably a 5-to 7-membered heterocyclic group, most preferably a 6-membered heterocyclic group; the nitrogen-containing heterocycle optionally further contains one or more heteroatoms selected from N, O, S in addition to N;

R ⁷ selected from hydrogen, halogen, cyano, oxo, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Hydroxyalkyl, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₁₀ Cycloalkyl, 5-to 7-membered heterocyclyl, C ₅ -C ₁₀ Aryl, 5-to 10-membered heteroaryl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b (ii) a Preferably hydrogen, halogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ A hydroxyalkyl group;

R ¹ 、R ² 、R ³ each independently selected fromHydrogen, halogen, C ₁ -C ₆ Alkyl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ Aryl and 5 to 10 membered heteroaryl, wherein said C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ Aryl and 5-to 10-membered heteroaryl optionally further substituted with one or more Q groups;

R ⁴ selected from hydrogen, halogen, nitro, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b (ii) a Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further substituted with one or more groups selected from halo, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^a and R ^b Each independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, are optionally further substituted with one or more groups selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

n is 1 or 2;

p is 1,2,3 or 4;

v is 1 or 2.

In another preferred embodiment, the compounds of the general formula (V) according to the invention or stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof,

wherein:

R ⁷ selected from hydrogen, halogen, cyano, oxo, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Hydroxyalkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₁₀ Cycloalkyl, 5-to 7-membered heterocyclyl, C ₅ -C ₁₀ Aryl, 5-to 10-membered heteroaryl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b ；

p is 1 or 2.

wherein:

R ⁴ selected from hydrogen, halogen, nitro, cyano, oxo, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Hydroxyalkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₁₀ Cycloalkyl, 5-to 7-membered heterocyclyl, C ₅ -C ₁₀ Aryl, 5-to 10-membered heteroaryl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b (ii) a Wherein said C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Hydroxyalkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₁₀ Cycloalkyl, 5-to 7-membered heterocyclyl, C ₅ -C ₁₀ Aryl, 5-to 10-membered heteroaryl optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^a and R ^b Each independently selected from hydrogen and C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₁₀ Cycloalkyl, 5-to 7-membered heterocyclyl, C ₅ -C ₁₀ Aryl and 5 to 10 membered heteroaryl, wherein said C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₁₀ Cycloalkyl, 5-to 7-membered heterocyclyl, C ₅ -C ₁₀ Aryl, 5-to 10-membered heteroaryl optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

preferably, R ⁴ Selected from hydrogen, halogen, nitro, cyano, C ₁ -C ₆ Alkyl, -C (O) R ^a and-C (O) OR ^a (ii) a And R is ^a Is C ₁ -C ₆ An alkyl group.

In another preferred embodiment, the compound of formula (I) according to the invention, in the form of its stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (VI), in the form of its stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof,

wherein:

x is a C atom;

y is a C atom or a N atom;

ring G is a nitrogen-containing heterocyclic ring, preferably a 3-to 12-membered heterocyclic ring, more preferably a 5-to 10-membered heterocyclic ring, further preferably a 5-to 7-membered heterocyclic ring, most preferably a 7-membered heterocyclic ring; the nitrogen-containing heterocycle optionally further contains one or more heteroatoms selected from N, O, S in addition to N;

R ⁸ selected from the group consisting of hydrogen, halogen, nitro, cyano, oxo, alkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b (ii) a Preferably, R ⁸ Is selected from C ₁ -C ₆ Alkyl or oxo;

R ⁵ selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ^a R ^b 、-C(O)R ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-S(O) _n R ^a and-S (O) _n NR ^a R ^b ；

n is 1 or 2;

q is 1,2,3 or 4;

v is 1 or 2.

In another preferred embodiment, the compounds of the general formula (IV), (V), (VI) according to the invention or stereoisomers, tautomers, meso-isomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof,

wherein:

R ¹ and R ³ Is hydrogen;

R ² selected from hydrogen, halogen, hydroxy, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy radical, C ₃ -C ₆ Cycloalkyl, 5-6 membered heterocyclyl preferably pyrrolidinyl, piperidinyl, piperazinyl, hydropyridinyl, C ₆ -C ₁₀ Aryl is preferably phenyl, 5-to 10-membered heteroaryl is preferably pyridyl, pyrimidinyl, wherein said C ₁ -C ₆ Alkyl, 5-6 membered heterocyclic group, C ₆ -C ₁₀ Aryl, 5-to 10-membered heteroaryl optionally substituted with one or more Q groups;

q is as defined for formula (I).

In another preferred embodiment, the compounds of the general formula according to the invention or stereoisomers, tautomers, meso-isomers, racemates, enantiomers, diastereomers or mixtures thereof, or the pharmaceutically acceptable salts thereof,

wherein:

q is selected from halogen and C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, 4-to 6-membered heterocyclyl, C ₆ -C ₁₀ Aryl, 6-to 10-membered heteroaryl, -OR ^a 、-SR ^a 、-(CH ₂ ) _v -NR ^a R ^b 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b Wherein said C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, 4-to 6-membered heterocyclyl, C ₆ -C ₁₀ Aryl, 6-to 10-membered heteroaryl optionally further selected from halogen, hydroxy, mercapto, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy radical, C ₃ -C ₆ Cycloalkyl, 4-to 6-membered heterocyclyl, C ₆ -C ₁₀ Aryl and 6 to 10 heteroaryl;

preferably, Q is selected from C ₁ -C ₆ Alkyl, 4-to 6-membered heterocyclyl, 6-membered heteroaryl, - (CH) ₂ ) _v -NR ^a R ^b 、-NR ^a R ^b 、-C(O)R ^a Wherein said C ₁ -C ₆ Alkyl, 4 to 6 membered heterocyclyl is optionally further selected from C ₁ -C ₆ Alkyl, one or more groups of a 4-to 6-membered heterocyclyl;

R ^a and R ^b Each independently selected from hydrogen and C ₁ -C ₆ Alkyl, 4 to 6 membered heterocyclyl; or

R ^a And R ^b Together with the nitrogen atom to which they are attached form a 4-6 membered nitrogen containing heterocyclic group optionally further containing one or more heteroatoms selected from N, O, S in addition to N, said nitrogen containing heterocyclic group optionally further selected from C ₁ -C ₆ One or more groups of alkyl are substituted;

v is 1.

In another preferred embodiment, the compound of formula (I) according to the present invention, which is a compound of formula (VII) or a stereoisomer, a tautomer, a meso, a racemic, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

x is a C atom or a N atom;

y is a C atom or a N atom;

s is 1,2 or 3;

R、R ⁴ 、R ⁵ 、R ⁶ and m is as defined for formula (I).

wherein:

x is a C atom;

y is an N atom.

In another preferred embodiment, the compound of formula (I) according to the invention, in the form of its stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (VIII), in the form of its stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R ¹ 、R ² 、R ³ each independently selected from hydrogen, halogen, cyano, oxo, alkyl, alkenyl, alkynyl, -OR ^a 、-SR ^a 、-NR ^a R ^b Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted with one or more Q groups;

R ⁴ selected from the group consisting of hydrogen, halogen, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、-SR ^a 、-(CH ₂ ) _v -NR ^a R ^b 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b (ii) a Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further substituted with one or more groups selected from halo, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁵ and R ⁶ Each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ^a R ^b 、-C(O)R ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-S(O) _n R ^a and-S (O) _n NR ^a R ^b (ii) a Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further selected from the group consisting of halogen, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、 -S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b Substituted with one or more groups of (a);

or, R ⁵ And R ⁶ Together with the nitrogen atom to which it is attached, form a nitrogen-containing heterocycle optionally further containing one OR more heteroatoms selected from N, O, S in addition to N, the nitrogen-containing heterocycle optionally further selected from halogen, nitro, cyano, oxo, alkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b Substituted with one or more groups of (a);

q is selected from the group consisting of halogen, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

n is 1 or 2;

v is 1.

In another preferred embodiment, the compounds of the general formula (VIII) according to the invention or stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or the pharmaceutically acceptable salts thereof,

wherein:

R ^a and R ^b Each independently selected from hydrogen and C ₁ -C ₆ Alkyl radical, C ₃ -C ₁₀ Cycloalkyl and 5 to 7 membered heterocyclyl.

In another preferred embodiment, the compounds of the general formula (VIII) according to the invention or stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof,

wherein: r is ⁴ Selected from hydrogen, halogen, nitro, cyano, C ₁ -C ₆ Alkyl, -C (O) R ^a and-C (O) OR ^a (ii) a And R is ^a Is C ₁ -C ₆ An alkyl group.

wherein:

R ¹ and R ³ Is hydrogen;

R ² selected from hydrogen, halogen, oxo, C ₁ -C ₆ Alkyl radical、C ₆ -C ₁₀ Aryl and 6 to 10 membered heteroaryl, wherein said C ₁ -C ₆ Alkyl radical, C ₆ -C ₁₀ Aryl, 6-to 10-membered heteroaryl optionally further substituted with one or more groups selected from Q;

q is selected from halogen and C ₁ -C ₆ Alkyl radical, C ₃ -C ₁₀ Cycloalkyl, 5-to 7-membered heterocyclyl, C ₆ -C ₁₀ Aryl, 6-10 heteroaryl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b Wherein said C ₁ -C ₆ Alkyl radical, C ₃ -C ₁₀ Cycloalkyl, 5-to 7-membered heterocyclyl, C ₆ -C ₁₀ Aryl, 6 to 10 heteroaryl optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^a and R ^b Each independently selected from hydrogen and C ₁ -C ₆ An alkyl group;

preferably, R ² Selected from hydrogen, halogen and C ₁ -C ₆ An alkyl group.

Typical compounds of the invention include, but are not limited to:

or a racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

The present invention further provides a process for the preparation of a compound of formula (I) according to the present invention or a racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

(1) When R is ⁴ In the case of hydrogen, the acid is,

firstly, compound Ia and DMB-NH are reacted under alkaline condition ₂ Reacting to obtain a compound Ib, wherein N, N-diisopropylethylamine is preferably selected as the basic condition; then, hydrolyzing the compound Ib under alkaline conditions, preferably NaOH, to obtain a compound Ic; then, carrying out decarboxylation on the compound Ic under high temperature conditions to obtain a compound Id, wherein the high temperature conditions are preferably 160 ℃; finally, carrying out deprotection reaction under acidic condition to obtain the compound shown in the general formula (I), wherein trifluoroacetic acid is preferred;

(2) When R is ⁴ In the case of a halogen, the halogen is,

reacting the compound Ie with N-chlorosuccinimide or N-bromosuccinimide to obtain a compound of a general formula (I);

(3) When R is ⁴ When the group is an ester group, a cyano group or a nitro group,

firstly, compound If and DMB-NH are reacted under alkaline condition ₂ Reacting to obtain a compound Ig, wherein the basic condition is preferably N, N-diisopropylethylamine; then, carrying out deprotection reaction under an acidic condition to obtain a compound shown in a general formula (I), wherein trifluoroacetic acid is preferred;

(4) When R is ⁴ And R ⁵ When a nitrogen-containing heterocyclic ring is formed,

firstly, compound Ih is mixed with H-L-N (R) under alkaline condition ⁵ R ⁶ ) The reaction yields the compound Ia, preferably N, N-diisopropylethylamine under basic conditions; then, compound Ia and DMB-NH are reacted under alkaline condition ₂ Reacting to obtain a compound Ib, wherein N, N-diisopropylethylamine is preferably selected as the basic condition; finally, carrying out deprotection reaction under an acidic condition to obtain the compound shown in the general formula (I), wherein trifluoroacetic acid is preferred;

wherein the content of the first and second substances,

DMB is 2, 4-dimethoxy benzyl,

ring A, X, L, R ⁵ 、R ⁶ M is defined as formula (I).

The present invention further provides a process for the preparation of a compound of formula (II) according to the present invention or a racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

(1) When R is ⁴ In the case of hydrogen, the acid is,

firstly, compound IIa and DMB-NH are reacted under alkaline condition ₂ The compound IIb is obtained by reaction, and N, N-diisopropylethylamine is preferably selected as the basic condition; then, hydrolyzing the compound IIb under alkaline conditions, preferably NaOH, to obtain a compound IIc; then, carrying out decarboxylation reaction on the compound IIc under the high-temperature condition to obtain a compound IId, wherein the high-temperature condition is preferably 160 ℃; finally, deprotection reaction is carried out under acidic condition to obtain the general formula (II)) A compound, preferably trifluoroacetic acid;

(2) When R is ⁴ In the case of a halogen, the halogen is,

reacting the compound IIe with N-chlorosuccinimide or N-bromosuccinimide to obtain a compound of a general formula (II);

firstly, compound IIf and DMB-NH are reacted under alkaline condition ₂ The compound IIg is obtained by reaction, and N, N-diisopropylethylamine is preferably selected as the basic condition; then, carrying out deprotection reaction under an acidic condition to obtain a compound shown in a general formula (II), wherein trifluoroacetic acid is preferred;

firstly, compound IIh is reacted with H-L-N (R) under alkaline condition ⁵ R ⁶ ) Reacting to obtain a compound IIa, wherein the basic condition is preferably N, N-diisopropylethylamine; then, under alkaline conditions, compound IIa is reacted with DMB-NH ₂ The compound IIb is obtained by reaction, and N, N-diisopropylethylamine is preferably selected as the basic condition; finally, carrying out deprotection reaction under an acidic condition to obtain the compound shown in the general formula (II), wherein trifluoroacetic acid is preferred;

DMB is 2, 4-dimethoxy benzyl,

ring A, X, R ⁵ 、R ⁶ M is as defined in formula (II).

The present invention further provides a process for the preparation of a compound of formula (III) according to the invention or a racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

(1) When R is ⁴ In the case of hydrogen, the acid is,

firstly, compound IIIa is reacted with DMB-NH under alkaline condition ₂ The compound IIIb is obtained through reaction, and the basic condition is preferably N, N-diisopropylethylamine; then, hydrolyzing the compound IIIb under alkaline conditions, preferably NaOH, to obtain a compound IIIc; then, carrying out decarboxylation on the compound IIIc under a high-temperature condition to obtain a compound IIId, wherein the high-temperature condition is preferably 160 ℃; finally, carrying out deprotection reaction under an acidic condition to obtain the compound shown in the general formula (III), wherein trifluoroacetic acid is preferred;

(2) When R is ⁴ In the case of a halogen, the halogen is,

reacting the compound IIIe with N-chlorosuccinimide or N-bromosuccinimide to obtain a compound in a general formula (III);

first of all, the first step is to,under the alkaline condition, the compound IIIf is mixed with DMB-NH ₂ The compound IIIg is obtained by reaction, and the basic condition is preferably N, N-diisopropylethylamine; then, carrying out deprotection reaction under an acidic condition to obtain a compound shown in a general formula (III), wherein trifluoroacetic acid is preferred;

firstly, compound IIIh is reacted with HN (R) under alkaline condition ⁵ R ⁶ ) The compound IIIa is obtained by reaction, and the basic condition is preferably N, N-diisopropylethylamine; then, compound IIIa is reacted with DMB-NH under alkaline condition ₂ Reacting to obtain a compound IIIb, wherein the basic condition is preferably N, N-diisopropylethylamine; finally, carrying out deprotection reaction under acidic condition to obtain the compound shown in the general formula (III), wherein trifluoroacetic acid is preferred;

DMB is 2, 4-dimethoxy benzyl,

X、Y、Z、R、R ⁵ 、R ⁶ m and s are as defined in formula (III).

The present invention further provides a method for preparing the compound represented by the general formula (IV) according to the present invention, or a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

(1) When R is ⁴ In the case of hydrogen, the acid is,

firstly, compound IVa and DMB-NH are reacted under alkaline condition ₂ Reacting to obtain compound IVb, the alkaline stripN, N-diisopropylethylamine is preferably used; then, hydrolyzing the compound IVb under alkaline conditions, preferably NaOH, to obtain a compound IVc; then, carrying out decarboxylation on the compound IVc under high temperature conditions to obtain a compound IVd, wherein the high temperature conditions are preferably 160 ℃; finally, carrying out deprotection reaction under acidic condition to obtain the compound shown in the general formula (IV), wherein trifluoroacetic acid is preferred;

(2) When R is ⁴ In the case of a halogen, the halogen is,

reacting the compound IVe with N-chlorosuccinimide or N-bromosuccinimide to obtain a compound with a general formula (IV);

firstly, under alkaline condition, the compound IVf and DMB-NH are mixed ₂ Reacting to obtain a compound IVg, wherein the basic condition is preferably N, N-diisopropylethylamine; then, carrying out deprotection reaction under an acidic condition to obtain a compound shown in a general formula (IV), wherein trifluoroacetic acid is preferred;

firstly, compound IVh is reacted with HN (R) under basic conditions ⁵ R ⁶ ) The compound IVa is obtained through reaction, and the basic condition is preferably N, N-diisopropylethylamine; then, under alkaline conditions, the compound IVa is reacted with DMB-NH ₂ Reacting to obtain a compound IVb, wherein the basic condition is preferably N, N-diisopropylethylamine; finally, carrying out deprotection reaction under acidic conditions to obtain the compound shown in the general formula (IV), wherein trifluoroacetic acid is preferred;

wherein the content of the first and second substances,

DMB is 2, 4-dimethoxy benzyl,

X、Y、R ¹ 、R ² 、R ³ 、R ⁵ 、R ⁶ as defined by general formula (IV).

The invention further provides a pharmaceutical composition, which comprises the compound shown in the general formula (I) or the raceme, enantiomer, diastereoisomer or mixture form thereof, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

The invention further relates to application of the compound shown in the general formula (I) or raceme, enantiomer, diastereoisomer or mixture form thereof, or pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same in preparation of the TLR8 agonist.

The invention further relates to application of the compound shown in the general formula (I) or racemate, enantiomer, diastereomer or mixture form thereof, or pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same in preparation of a medicament for preventing or treating TLR 8-related diseases, wherein the diseases can be viral infectious diseases such as viral hepatitis B and HIV virus infection or malignant tumors such as breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostatic cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, melanoma, solid tumor, glioma, glioblastoma, hepatocellular carcinoma, papillary renal tumor, head and neck tumor, leukemia, lymphoma, myeloma and non-small cell lung cancer.

The invention further relates to a compound shown in the general formula (I) or a racemate, an enantiomer, a diastereoisomer or a mixture form thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, and application thereof as a TLR8 agonist.

The invention further relates to a compound of general formula (I) according to the invention or a racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, for use as a medicament; the medicament is used for preventing or treating TLR 8-related diseases, which can be virus infectious diseases such as viral hepatitis B and HIV virus infection or malignant tumors such as breast cancer, cervical cancer, colon cancer, lung cancer, gastric 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, melanoma, solid tumor, glioma, neuroblastoma, hepatocellular carcinoma, papillary renal tumor, head and neck tumor, leukemia, lymphoma, myeloma and non-small cell lung cancer.

The present invention further relates to a method for preventing or treating TLR 8-related diseases, comprising administering to a patient in need thereof an effective amount of a compound according to the invention of the general formula (I) or its racemates, enantiomers, diastereomers or the mixture thereof, or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same; the disease may be a viral infectious disease such as viral hepatitis b, HIV viral infection, or a malignancy such as 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, melanoma, solid tumor, glioma, glioblastoma, hepatocellular carcinoma, papillary renal tumor, head and neck tumor, leukemia, lymphoma, myeloma, and non-small cell lung cancer.

The compounds of the general formula (I) according to the present invention may be used to form pharmaceutically acceptable basic addition salts or acid addition salts with bases or acids according to conventional methods in the art to which the present invention pertains. The base includes inorganic bases and organic bases, acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like, and acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide and the like. The acids include inorganic and organic acids, and acceptable inorganic acids include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and the like. Acceptable organic acids include acetic acid, trifluoroacetic acid, formic acid, ascorbic acid and the like.

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for the preparation of pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a pleasant to the eye and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binding agents, such as starch, gelatin, polyvinylpyrrolidone or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, water soluble taste masking substances such as hydroxypropylmethyl cellulose or hydroxypropyl cellulose, or time extending substances such as ethyl cellulose, cellulose acetate butyrate may be used.

Oral formulations may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with a water soluble carrier, for example polyethylene glycol, or an oil vehicle, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol (heptadecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyethylene oxide sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene oxide sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl paraben, one or more colouring agents, one or more flavouring agents and one or more sweetening agents, such as sucrose, saccharin or aspartame.

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oil suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants such as butylated hydroxyanisole or alpha-tocopherol.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water may provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent or one or more preservatives. Suitable dispersing or wetting agents and suspending agents are as described above. Other excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions are preserved by the addition of an antioxidant such as ascorbic acid.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyethylene oxide sorbitol monooleate. The emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.

The pharmaceutical compositions of the present invention may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion, in which the active ingredient is dissolved in the oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then treated to form a microemulsion by adding it to a mixture of water and glycerol. The injection solution or microemulsion may be injected into the bloodstream of a patient by local bolus injection. Alternatively, it may be desirable to administer the solutions and microemulsions in such a way as to maintain a constant circulating concentration of the compounds of the present invention. To maintain such a constant concentration, a continuous intravenous delivery device may be used.

The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspensions may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend fixed oil may be used, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compounds of the present invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, glycerogelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.

It is well known to those skilled in the art that the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound employed, the age of the patient, the weight of the patient, the health of the patient, the patient's integument, the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, and the like. In addition, the optimal treatment regimen, such as mode of treatment, daily amount of the compound of formula (I) or type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

The compound of the invention can be used as an active ingredient, and the compound shown in the general formula (I), and pharmaceutically acceptable salts, hydrates or solvates thereof are mixed with pharmaceutically acceptable carriers or excipients to prepare a composition and prepare a clinically acceptable dosage form. The derivatives of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects such as allergic reactions and the like. The compounds of the present invention may be used as the sole active ingredient or in combination with other agents for the treatment of diseases associated with tyrosine kinase activity. Combination therapy is achieved by administering the individual therapeutic components simultaneously, separately or sequentially.

Detailed description of the invention

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

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms. <xnotran> , , , , , , , , ,1,1- ,1,2- ,2,2- ,1- ,2- ,3- , ,1- -2- ,1,1,2- ,1,1- ,1,2- ,2,2- ,1,3- ,2- ,2- ,3- ,4- ,2,3- , ,2- ,3- ,4- ,5- ,2,3- ,2,4- ,2,2- ,3,3- ,2- ,3- , ,2,3- ,2,4- ,2,5- ,2,2- ,3,3- ,4,4- ,2- ,3- ,4- ,2- -2- ,2- -3- , ,2- -2- ,2- -3- ,2,2- , ,3,3- ,2,2- , </xnotran> And various branched chain isomers thereof, and the like. More preferred are lower alkyl groups having 1 to 6 carbon atoms, and non-limiting examples include 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 and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.

The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, e.g., ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, e.g., ethynyl, propynyl, 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 alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 10 carbon atoms, even more preferably from 3 to 8 carbon atoms, and most preferably from 3 to 6 carbon atoms. 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.

The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. Spiro cycloalkyl groups are classified into mono-spiro cycloalkyl groups, di-spiro cycloalkyl groups or multi-spiro cycloalkyl groups, preferably mono-spiro cycloalkyl groups and di-spiro cycloalkyl groups, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

the term "fused cyclic alkyl" refers to a 5 to 20 membered 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 completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl. Non-limiting examples of fused ring alkyl groups include:

the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, depending on the number of constituent rings. Non-limiting examples of bridged cycloalkyl groups 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 a 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 groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O) _m (wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably 5 to 7 ring atoms, of which 1-2 or 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, preferably 1,2, 5-oxadiazolyl, pyranyl, or morpholinyl. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which one atom (referred to as a spiro atom) is shared between monocyclic rings, wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O) _m (wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. The spiro heterocyclic group is classified into a single spiro heterocyclic group, a double spiro heterocyclic group or a multi spiro heterocyclic group according to the number of spiro atoms shared between rings, and preferably the single spiro heterocyclic group and the double spiro heterocyclic group. More preferred are 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclic groups. Non-limiting examples of spiro heterocyclic groups include:

the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system in which one or more ring atoms is selected from nitrogen, oxygen or S (O) _m (wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

the term "bridged heterocyclyl" refers to 5 to 14 membered polycyclic heterocyclic group wherein 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 wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O) _m (wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups 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:

and the like.

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

The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. More preferably phenyl. 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:

the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 or 6 membered, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like, preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to 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 alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.

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

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens wherein alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein alkyl is as defined above.

The term "hydroxy" refers to an-OH group.

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

The term "amino" refers to the group-NH ₂ 。

The term "cyano" refers to — CN.

The term "nitro" means-NO ₂ 。

The term "oxo" means = O.

The term "carboxy" refers to-C (O) OH.

The term "mercapto" refers to-SH.

The term "ester group" refers to-C (O) O (alkyl) or-C (O) O (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

The term "acyl" refers to compounds containing a-C (O) R group, where R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

"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 group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the heterocyclic group is not substituted with an alkyl group.

"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, 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, an amino or hydroxyl group having a free hydrogen may be unstable in combination with a carbon atom having an unsaturated (e.g., olefinic) bond.

"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.

"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.

Synthesis of the Compounds of the invention

To accomplish the objects of the present invention, the present invention employs the following synthetic schemes to prepare the compounds of the present invention.

The invention provides a method for preparing a compound shown as a general formula (I) or a racemate, an enantiomer, a diastereoisomer or a mixture form thereof or a pharmaceutically acceptable salt thereof, which comprises the following steps:

(1) When R is ⁴ In the case of hydrogen, the acid is,

firstly, compound Ia and DMB-NH are reacted under alkaline condition ₂ Reacting to obtain a compound Ib, wherein N, N-diisopropylethylamine is preferably selected as the basic condition; then, hydrolyzing the compound Ib under alkaline conditions, preferably NaOH, to obtain a compound Ic; then, carrying out decarboxylation on the compound Ic under high temperature conditions to obtain a compound Id, wherein the high temperature conditions are preferably 160 ℃; finally, deprotection takes place under acidic conditions, preferably trifluoroacetic acid, to give the compound of general formula (I).

(2) When R is ⁴ In the case of a halogen, the halogen is,

and (3) reacting the compound Ie with N-chlorosuccinimide or N-bromosuccinimide to obtain the compound of the general formula (I).

firstly, compound If and DMB-NH are reacted under alkaline condition ₂ Reacting to obtain a compound Ig, wherein the basic condition is preferably N, N-diisopropylethylamine; deprotection under acidic conditions, preferably trifluoroacetic acid, then occurs to give the compound of formula (I).

firstly, the compound Ih is reacted with H-L-N (R) under alkaline conditions ⁵ R ⁶ ) The reaction gives the compound Ia, the basic conditions are preferably N, N-diisopropylethylamine; then, compound Ia and DMB-NH are reacted under alkaline condition ₂ Reacting to obtain a compound Ib, wherein N, N-diisopropylethylamine is preferably selected as the basic condition; finally, carrying out deprotection reaction under acidic condition to obtain the compound shown in the general formula (I), wherein trifluoroacetic acid is preferred;

DMB is 2, 4-dimethoxy benzyl,

ring A, X, L, R ⁵ 、R ⁶ M is defined as formula (I).

The present invention provides a method for preparing a compound represented by the general formula (II) or its racemate, enantiomer, diastereomer or mixture form, or pharmaceutically acceptable salt, comprising the steps of:

(1) When R is ⁴ In the case of hydrogen, the acid is,

firstly, compound IIa and DMB-NH are reacted under alkaline condition ₂ The compound IIb is obtained by reaction, and N, N-diisopropylethylamine is preferably selected as the basic condition; then, hydrolyzing the compound IIb under alkaline conditions, preferably NaOH, to obtain a compound IIc; then, carrying out decarboxylation reaction on the compound IIc under the high-temperature condition to obtain a compound IId, wherein the high-temperature condition is preferably 160 ℃; finally, carrying out deprotection reaction under acidic condition to obtain the compound shown in the general formula (II), wherein trifluoroacetic acid is preferred;

(2) When R is ⁴ In the case of a halogen, the halogen is,

firstly, the compound IIf is reacted with DMB-NH under alkaline condition ₂ The compound IIg is obtained by reaction, and N, N-diisopropylethylamine is preferably selected as the basic condition; then, carrying out deprotection reaction under an acidic condition to obtain a compound shown in a general formula (II), wherein trifluoroacetic acid is preferred;

firstly, compound IIh is reacted with H-L-N (R) under alkaline condition ⁵ R ⁶ ) The reaction gives compound IIa, the basic conditions preferably being N, N-diisopropylethylamine; then, under alkaline conditions, compound IIa is reacted with DMB-NH ₂ The compound IIb is obtained by reaction, and N, N-diisopropylethylamine is preferably selected as the basic condition; finally, carrying out deprotection reaction under acidic condition to obtain the compound shown in the general formula (II), wherein trifluoroacetic acid is preferred;

wherein the content of the first and second substances,

DMB is 2, 4-dimethoxy benzyl,

ring A, X, R ⁵ 、R ⁶ And m is as defined in formula (II).

The present invention provides a method for preparing a compound represented by the general formula (III) or a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

(1) When R is ⁴ In the case of hydrogen, the acid is,

firstly, compound IIIa is reacted with DMB-NH under alkaline condition ₂ The compound IIIb is obtained through reaction, and the basic condition is preferably N, N-diisopropylethylamine; then, hydrolyzing the compound IIIb under alkaline conditions, preferably NaOH, to obtain a compound IIIc; then, carrying out decarboxylation on the compound IIIc under a high-temperature condition to obtain a compound IIId, wherein the high-temperature condition is preferably 160 ℃; finally, carrying out deprotection reaction under acidic condition to obtain the compound shown in the general formula (III), wherein trifluoroacetic acid is preferred;

(2) When R is ⁴ In the case of a halogen, the halogen is,

reacting the compound IIIe with N-chlorosuccinimide or N-bromosuccinimide to obtain a compound of a general formula (III);

firstly, compound IIIf and DMB-NH are mixed under alkaline condition ₂ The compound IIIg is obtained by reaction, and the basic condition is preferably N, N-diisopropylethylamine; then, carrying out deprotection reaction under an acidic condition to obtain a compound shown in a general formula (III), wherein trifluoroacetic acid is preferred;

firstly, compound IIIh is reacted with HN (R) under alkaline condition ⁵ R ⁶ ) The compound IIIa is obtained through reaction, and the basic condition is preferably N, N-diisopropylethylamine; then, compound IIIa is reacted with DMB-NH under alkaline condition ₂ The compound IIIb is obtained through reaction, and the basic condition is preferably N, N-diisopropylethylamine; finally, carrying out deprotection reaction under acidic condition to obtain the compound shown in the general formula (III), wherein trifluoroacetic acid is preferred;

wherein the content of the first and second substances,

DMB is 2, 4-dimethoxy benzyl,

X、Y、Z、R、R ⁵ 、R ⁶ m and s are as defined in formula (III).

The present invention provides a method for preparing a compound represented by the general formula (IV) or a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

(1) When R is ⁴ In the case of hydrogen, the acid is,

firstly, compound IVa and DMB-NH are reacted under alkaline condition ₂ Reacting to obtain a compound IVb, wherein N, N-diisopropylethylamine is preferably selected as the basic condition; then, hydrolyzing the compound IVb under alkaline conditions, preferably NaOH, to obtain a compound IVc; then, carrying out decarboxylation on the compound IVc under high temperature conditions to obtain a compound IVd, wherein the high temperature conditions are preferably 160 ℃; finally, carrying out deprotection reaction under acidic condition to obtain the compound shown in the general formula (IV), wherein trifluoroacetic acid is preferred;

(2) When R is ⁴ In the case of a halogen, the halogen is,

(4) When in useR ⁴ And R ⁵ When a nitrogen-containing heterocyclic ring is formed,

firstly, compound IVh is reacted with HN (R) under basic conditions ⁵ R ⁶ ) The compound IVa is obtained by reaction, and the basic condition is preferably N, N-diisopropylethylamine; then, under alkaline conditions, the compound IVa is mixed with DMB-NH ₂ Reacting to obtain a compound IVb, wherein N, N-diisopropylethylamine is preferably selected as the basic condition; finally, carrying out deprotection reaction under acidic condition to obtain the compound shown in the general formula (IV), wherein trifluoroacetic acid is preferred;

wherein the content of the first and second substances,

DMB is 2, 4-dimethoxy benzyl,

Detailed Description

The compounds of the present invention and their preparation are further understood by the examples which illustrate some of the methods of making or using the compounds. However, it is to be understood that these examples do not limit the present invention. Variations of the invention, now known or further developed, are considered to fall within the scope of the invention as described and claimed herein.

The compounds of the present invention are prepared using convenient starting materials and general preparative procedures. Typical or preferential reaction conditions are given in the present invention, such as reaction temperature, time, solvent, pressure, molar ratio of reactants. However, other reaction conditions can be adopted unless otherwise specified. The optimum conditions may vary with the particular reactants or solvents used, but in general, reaction optimization steps and conditions can be determined.

In addition, some protecting groups may be used in the present invention to protect certain functional groups from unwanted reactions. Protecting groups suitable for various functional groups and their protecting or deprotecting conditions are well known to those skilled in the art. For example, T.W.Greene and G.M.Wuts, protective groups in organic preparations (3 rd edition, wiley, new York,1999 and literature references therein), describe in detail the protection or deprotection of a number of protective groups.

The isolation and purification of the compounds and intermediates may be carried out by any suitable method or procedure depending on the particular requirements, for example, filtration, extraction, distillation, crystallization, column chromatography, preparative thin-layer plate chromatography, preparative high-performance liquid chromatography or a mixture of the above methods. The specific use method can be referred to the described examples of the invention. Of course, other similar means of separation and purification may be employed. It can be characterized using conventional methods, including physical constants and spectroscopic data.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift at 10 ^-6 The units in (ppm) are given. NMR was measured using a Brukerdps model 300 nuclear magnetic spectrometer using deuterated dimethyl sulfoxide (DMSO-d) as the solvent ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard Tetramethylsilane (TMS).

MS is determined using an LC (Waters 2695)/MS (Quattro Premier xE) mass spectrometer (manufacturer: watt. TM.) (Photodiode Array Detector).

Preparative liquid chromatography lc6000 high performance liquid chromatography was used (manufacturer: innovation). Column Daisogel C18 μm 100A (30 mm. Times.250 mm), mobile phase: acetonitrile/water.

The thin-layer chromatography (TLC) uses GF254 silica gel plate of Qingdao ocean chemical industry, the specification of the silica gel plate used for the thin-layer chromatography for reaction monitoring is 0.20 mm-0.25 mm, and the specification of the silica gel plate used for the thin-layer chromatography for preparation is 0.5mm.

The silica gel column chromatography uses Qingdao marine silica gel 100-200 meshes, 200-300 meshes and 300-400 meshes as a carrier.

Known starting materials of the present invention may be synthesized using or according to methods known in the art, or may be purchased from the companies of the networked mall, beijing coup, sigma, carbofuran, yishiming, shanghai khia, shanghai einoku, annagi chemical, shanghai bidi, etc.

The reactions can all be carried out under a nitrogen atmosphere without specific reference in the examples.

An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.

The reaction solvent, organic solvent or inert solvent each means that the solvent used does not participate in the reaction under the reaction conditions described, and includes, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane, diethyl ether, methanol, N-methylpyrrolidone (NMP), pyridine, and the like. In the examples, the solution means an aqueous solution unless otherwise specified.

The chemical reactions described in the present invention are generally carried out at atmospheric pressure. The reaction temperature is between-78 ℃ and 200 ℃. The reaction time and conditions are, for example, one atmosphere at-78 ℃ to 200 ℃ and are completed in about 1 to 24 hours. If the reaction is carried out overnight, the reaction time is generally 16 hours. In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention.

Abbreviations

μ L = microliter;

μ M = micromolar;

NMR = nuclear magnetic resonance;

boc = tert-butoxycarbonyl group

br = broad peak

d = doublet

δ = chemical shift

DEG C = degree centigrade

dd = doublet

DIPEA = diisopropylethylamine

DMB =2, 4-dimethoxybenzyl

DMF = N, N-dimethylformamide

DMSO = dimethyl sulfoxide

DCM = dichloromethane

EA = ethyl acetate

HATU =2- (7-azobenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate

HPLC = high performance liquid phase

Hz = Hertz

IC ₅₀ Concentration for 50% inhibition of activity

J = coupling constant (Hz)

LC-MS = liquid chromatography-mass spectrometry

m = multiplet

M+H ⁺ = parent compound mass + proton

mg = mg

mL = mL

mmol = mmol

MS = mass spectrum

m/z = mass to charge ratio

nM = nanomolar

PE = petroleum ether

ppm = parts per million

Pro = protecting group

s = single peak

t = triplet peak

TEA = triethylamine

TFA = trifluoroacetic acid

THF = tetrahydrofuran

t _R = retention time

Example 1: preparation of ethyl 2-amino-4- ((1-hydroxyhex-3-yl) amino) -1, 5-naphthyridine-3-carboxylate (1)

Step 1: preparation of methyl 3- (3-ethoxy-3-oxopropanoylamino) picolinate (1 b)

Methyl 3-aminopyridinecarboxylate 1a (15.6 g,0.10 mol) and triethylamine (31.1 g, 0.31mol) were dissolved in dichloromethane (150 mL) at room temperature. Malonic acid monoethyl ester acid chloride (18.5g, 0.12mol) was slowly added dropwise at 0 ℃ and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was quenched with water (100 mL), dichloromethane (3X 100 mL) was added to the system for extraction, the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting yellow crude product was isolated and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether = 0-10%) to obtain compound 1b (15.3 g, 56.1%) as a brown solid.

LC-MS：m/z 267.1[M+H] ⁺ 。

Step 2: preparation of ethyl 2, 4-dioxo-1, 2,3, 4-tetrahydro-1, 5-naphthyridine-3-carboxylate (1 c)

Compound 1b (15.3g, 57.5 mmol) and sodium ethoxide (7.82g, 114.9 mmol) were dissolved in ethanol (150 mL) at room temperature, and the reaction mixture was stirred at 80 ℃ for 4 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, diluted with water (50 mL), and the pH of the reaction mixture was adjusted to 6 with 1mol/L dilute hydrochloric acid. The resulting mixture was concentrated under reduced pressure to give crude compound 1c (35.0 g, crude) as a yellow solid, which was used in the next step without purification.

LC-MS：m/z 235.1[M+H] ⁺ 。

And step 3: preparation of ethyl 2, 4-dichloro-1, 5-naphthyridine-3-carboxylate (1 d)

Compound 1c (35.0 g, crude) was combined with phosphorus oxychloride (350 mL) at 0 ℃. The reaction solution was stirred at 100 ℃ for 1.5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, quenched with ice water, adjusted to pH =7 with saturated sodium bicarbonate solution, ethyl acetate (3 × 300 mL) was added to the system for extraction, the combined organic phases were washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude dark brown compound 1d (9.9 g, 63.5% yield in two steps).

LC-MS：m/z 271.0[M+H] ⁺ 。

And 4, step 4: preparation of ethyl 2-chloro-4- ((1-hydroxyhex-3-yl) amino) -1, 5-naphthyridine-3-carboxylate (1 e)

Compound 1d (100mg, 0.37mmol) was dissolved in N, N-dimethylformamide (5 mL) at room temperature. To the reaction mixture were added 3-amino-1-hexanol hydrochloride (62.3 mg, 0.41mmol) and N, N-diisopropylethylamine (143.0 mg, 1.11mmol) in this order, and the mixture was reacted at 80 ℃ overnight. After the reaction was complete, it was cooled to room temperature. The reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (3X 30 mL), the organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 1e was obtained as a brown oil (129mg, 99.4%).

LC-MS：m/z 352.1[M+H] ⁺ 。

And 5: preparation of ethyl 2- ((2, 4-dimethoxybenzyl) amino) -4- ((1-hydroxyhex-3-yl) amino) -1, 5-naphthyridine-3-carboxylate (1 f)

Compound 1e (129mg, 0.37mmol) was dissolved in 2, 4-dimethoxybenzylamine (2.5 mL) at room temperature. N, N-diisopropylethylamine (142.2mg, 1.10 mmol) was added to the reaction mixture, and the mixture was reacted at 100 ℃ overnight. After the reaction was complete, it was cooled to room temperature. The reaction mixture was diluted with water (40 mL), extracted with ethyl acetate (3X 30 mL), and the combined organic phases were washed with saturated ammonium chloride (2X 50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was isolated and purified by preparative thin layer chromatography (mobile phase: ethyl acetate/petroleum ether = 1) to give compound 1f (100mg, 56.5%) as a yellow oil.

LC-MS：m/z 483.3[M+H] ⁺ 。

Step 6: preparation of ethyl 2-amino-4- ((1-hydroxyhex-3-yl) amino) -1, 5-naphthyridine-3-carboxylate (1)

Compound 1f (100mg, 0.21mmol) was dissolved in dichloromethane (10.0 mL) at room temperature. Trifluoroacetic acid (3.0 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, diluted with saturated sodium bicarbonate solution (20 mL), extracted with ethyl acetate (3X 30 mL), the organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was isolated and purified by preparative thin layer chromatography (mobile phase: ethyl acetate/petroleum ether = 1) to give compound 1 as a yellow oil (8mg, 11.6%).

¹ H NMR (400 MHz, methanol-d) ₄ )δ8.40(dd,J＝4.1,1.6Hz,1H),7.67(dd,J＝8.5,1.6Hz,1H),7.47(dd,J＝8.5,4.1Hz,1H),4.49–4.39(m,2H),3.92–3.71(m,1H), 3.71–3.63(m,2H),1.99–1.87(m,1H),1.86–1.75(m,1H),1.70–1.55(m,2H),1.42(t,J＝7.1Hz,3H),1.39–1.26(m,2H),0.89(t,J＝7.4Hz,3H)。

LC-MS：m/z 333.0[M+H] ⁺ 。

Example 2: preparation of 3- ((2-amino-1, 5-naphthyridin-4-yl) amino) hex-1-ol (2)

Step 1: preparation of 3- ((2-amino-1, 5-naphthyridin-4-yl) amino) hex-1-ol (2)

To compound 1 (85mg, 0.26mmol) was added aqueous sodium hydroxide (2mL, 12.5 mol/L) at room temperature, and the mixture was stirred at 120 ℃ for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, water (5 mL) was added, ethyl acetate (3X 10 mL) was further added for extraction, and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (mobile phase: methanol/dichloromethane = 0-10%) to obtain compound 2 (22.5mg, 32.6%) as a white solid.

¹ H NMR (300 MHz, methanol-d) ₄ )δ8.37(dd,J＝4.3,1.4Hz,1H),7.75(dd,J＝8.5,1.5Hz,1H),7.45(dd,J＝8.5,4.3Hz,1H),6.03(s,1H),3.81–3.74(m,1H),3.73–3.64(m,2H),1.98–1.75(m,2H),1.73–1.55(m,2H),1.54–1.32(m,2H),1.00–0.87(m,3H).

LC-MS：m/z 261.0[M+H] ⁺ 。

Example 3: preparation of 2-amino-4- ((1-hydroxyhex-3-yl) amino) -1, 5-naphthyridine-3-carbonitrile (3)

Step 1: preparation of 3- (cyclohexylcarbamoyl) -2, 4-dioxo-1, 2,3, 4-tetrahydro-1, 5-naphthyridine (3 a)

Compound 1c (300mg, 1.28mmol) was combined with cyclohexylamine (6.0 mL) at room temperature. The reaction was stirred overnight at 110 ℃ under nitrogen. After the reaction was complete, cool to room temperature. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (3X 20 mL), and the organic phases were combined and washed successively with saturated ammonium chloride solution (30 mL), saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 3a (315mg, 68.5%) was obtained as a dark orange solid.

LC-MS：m/z 288.1[M+H] ⁺ 。

Step 2: preparation of 2, 4-dichloro-1, 5-naphthyridine-3-carbonitrile (3 b)

Compound 3a (100mg, 0.35mmol) was combined with phosphorus oxychloride (2.0 mL) at 0 ℃. Triethylamine (140.9 mg, 1.39mmol) was added to the reaction solution, and the mixture was stirred overnight at 120 ℃ under nitrogen atmosphere. After completion of the reaction, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was quenched with ice water, then adjusted to pH =7 with saturated sodium bicarbonate solution, ethyl acetate (2 × 30 mL) was added to the system for extraction, and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 3b (78mg, 100.0%) as a brown oil, which was used in the next step without purification.

LC-MS：m/z 224.0[M+H] ⁺ 。

And step 3: preparation of 2-chloro-4- ((1-hydroxyhex-3-yl) amino) -1, 5-naphthyridine-3-carbonitrile (3 c)

Compound 3b (78mg, 0.35mmol) was dissolved in N, N-dimethylformamide (2.0 mL) at room temperature. To the reaction mixture were added 3-amino-1-hexanol hydrochloride (53.5mg, 0.35mmol) and N, N-diisopropylethylamine (180mg, 1.39mmol) in this order, and the mixture was stirred at 80 ℃ under nitrogen for 2.5 hours. After the reaction was complete, it was cooled to room temperature. The reaction mixture was diluted with water (40 mL), extracted with ethyl acetate (3X 30 mL), the organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 3c was obtained as a brown oil (106mg, 99.9%) which was used in the next step without purification.

LC-MS：m/z 305.1[M+H] ⁺ 。

And 4, step 4: preparation of 2- ((2, 4-dimethoxybenzyl) amino) -4- ((1-hydroxyhex-3-yl) amino) -1, 5-naphthyridine-3-carbonitrile (3 d)

Compound 3c (105mg, 0.35mmol) was dissolved in 2, 4-dimethoxybenzylamine (2.0 mL) at room temperature. N, N-diisopropylethylamine (178mg, 1.38mmol) was added to the reaction solution, and the mixture was stirred at 100 ℃ under nitrogen for 2 hours. After the reaction was complete, it was cooled to room temperature. The reaction solution was diluted with water (40 mL), extracted with ethyl acetate (3X 30 mL), and the combined organic phases were washed with saturated ammonium chloride (2X 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was isolated and purified by preparative thin layer chromatography (mobile phase: ethyl acetate/petroleum ether =2: 3) to give light brown semisolid compound 3d (47mg, 31.3%).

LC-MS：m/z 436.2[M+H] ⁺ 。

And 5: preparation of 2-amino-4- ((1-hydroxyhex-3-yl) amino) -1, 5-naphthyridine-3-carbonitrile (3)

Compound 3d (47mg, 0.11mmol) was dissolved in dichloromethane (2.0 mL) at room temperature. Trifluoroacetic acid (1.0 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, diluted with saturated sodium bicarbonate solution (20 mL), extracted with ethyl acetate (3X 30 mL), the organic phases were combined and washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was isolated and purified by preparative thin layer chromatography (mobile phase: dichloromethane/methanol = 10).

¹ H NMR (400 MHz, methanol-d) ₄ )δ8.43(dd,J＝4.2,1.5Hz,1H),7.73(dd,J＝8.5,1.5Hz,1H),7.54(dd,J＝8.5,4.2Hz,1H),4.82–4.75(m,1H),3.76–3.67(m,2H),2.09–1.96(m,1H),1.95–1.83(m,1H),1.80–1.71(m,2H),1.55–1.42(m,2H),0.98(t,J＝7.3Hz,3H)。

LC-MS：m/z 286.1[M+H] ⁺ 。

Example 4: preparation of 3- ((2-amino-3-nitroquinolin-4-yl) amino) hex-1-ol (4)

Step 1: preparation of 3- ((2-chloro-3-nitroquinolin-4-yl) amino) hex-1-ol (4 b)

2, 4-dichloro-3-nitroquinoline 4a (50mg, 0.21mmol) was dissolved in N, N-dimethylformamide (1.5 mL) at room temperature. To the reaction mixture were added 3-amino-1-hexanol hydrochloride (31.6 mg, 0.21mmol) and N, N-diisopropylethylamine (106.4 mg, 0.82mmol) in this order, and the mixture was stirred at 80 ℃ under nitrogen for 2 hours. After the reaction was complete, it was cooled to room temperature. The reaction mixture was diluted with water (40 mL), extracted with ethyl acetate (3X 30 mL), the organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 4b (66mg, 99.1%) was obtained as a brown oil, which was used in the next step without purification.

LC-MS：m/z 324.1[M+H] ⁺ 。

And 2, step: preparation of 3- ((2, 4-dimethoxybenzyl) amino) -3-nitroquinolin-4-yl) amino) hex-1-ol (4 c)

Compound 4b (66mg, 0.20mmol) was dissolved in 1, 4-dioxane (2.0 mL) at room temperature. 2, 4-dimethoxybenzylamine (170.4mg, 1.02mmol) and N, N-diisopropylethylamine (52.7mg, 0.41mmol) were added to the reaction mixture in this order, and the mixture was stirred at 100 ℃ under nitrogen for 3 hours. After the reaction was complete, it was cooled to room temperature. The reaction mixture was diluted with water (40 mL), extracted with ethyl acetate (3X 30 mL), and the combined organic phases were washed successively with saturated ammonium chloride (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was isolated and purified by preparative thin layer chromatography (mobile phase: ethyl acetate/petroleum ether =2.

LC-MS：m/z 455.2[M+H] ⁺ 。

And step 3: preparation of 3- ((2-amino-3-nitroquinolin-4-yl) amino) hex-1-ol (4)

Compound 4c (24mg, 0.053 mmol) was dissolved in dichloromethane (2.0 mL) at room temperature. Trifluoroacetic acid (0.8 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained crude product was separated and purified by means of a preparative chromatography column (column: sunAire Prep C18 OBD column, 5um, 19X 150mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 9% to 27% acetonitrile within 8 minutes; detection wavelength: 254 nm) to obtain orange solid compound 4 (10mg, 62.2%).

¹ H NMR (400 MHz, methanol-d) ₄ )δ8.24(d,J＝8.4Hz,1H),7.74(t,J＝7.6Hz,1H),7.52(d,J＝8.4Hz,1H),7.39(t,J＝7.8Hz,1H),4.38–4.18(m,1H),3.71(t,J＝5.9Hz,2H),2.15–1.89(m,2H),1.86–1.70(m,2H),1.45–1.30(m,2H),0.91(t,J＝7.3Hz,3H)。

LC-MS：m/z 304.9[M+H] ⁺ 。

Example 5 and example 6: preparation of (R) -3- ((2-amino-1, 5-naphthyridin-4-yl) amino) hex-1-ol (5) and (S) -3- ((2-amino-1, 5-naphthyridin-4-yl) amino) hex-1-ol (6)

Chiral separation (column type: CHIRALPAK IC column, 2 x 25cm,5um; mobile phase A: n-hexane (10 mmol/L ammonia methanol), mobile phase B: ethanol; flow rate: 20mL/min; gradient: 30% -30% in 12.5 min; detection wavelength: 254/220 nm) of Compound 2 (20mg, 0.077mmol) to give Compound 5 (2.9mg, 14.5%) as a white solid product _R =1.360min, ee value (enantiomeric excess): 100 percent; and white solid product Compound 6 (3.5mg, 17.5%), t _R =2.142min, ee value (enantiomeric excess): 98.5 percent.

Compound 5:

¹ h NMR (300 MHz, methanol-d) ₄ )δ8.40(dd,J＝4.3,1.5Hz,1H),7.75(dd,J＝8.4,1.5Hz,1H),7.46(dd,J＝8.4,4.3Hz,1H),6.03(s,1H),3.86–3.74(m,1H),3.74–3.64(m,2H),1.98–1.78(m,2H),1.76–1.59(m,2H),1.57–1.37(m,2H),0.97(t,J＝7.3Hz,3H)。

LC-MS：m/z 261.1[M+H] ⁺ 。

Compound 6:

¹ h NMR (300 MHz, methanol-d ₄ )δ8.41(dd,J＝4.3,1.5Hz,1H),7.76(dd,J＝8.5,1.5Hz,1H),7.48(dd,J＝8.5,4.3Hz,1H),6.03(s,1H),3.86–3.75(m,1H),3.74–3.64(m,2H),1.97–1.78(m,2H),1.76–1.59(m,2H),1.56–1.37(m,2H),0.97(t,J＝7.3Hz,3H)。

LC-MS：m/z 261.0[M+H] ⁺ 。

Example 7: preparation of (R) -2- ((5-aminopyrazolo [1,5-a ] pyrimidin-7-yl) amino) hex-1-ol (7)

Step 1: preparation of (R) -2- ((5-chloropyrazolo [1,5-a ] pyrimidin-7-yl) amino) hex-1-ol (7 b)

5, 7-dichloropyrazolo [1,5-a ] pyrimidine 7a (120mg, 0.64mmol), (R) -2-amino-1-hexanol hydrochloride (98.1mg, 0.64mmol) was dissolved in N-butanol (5 mL) at room temperature, followed by addition of N, N-diisopropylethylamine (247mg, 1.91mmol). The reaction mixture was reacted at 100 ℃ for 2 hours. After completion of the reaction, concentration under reduced pressure was carried out, a saturated ammonium chloride solution (20 mL) was added to the residue, extraction was carried out with ethyl acetate (3X 15 mL), the combined organic phases were washed with a saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude 7b (150mg, 87.5%) as a yellow viscous liquid.

LC-MS：m/z 269.1[M+H] ⁺ 。

Step 2: preparation of (R) -2- ((5- ((2, 4-dimethoxybenzyl) amino) pyrazolo [1,5-a ] pyrimidin-7-yl) amino) hex-1-ol (7 c)

Compound 7b (150mg, 0.56mmol) was mixed with 2, 4-dimethoxybenzylamine (2.0 mL) at room temperature, followed by the addition of N, N-diisopropylethylamine (216mg, 1.67mmol). The reaction mixture was reacted at 100 ℃ for 6 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, a saturated ammonium chloride solution (30 mL) was added to the reaction mixture, ethyl acetate (3 × 20 mL) was extracted, the combined organic phases were washed with a saturated saline solution (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether = 0-50%) to obtain a yellow viscous liquid 7c (200mg, 89.7%).

LC-MS:m/z 400.2[M+H] ⁺ 。

And step 3: preparation of (R) -2- ((5-aminopyrazolo [1,5-a ] pyrimidin-7-yl) amino) hex-1-ol (7)

Compound 7c (200mg, 0.50mmol) was dissolved in dichloromethane (5.0 mL) at room temperature, followed by the addition of trifluoroacetic acid (2.5 mL). The reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, water (20 mL) was added to the reaction mixture, ethyl acetate (3X 20 mL) was extracted, the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was separated and purified by preparative chromatography (column type: XSelect CSH Prep C18 OBD column, 5um, 19X 150mm; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 25% -45% acetonitrile within 8 minutes; detection wavelength: 254 nm) to obtain white compound 7 (17.2mg, 13.8%).

¹ H NMR (400 MHz, methanol-d) ₄ )δ7.75(d,J＝2.2Hz,1H),5.89(d,J＝2.2Hz,1H),5.42(s,1H),3.74–3.63(m,2H),3.63–3.55(m,1H),1.85–1.56(m,2H),1.52–1.30(m,4H),0.93(t,J＝7.0Hz,3H).

LC-MS:m/z 250.1[M+H] ⁺ 。

Example 8: preparation of (R) -2- ((2-amino-1, 5-naphthyridin-4-yl) amino) hex-1-ol (8)

Step 1: preparation of ethyl (R) -2-chloro-4- ((1-hydroxyhex-2-yl) amino) -1, 5-naphthyridine-3-carboxylate (8 a)

Compound 1d (200mg, 0.74mmol), (R) -2-amino-1-hexanol hydrochloride (124mg, 0.81mmol) was dissolved in N-butanol (3 mL) at room temperature, followed by addition of N, N-diisopropylethylamine (286 mg, 2.21mmol). The reaction solution was stirred at 100 ℃ for 2 hours. After completion of the reaction, filtration was carried out, the filtrate was concentrated under reduced pressure, a saturated ammonium chloride solution (30 mL) was added to the reaction mixture, extraction was carried out with ethyl acetate (3X 20 mL), the combined organic phases were washed with a saturated saline solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 8a (200mg, 77.0%) as a yellow viscous liquid. It was used in the next step without purification.

LC-MS：m/z 352.1[M+H] ⁺ 。

And 2, step: preparation of ethyl (R) -2- ((2, 4-dimethoxybenzyl) amino) -4- ((1-hydroxyhex-2-yl) amino) -1, 5-naphthyridine-3-carboxylate (8 b) and (R) -2-butyl-N- (2, 4-dimethoxybenzyl) -1,2,3, 5-tetrahydro- [1,4] oxazepino [6,5-c ] [1,5] naphthyridin-6-amine (8 c)

Compound 8a (200mg, 0.59mmol) was mixed with 2, 4-dimethoxybenzylamine (1.0 mL) at room temperature, followed by the addition of N, N-diisopropylethylamine (228mg, 1.77mmol). The reaction mixture was stirred at 100 ℃ for 6 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, a saturated ammonium chloride solution (30 mL) was added to the reaction mixture, extraction was performed with ethyl acetate (3X 20 mL), and the combined organic phases were washed with a saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether = 0-25%) to obtain yellow liquid mixtures 8b and 8c (239.3mg, 87.2%).

LC-MS：m/z 8b 483.3[M+H] ⁺ ；LC-MS：m/z 8c 423.2[M+H] ⁺ 。

And step 3: preparation of ethyl (R) -2-amino-4- ((1-hydroxyhex-2-yl) amino) -1, 5-naphthyridin-3-carboxylate (8 d) and (R) -2-butyl-1, 2,3, 5-tetrahydro- [1,4] oxazepino [6,5-c ] [1,5] naphthyridin-6-amine (8 e)

Mixtures 8b and 8c (239.3mg, 0.50mmol) were dissolved in dichloromethane (2.5 mL) at room temperature, followed by the addition of trifluoroacetic acid (1.25 mL). The reaction solution was stirred at room temperature for 2 hours. After completion of the reaction, filtration was carried out, the filtrate was concentrated under reduced pressure, water (30 mL) was added to the reaction solution, ethyl acetate (3 × 20 mL) was extracted, the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting crude yellow viscous liquid was purified by silica gel column chromatography (mobile phase: methanol/dichloromethane = 0-10%) to obtain yellow oily liquid mixtures 8d and 8e (118mg, 71.5%).

LC-MS：m/z 8d 333.2[M+H] ⁺ ；LC-MS：m/z 8e 273.2[M+H] ⁺ 。

And 4, step 4: preparation of (R) -2- ((2-amino-1, 5-naphthyridin-4-yl) amino) hex-1-ol (8)

To mixtures 8d and 8e (118mg, 0.35mmol) was added sodium hydroxide solution (12.5M, 5 mL) at room temperature. The reaction mixture was stirred at 120 ℃ for 24 hours. After the reaction is finished, 1mol/L diluted hydrochloric acid is added to adjust the pH of the reaction solution to 7. To the reaction mixture was added water (30 mL), extracted with ethyl acetate (3X 20 mL), and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative chromatography (column type: YMC-Actus Triart C18 OBD column, 5um,20 x 250mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 12% -37% acetonitrile within 8 minutes; detection wavelength: 254/220 nm) to give compound 8 as a white solid (4.6 mg, 5.0%).

¹ H NMR (400 MHz, methanol-d) ₄ )δ8.64(d,J＝4.3Hz,1H),7.90(d,J＝8.4Hz,1H),7.69(dd,J＝8.4,4.4Hz,1H),6.03(s,1H),3.80–3.67(m,3H),1.89–1.62(m,2H),1.50–1.32(m,4H),0.93(t,J＝6.8Hz,3H)。

LC-MS：m/z 261.1[M+H] ⁺ 。

Example 9: preparation of (R) -2- ((2-amino-1, 5-naphthyridin-4-yl) amino) pentan-1-ol (9)

Step 1: preparation of ethyl (R) -2-chloro-4- ((1-hydroxypentan-2-yl) amino) -1, 5-naphthyridine-3-carboxylate (9 a)

Compound 1d (200mg, 0.74mmol) was dissolved in N, N-dimethylformamide (2.0 mL) at room temperature. D-pentylaminoalcohol (76mg, 0.74mmol) and N, N-diisopropylethylamine (391. Mu.L, 2.21 mmol) were sequentially added to the reaction mixture, and the mixture was stirred at 80 ℃ for 2 hours. After the reaction was complete, it was cooled to room temperature. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (3X 20 mL), the organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was isolated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 2/1) to give compound 9a as a yellow solid (233mg, 93.4%).

LC-MS：m/z 338.1[M+H] ⁺ 。

And 2, step: preparation of ethyl (R) -2- ((2, 4-dimethoxybenzyl) amino) -4- ((1-hydroxypentan-2-yl) amino) -1, 5-naphthyridine-3-carboxylate (9 b) and (R) -6- ((2, 4-dimethoxybenzyl) amino) -2-propyl-2, 3-dihydro- [1,4] oxazepino [6,5-c ] [1,5] naphthyridin-5 (1H) -one (9 c)

Compound 9a (233mg, 0.69mmol) was dissolved in 2, 4-dimethoxybenzylamine (1.0 mL) at room temperature. N, N-diisopropylethylamine (366. Mu.l, 2.07 mmol) was added to the reaction mixture, and the mixture was stirred at 100 ℃ for 2 hours. After the reaction was complete, it was cooled to room temperature. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (3X 20 mL), the organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was isolated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 2/1) to give yellow solid mixtures 9b and 9c (42mg, 15.0%).

LC-MS：m/z 9b 469.2[M+H] ⁺ ；LC-MS：m/z 9c 423.2[M+H] ⁺ 。

And step 3: preparation of ethyl (R) -2-amino-4- ((1-hydroxypentan-2-yl) amino) -1, 5-naphthyridine-3-carboxylate (9 d)

Mixtures 9b and 9c (42mg, 0.101mmol) were dissolved in dichloromethane (1.5 mL) at room temperature. Trifluoroacetic acid (0.5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting crude product was isolated and purified by silica gel column chromatography (mobile phase: dichloromethane/methanol = 12/1) to obtain compound 9d (20mg, 62.1%) as a yellow solid.

LC-MS：m/z 319.2[M+H] ⁺ 。

And 4, step 4: preparation of (R) -2- ((2-amino-1, 5-naphthyridin-4-yl) amino) pentan-1-ol (9)

To compound 9d (20mg, 0.062mmol) was added an aqueous sodium hydroxide solution (0.5mL, 12.5mol/L,6.25 mmol) at room temperature. Stirred at 120 ℃ for 20 hours. After the reaction was completed, the reaction solution was cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the resulting crude product was separated and purified by preparative chromatography (column type: XBridge Prep C18 OBD column, 5um, 19X 150mm; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 17% -37% acetonitrile in 8 minutes; detection wavelength: 254/220 nm) to give compound 9 (7.3mg, 47.8%) as a white solid.

¹ H NMR (300 MHz, methanol-d) ₄ )δ8.44(dd,J＝4.3,1.5Hz,1H),7.77(dd,J＝8.5,1.5Hz,1H),7.50(dd,J＝8.5,4.3Hz,1H),6.02(s,1H),3.76–3.59(m,3H),1.87–1.59(m,2H),1.58–1.38(m,2H),1.00(t,J＝7.3Hz,3H)。

LC-MS：m/z 247.0[M+H] ⁺ 。

Example 10: preparation of (S) -2- ((2-amino-1, 5-naphthyridin-4-yl) amino) hex-1-ol (10)

Step 1: preparation of ethyl (S) -2-chloro-4- ((1-hydroxyhex-2-yl) amino) -1, 5-naphthyridine-3-carboxylate (10 a)

Compound 1d (200mg, 0.74mmol) and (S) -2-amino-1-hexanol (95mg, 0.81mmol) were dissolved in N, N-dimethylformamide (10 mL) at room temperature under nitrogen atmosphere, followed by the addition of N, N-diisopropylethylamine (286mg, 2.21mmol). The reaction was stirred at 80 ℃ under nitrogen for 6 hours. After cooling to room temperature, water (50 mL) was added, ethyl acetate (3X 50 mL) was added to the system for extraction, and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 10a (160mg, 61.6%) as a yellow oily liquid.

LC-MS：m/z 352.1[M+H] ⁺ 。

Step 2: preparation of ethyl (S) -2- ((2, 4-dimethoxybenzyl) amino) -4- ((1-hydroxyhex-2-yl) amino) -1, 5-naphthyridine-3-carboxylate (10 b) and (S) -2-butyl-6- ((2, 4-dimethoxybenzyl) amino) -2, 3-dihydro- [1,4] oxazepino [6,5-c ] [1,5] naphthyridin-5 (1H) -one (10 c)

Compound 10a (160mg, 0.46mmol) was dissolved in 2, 4-dimethoxybenzylamine (2.0 mL) at room temperature, and N, N-diisopropylethylamine (178mg, 1.38mmol) was added. The reaction mixture was stirred at 100 ℃ for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, a saturated ammonium chloride solution (30 mL) was added, ethyl acetate (3X 20 mL) was added to the reaction mixture to extract the mixture, the combined organic phases were washed with a saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain yellow oily liquid mixtures 10b and 10c (150mg, 75.6%).

LC-MS：m/z 10b 483.3[M+H] ⁺ ；LC-MS： 10c m/z 437.2[M+H] ⁺ 。

And step 3: preparation of ethyl (S) -2-amino-4- ((1-hydroxyhex-2-yl) amino) -1, 5-naphthyridine-3-carboxylate (10 d) and (S) -6-amino-2-butyl-2, 3-dihydro- [1,4] oxazepino [6,5-c ] [1,5] naphthyridin-5 (1H) -one (10 e)

The mixtures 10b and 10c (150mg, 0.34mmol) were dissolved in dichloromethane (2.0 mL), and trifluoroacetic acid (1.0 mL) was added thereto while cooling on ice, followed by stirring at room temperature for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, water (30 mL) was added, and ethyl acetate (3X 20 mL) was added for extraction. The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting yellow crude product was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether = 1/1) to give yellow oily liquid mixtures 10d and 10e (65mg, 66.1%).

LC-MS：m/z 10d 333.2[M+H] ⁺ ；LC-MS：m/z 10e 287.1[M+H] ⁺ 。

And 4, step 4: preparation of (S) -2- ((2-amino-1, 5-naphthyridin-4-yl) amino) hex-1-ol (10)

The mixtures 10d and 10e (65mg, 0.23mmol) were added to an aqueous sodium hydroxide solution (2mL, 12.5 mol/L) and stirred at 120 ℃ for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, water (30 mL) was added, ethyl acetate (3X 20 mL) was further added for extraction, and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was isolated and purified by preparative chromatography (column type: xbridge Shield RP18 OBD column, 5um, 19X 150mm; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 25% -50% acetonitrile in 8 min; detection wave: 254/220 nm) to give compound 10 as a white solid (11.9mg, 20.1%).

¹ H NMR (300 MHz, methanol-d ₄ )δ8.41(dd,J＝4.3,1.5Hz,1H),7.76(dd,J＝8.5,1.5Hz,1H),7.47(dd,J＝8.5,4.3Hz,1H),6.01(s,1H),3.71(d,J＝4.9Hz,2H),3.67– 3.57(m,1H),1.91–1.74(m,1H),1.73–1.57(m,1H),1.55–1.32(m,4H),0.93(t,J＝6.9Hz,3H)。

LC-MS：m/z 261.0[M+H] ⁺ 。

Example 11: preparation of (R) -2- ((2-amino-1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (11)

Step 1: preparation of 1- ((tert-butyldimethylsilyl) oxy) propan-2-one (11 b)

Hydroxyacetone 11a (100g, 1.35mol) was dissolved in dichloromethane (1L) at room temperature. The solution was cooled to 0 ℃ and imidazole (175g, 2.57mol) and tert-butyldimethylsilyl chloride (24pg, 1.63mol) were added in sequence. The reaction was stirred at 0 ℃ for 1 hour, then slowly warmed to room temperature, and stirred for another 12 hours. After completion of the reaction, the reaction mixture was washed with water (3X 1L), and the organic phase was concentrated under reduced pressure to give Compound 11b as a pale yellow liquid (200g, 78.7%).

¹ H-NMR(CDCl ₃ )δ:4.15(s,2H),2.17(s,3H),0.93(s,9H),0.09(s,6H)。

Step 2: preparation of (S, E) -N- (1- ((tert-butyldimethylsilyl) oxy) propan-2-ylidene) -2-methylpropan-2-sulfonamide (11 c)

Compound 11b (200g, 1.06mol) and S-tert-butylsulfinamide (129g, 1.06mol) were dissolved in tetrahydrofuran (3.6L) at room temperature. The reaction was added dropwise to tetraisopropyl orthotitanate (800mL, 2.66mol). The reaction solution was stirred at 70 ℃ for 12 hours. After the reaction was completed, it was cooled to room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting brown liquid was added to ice water (1L), the resulting solid was removed by filtration, and the resulting mixture was extracted with ethyl acetate (3X 500 mL), and the combined organic phases were washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude brown oil was isolated and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether =3% -20%) to give compound 11c (50g, 16.1%) as a brown yellow liquid. ¹ H NMR (300 MHz, chloroform-d) delta 4.23 (s, 2H), 2.32 (s, 3H), 1.23 (s, 9H), 0.90 (s, 9H), 0.07 (s, 6H). LC-MS: m/z 292.2[ m ] +H] ⁺ 。

And step 3: preparation of (S) -N- ((R) -1- ((tert-butyldimethylsilyl) oxy) -2-methylhexan-2-yl) -2-methylpropan-2-sulfonamide (11 d)

Compound 11c (50g, 0.171mol) was dissolved in toluene (500 mL) at room temperature under a nitrogen atmosphere. A heptane solution of trimethylaluminum (207mL, 1mol/L,0.21 mol) was added dropwise to the reaction mixture at-78 ℃ and, after the addition was complete, stirring was continued for 0.5 hour. Then, a solution of n-butylaluminum in n-hexane (102mL, 2.5mol/L,0.26 mol) was added dropwise at-78 ℃ and, after completion of the addition, stirred at-78 ℃ for 4 hours. After the reaction was complete, water (500 mL) was added and quenched, filtered, extracted with ethyl acetate (3X 200 mL), and the combined organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting yellow crude product was isolated and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether =7% -10%) to give compound 11d (26g, 43.4%) as a yellow liquid.

¹ H NMR (400 MHz, chloroform-d) δ 3.66 (s, 1H), 3.51 (d, J =9.4hz, 1h), 3.32 (d, J =9.4hz, 1h), 1.72-1.62 (m, 2H), 1.35-1.24 (m, 4H), 1.18 (s, 9H), 1.14 (s, 3H), 0.92-0.87 (m, 12H), 0.05 (s, 3H).

LC-MS：m/z 350.3[M+H] ⁺ 。

And 4, step 4: preparation of (R) -1- ((tert-butyldimethylsilyl) oxy) -2-methylhexan-2-amine hydrochloride (11 e)

Compound 11d (26g, 0.074 mol) was dissolved in methanol (260 mL) at room temperature, and a solution of hydrogen chloride in 1, 4-dioxane (55.5mL, 4mol/L,0.222 mol) was added. The reaction solution was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain compound 11e (15g, 71.9%) as a pale yellow liquid.

¹ H NMR (400 MHz, chloroform-d) δ 3.30 (q, J =9.4hz, 2h), 1.54 (s, 2H), 1.40-1.20 (m, 6H), 0.98 (s, 3H), 0.93-0.87 (m, 12H), 0.04 (s, 6H).

LC-MS：m/z 246.2[M+H] ⁺ 。

And 5: preparation of ethyl (R) -4- ((1- ((tert-butyldimethylsilyl) oxy) -2-methylhexan-2-yl) amino) -2-chloro-1, 5-naphthyridine-3-carboxylate (11 f)

Compound 1d (120mg, 0.44mmol) and compound 11e (150mg, 0.53mmol) were dissolved in N-methylpyrrolidone (5 mL) at room temperature under a nitrogen atmosphere, and N, N-diisopropylethylamine (172mg, 1.33mmol) was added. The reaction was stirred at 100 ℃ under nitrogen for 4 hours. After cooling to room temperature, a saturated ammonium chloride solution (30 mL) was added, ethyl acetate (3 × 20 mL) was added to the system to extract, and the combined organic phases were washed with a saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether = 0-20%) to obtain compound 11f (80.0 mg, 37.6%) as a yellow oily liquid.

LC-MS：m/z 480.2[M+H] ⁺ 。

And 6: preparation of ethyl (R) -4- ((1- ((tert-butyldimethylsilyl) oxy) -2-methylhexan-2-yl) amino) -2- ((2, 4-dimethoxybenzyl) amino) -1, 5-naphthyridine-3-carboxylate (11 g)

Compound 11f (80.0 mg, 0.17mmol) and N, N-diisopropylethylamine (64.6 mg, 0.50mmol) were dissolved in 2, 4-dimethoxybenzylamine (2.0 mL) at room temperature. The reaction solution was stirred at 100 ℃ for 1 hour. After the reaction was complete, it was cooled to room temperature, diluted with water (30 mL) and extracted with ethyl acetate (3X 30 mL). The combined organic phases were washed with saturated ammonium chloride (2X 50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether = 0-40%) to obtain 11g (60.0 mg, 58.8%) of the compound as a yellow oily liquid.

LC-MS：m/z 611.4[M+H] ⁺ 。

And 7: preparation of (R) -4- ((1- ((tert-butyldimethylsilyl) oxy) -2-methylhexan-2-yl) amino) -2- ((2, 4-dimethoxybenzyl) amino) -1, 5-naphthyridine-3-carboxylic acid (11 h)

At room temperature, 11g (20mg, 0.033mmol) of the compound was dissolved in absolute ethanol (2 mL), and an aqueous solution of sodium hydroxide (12.5 mol/L,2 mL) was added. The reaction solution was stirred at 80 ℃ for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the resulting yellow crude product was added with water (20 mL) and 1mol/L dilute hydrochloric acid to adjust the pH to 5. Ethyl acetate (3X 20 mL) was added to the system for extraction, and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 11h (18.0 mg, 94.7%) as a yellow solid.

LC-MS：m/z 583.3[M+H] ⁺ 。

And 8:(R)-N ⁴ - (1- ((tert-butyldimethylsilyl) oxy) -2-methylhexan-2-yl) -N ² Preparation of- (2, 4-dimethoxybenzyl) -1, 5-naphthyridine-2, 4-diamine (11 i)

Compound 11h (18.0 mg, 0.03mmol) was dissolved in diphenyl ether (0.5 mL) at room temperature. Stirred at 160 ℃ for 2 hours. After completion of the reaction, the reaction liquid was cooled to room temperature, and the resulting mixture was directly separated and purified by preparative thin layer chromatography (developing solvent: ethyl acetate/petroleum ether = 1) to obtain compound 11i (9.0 mg, 54.2%) as a pale yellow oily liquid.

LC-MS：m/z 539.33[M+H] ⁺ 。

And step 9: preparation of (R) -2- ((2-amino-1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (11)

Compound 11i (9.0mg, 0.017mmol) was dissolved in methylene chloride (0.5 mL), and trifluoroacetic acid (0.5 mL) was added thereto while cooling on ice, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained crude product was separated and purified by means of preparative chromatography (column type: XBridge Prep C18 OBD column, 5. Mu.m, 19X 150mm; mobile phase A: water (10 mmol/L ammonium hydrogencarbonate), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 20% -48% acetonitrile within 9 minutes; detection wavelength: 254/220 nm) to obtain off-white solid compound 11 (2.7 mg, 88.4%).

¹ H NMR (400 MHz, methanol-d) ₄ )δ8.28(dd,J＝4.3,1.5Hz,1H),7.62(dd,J＝8.4,1.6Hz,1H),7.35(dd,J＝8.4,4.3Hz,1H),6.11(s,1H),3.69(d,J＝11.2Hz,1H),3.52(d,J＝11.2Hz,1H),1.86–1.63(m,2H),1.33(s,3H),1.30–1.20(m,4H),0.80(t,J＝6.9Hz,3H)。

LC-MS：m/z 275.1[M+H] ⁺ 。

Example 12: preparation of (S) -2- ((2-amino-1, 5-naphthyridin-4-yl) amino) pentan-1-ol (12)

Step 1: preparation of ethyl (S) -2-chloro-4- ((1-hydroxypentan-2-yl) amino) -1, 5-naphthyridine-3-carboxylate (12 a)

Compound 1d (289mg, 1.07mmol) and (S) -2-amino-1-pentanol (110.0mg, 1.07mmol) were dissolved in N, N-dimethylformamide (3 mL) at room temperature, followed by addition of N, N-diisopropylethylamine (413.3mg, 3.20mmol). The reaction mixture was stirred at 80 ℃ for 2 hours. After completion of the reaction, water (30 mL) was added to the reaction mixture, which was extracted with ethyl acetate (3X 20 mL), and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude compound 12a (560 mg, crude) as a yellow viscous liquid. It was used in the next step without purification.

LC-MS：m/z 338.0[M+H] ⁺ 。

And 2, step: preparation of ethyl (S) -2- ((2, 4-dimethoxybenzyl) amino) -4- ((1-hydroxypentan-2-yl) amino) -1, 5-naphthyridine-3-carboxylate (12 b) and (S) -6- ((2, 4-dimethoxybenzyl) amino) -2-propyl-2, 3-dihydro- [1,4] oxazepino [6,5-c ] [1,5] naphthyridin-5 (1H) -one (12 c)

Compound 12a (560 mg, crude) was mixed with 2, 4-dimethoxybenzylamine (2 mL) at room temperature, followed by the addition of N, N-diisopropylethylamine (644mg, 4.98mmol). The reaction solution was stirred at 100 ℃ for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, a saturated ammonium chloride solution (50 mL) was added to the reaction mixture, extraction was performed with ethyl acetate (3X 30 mL), and the combined organic phases were washed with a saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude yellow viscous liquid was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether = 10-25%) to give yellow oily liquid mixtures 12b and 12c (152.4 m g, 19.2%).

LC-MS：m/z 12b 469.2[M+H] ⁺ ；LC-MS：m/z 12c 423.2[M+H] ⁺ 。

And step 3: preparation of ethyl (S) -2-amino-4- ((1-hydroxypentan-2-yl) amino) -1, 5-naphthyridine-3-carboxylate (12 d) and (S) -2-propyl-1, 2,3, 5-tetrahydro- [1,4] oxazepino [6,5-c ] [1,5] naphthyridin-6-amine (12 e)

Mixtures 12b and 12c (154.2mg, 0.33mmol) were dissolved in dichloromethane (2.5 mL) at room temperature, followed by the addition of trifluoroacetic acid (1.25 mL). The reaction solution was stirred at room temperature for 2 hours. After the reaction, filtering, and concentrating the filtrate under reduced pressure. To the residue was added water (30 mL), extracted with ethyl acetate (3X 20 mL), and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude yellow viscous liquid was purified by silica gel column chromatography (mobile phase: methanol/dichloromethane = 0-10%) to give yellow oily mixtures 12d and 12e (61.5mg, 58.6%).

LC-MS：m/z 12d 319.2[M+H] ⁺ ；LC-MS：m/z 12e 273.1[M+H] ⁺ 。

And 4, step 4: preparation of (S) -2- ((2-amino-1, 5-naphthyridin-4-yl) amino) pentan-1-ol (12)

To the mixtures 12d and 12e (61.5 mg) was added sodium hydroxide solution (12.5M, 10 mL) at room temperature. The reaction was stirred at 120 ℃ overnight. After the reaction is finished, 1mol/L diluted hydrochloric acid is added to adjust the pH value to 7. Water (20 mL) was added to the reaction mixture, which was extracted with ethyl acetate (3X 20 mL), and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude yellow viscous liquid was purified by preparative chromatography (column: XBridge Prep C18 OBD column, 5um, 20X 250mm; mobile phase A: water (0.05% trifluoroacetic acid), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 17% -40% acetonitrile in 2 minutes; detection wavelength: 254/220 nm) to give compound 12 as a white solid (15.3mg, 34.0%).

¹ H NMR (400 MHz, methanol-d) ₄ )δ8.63(dd,J＝4.4,1.3Hz,1H),7.88(dd,J＝8.5,1.4Hz,1H),7.68(dd,J＝8.5,4.4Hz,1H),6.03(s,1H),3.79–3.68(m,3H),1.84–1.63(m,2H),1.56–1.37(m,2H),0.98(t,J＝7.3Hz,3H)。

LC-MS：m/z 247.0[M+H] ⁺ 。

Example 13: preparation of (S) -2- ((2-amino-3-bromo-1, 5-naphthyridin-4-yl) amino) pentan-1-ol (13)

Step 1: preparation of (S) -2- ((2-amino-3-bromo-1, 5-naphthyridin-4-yl) amino) pentan-1-ol (13)

Compound 12 (5.0 mg, 0.020mmol) was dissolved in glacial acetic acid (0.5 mL) at room temperature under nitrogen and bromine (6.5 mg, 0.041mmol) was added. After the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours, water (20 mL) was added to dilute the reaction mixture, and ethyl acetate (2X 20 mL) was added to the system to extract the mixture. The combined organic phases were washed successively with saturated sodium bicarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by preparative chromatography (preparative column: xbridge Prep C18 OBD column, 5um, 19X 150mm; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25ml/min; gradient: 24% -36% in 8 min; detection wavelength: 254/220 nm) to give compound 13 as a white solid (2mg, 30.3%).

¹ H NMR (400 MHz, methanol-d) ₄ )δ8.35(dd,J＝4.2,1.6Hz,1H),7.68(dd,J＝8.5,1.6Hz,1H),7.39(dd,J＝8.5,4.2Hz,1H),4.96–4.87(m,1H),3.70–3.55(m,2H),1.70–1.58(m,1H),1.57–1.46(m,1H),1.44–1.24(m,2H),0.83(t,J＝7.3Hz,3H)。

LC-MS：m/z 325.0[M+H] ⁺ 。

Example 14 and example 15: preparation of (R) -2- ((2-amino-7-fluoro-1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (14) and (S) -2- ((2-amino-7-fluoro-1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (15)

Step 1: preparation of methyl 3-amino-5-fluoropicolinate (14 b)

2-bromo-5-fluoropyridin-3-amine 14a (5.0g, 26.3mmol) was dissolved in methanol (250 mL) at room temperature, and triethylamine (5.32g, 52.6 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (1.07g, 1.3mmol) were added. The reaction mixture was reacted with carbon monoxide (10 atm) at 80 ℃ overnight. After completion of the reaction, the reaction mixture was concentrated, water (200 mL) was added thereto, the mixture was extracted with ethyl acetate (3X 100 mL), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether = 0-20%) to obtain compound 14b (4.3g, 96.2%) as a white solid.

LC-MS：m/z 171.1[M+H] ⁺ 。

Step 2: preparation of methyl 3- (3-ethoxy-3-oxopropanoylamino) -5-fluoropyridinecarboxylate (14 c)

Compound 14b (1.0 g, 5.88mmol) and triethylamine (1.78g, 17.6 mmol) were dissolved in dichloromethane (100 mL) at room temperature, monoethyl malonyl chloride (1.06g, 7.05mmol) was slowly added dropwise at 0 deg.C, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was quenched with water (100 mL), and ethyl acetate (3X 100 mL) was added to the system to extract, and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting yellow crude product was isolated and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether = 0-35%) to obtain compound 14c (0.45g, 26.9%) as a yellow solid.

LC-MS：m/z 285.1[M+H] ⁺ 。

And step 3: preparation of 7-fluoro-2, 4-dioxo-1, 2,3, 4-tetrahydro-1, 5-naphthyridine-3-carboxylic acid ethyl ester (14 d)

Compound 14c (0.45g, 1.58mmol) and sodium ethoxide (0.21g, 3.20mmol) were dissolved in ethanol (5 mL) at room temperature, and the reaction mixture was stirred at 80 ℃ for 4 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting solid was filtered and washed three times with a small amount of cold ethanol to obtain crude compound 14d (0.19g, 47.6%) as a yellow solid. It was used in the next step without purification.

LC-MS：m/z 253.1[M+H] ⁺ 。

And 4, step 4: preparation of ethyl 2, 4-dichloro-7-fluoro-1, 5-naphthyridine-3-carboxylate (14 e)

To compound 14d (0.19g, 0.75mmol) was added phosphorus oxychloride (2.0 mL) at 0 ℃. The reaction solution was stirred at 100 ℃ for 1.5 hours. After the reaction, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. To the residue was added ice water, the pH was adjusted to 7 with saturated sodium bicarbonate solution, ethyl acetate (3X 20 mL) was added to the system for extraction, and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting yellow crude product was isolated and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether = 0-7%) to give compound 14e (0.19g, 87.2%) as a yellow solid.

LC-MS：m/z 289.0[M+H] ⁺ 。

And 5: preparation of ethyl 4- ((1- ((tert-butyldimethylsilyl) oxy) -2-methylhexan-2-yl) amino) -2-chloro-7-fluoro-1, 5-naphthyridine-3-carboxylate (14 f)

Compound 14e (0.19g, 0.66mmol) and compound 1- ((tert-butyldimethylsilyl) oxy) -2-methylhexan-2-amine hydrochloride (204mg, 0.72mmol) were dissolved in N-methylpyrrolidinone (NMP) (2 mL) at room temperature under a nitrogen atmosphere and N, N-Diisopropylethylamine (DIEA) (254mg, 1.97mmol) was added. The reaction was stirred at 100 ℃ under nitrogen for 4 hours. After cooling to room temperature, a saturated ammonium chloride solution (20 mL) was added, ethyl acetate (3 × 20 mL) was added to the system to extract, and the combined organic phases were washed with a saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting yellow crude product was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether = 0-20%) to obtain compound 14f (88mg, 26.9%) as a yellow oily liquid.

LC-MS：m/z 498.2[M+H] ⁺ 。

Step 6:4- ((1- ((tert-butyldimethylsilyl) oxy) -2-methylhexan-2-yl) amino) -2- ((2, 4-dimethoxybenzyl) amino) -7-fluoro-1, 5-naphthyridine-3-carboxylic acid ethyl ester (14 g) and N ⁴ - (1- ((tert-butyldimethylsilyl) oxy) -2-methylhexan-2-yl) -N ² Preparation of- (2, 4-dimethoxybenzyl) -7-fluoro-1, 5-naphthyridine-2, 4-diamine (14 h)

Compound 14f (88mg, 0.18mmol) and N, N-diisopropylethylamine (68.5mg, 0.53mmol) were dissolved in 2, 4-dimethoxybenzylamine (2 mL) at room temperature. The reaction solution was stirred at 100 ℃ for 6 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, a saturated ammonium chloride solution (20 mL) was added, ethyl acetate (3X 20 mL) was added to the reaction mixture to extract the mixture, and the combined organic phases were washed with a saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether = 0-40%) to obtain 14g (22mg, 19.8%) of the compound as a yellow oily liquid and 14h (0.033g, 33.6%).

LC-MS：m/z 14g：629.4[M+H] ⁺ ； 14h：557.3[M+H] ⁺ 。

And 7: preparation of 2- ((2-amino-7-fluoro-1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (14 i)

Compound 14h (33mg, 0.059 mmol) was dissolved in DCM (1.5 mL) at RT, and trifluoroacetic acid (1.5 mL) was added and reacted at RT for 1 h. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained crude product was separated and purified by preparative chromatography (column type: XBridge Prep C18 OBD column, 5. Mu.m, 19X 150mm; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 25% -45% acetonitrile in 8 minutes; detection wavelength: 254/220 nm) to give a pale yellow solid compound 14i (4.7mg, 27.2%).

And step 8: preparation of (R) -2- ((2-amino-7-fluoro-1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (14) and (S) -2- ((2-amino-7-fluoro-1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (15)

Compound 14i was further subjected to chiral resolution. Column type: CHIRAL ART Cellulose-SB,2 × 25cm,5um; a mobile phase A: n-hexane (10 mM methanolic ammonia solution), mobile phase B: ethanol; flow rate: 20mL/min; gradient: a constant gradient of 5% acetonitrile over 26 minutes; detection wavelength: 262/220nm; to obtain a white solid compound 14,t _R =17.6min, ee value (enantiomeric excess): 98.3 percent; and a white solid compound 15,t _R =16.5min, ee value (enantiomeric excess): 85.0 percent.

Compound 14

¹ H NMR (300 MHz, methanol-d ₄ )δ8.30(d,J＝2.6Hz,1H),7.40(dd,J＝10.3,2.6Hz,1H),6.19(s,1H),3.79(d,J＝11.1Hz,2H),3.62(d,J＝11.2Hz,1H),1.96–1.74(m,2H),1.44(s,3H),1.41–1.26(m,4H),0.92(t,J＝6.8Hz,3H)。

LC-MS：m/z 293.2[M+H] ⁺ 。

Compound 15

¹ H NMR (300 MHz, methanol-d ₄ )δ8.58(d,J＝2.5Hz,1H),7.69(dd,J＝9.0,2.5Hz,1H),6.28(s,1H),3.81(d,J＝11.3Hz,1H),3.62(d,J＝11.3Hz,1H),1.94–1.83(m,2H),1.48(s,3H),1.42–1.31(m,4H),0.94(t,J＝6.8Hz,3H)。

LC-MS：m/z 293.2[M+H] ⁺ 。

Example 16: preparation of (S) -2- ((2-amino-3-chloro-1, 5-naphthyridin-4-yl) amino) pentan-1-ol (16)

Step 1: preparation of (S) -2- ((2-amino-3-chloro-1, 5-naphthyridin-4-yl) amino) pentan-1-ol (16)

Compound 12 (10.0 mg, 0.041mmol) was dissolved in dry N, N-dimethylformamide (0.8 mL) at room temperature under nitrogen and N-chlorosuccinimide (10.8 mg, 0.081mmol) was added. The reaction was stirred overnight at room temperature under nitrogen and then quenched by the addition of water (20 mL). Ethyl acetate (2X 20 mL) was added to the system for extraction. The target product was dissolved in the aqueous phase and the resulting aqueous phase was concentrated under reduced pressure. The crude product was purified by preparative chromatography (preparative column: XBridge Prep C18 OBD column, 5um,19 × 150mm, mobile phase A: water (0.05% ammonia), mobile phase B: acetonitrile, flow rate: 25ml/min, gradient: 19% -35% in 8 minutes, detection wavelength: 254/220 nm) to obtain off-white solid compound 16 (0.3 mg, 2.6%).

¹ H NMR (300 MHz, methanol-d ₄ )δ8.46(dd,J＝4.2,1.5Hz,1H),7.79(dd,J＝8.5,1.6Hz,1H),7.50(dd,J＝8.4,4.2Hz,1H),3.83–3.61(m,3H),1.69–1.56(m,1H),1.55–1.40(m,1H),1.36–1.28(m,2H),0.97(t,J＝7.3Hz,3H)。

LC-MS：m/z 281.1[M+H] ⁺ 。

Example 17: preparation of N- (2- ((2-amino-1, 5-naphthyridin-4-yl) amino) -2-methylhexyl) acetamide (17)

Step 1: preparation of 2-amino-2-methylhexanenitrile (17 b)

Sodium cyanide (4.9 g,0.1 mol) was added to aqueous ammonia (60 mL) at room temperature, followed by the addition of 2-hexanone 17a (10.0 g,0.1 mol) and ammonium chloride (5.35g, 0.1 mol) in that order. The reaction mixture was stirred at room temperature overnight, followed by extraction with dichloromethane (4X 50 mL), and the combined organic phases were washed successively with saturated ferrous sulfate, water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 17b (11.28g, 89.5%) as a yellow oily liquid. It was used in the next step without purification.

Step 2: preparation of benzyl (2-cyanohex-2-yl) carbamate (17 c)

Compound 17b (11.0 g,87.2 mmol) and sodium carbonate (18.65g, 174mmol) were dissolved in water (50 mL) and tetrahydrofuran (50 mL) at room temperature, and benzyloxycarbonyl chloride (16.36g, 95.88mmol) was slowly added dropwise at 0 ℃. The reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and water (100 mL) was added to the residue, followed by extraction with ethyl acetate (3X 50 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting yellow crude product was isolated and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether = 1/1) to obtain compound 17c (12.60g, 55.5%) as a colorless oily liquid.

LC-MS：m/z 261.2[M+H] ⁺ 。

And step 3: preparation of benzyl (1-amino-2-methylhexan-2-yl) carbamate (17 d)

Compound 17c (12.60g, 48.40mmol) was dissolved in methanolic ammonia (7 mol/L,150 mL) at room temperature under nitrogen, then placed in a 300mL reaction vessel and Raney nickel (2.07g, 24.20mmol) was added. The reaction solution was placed under a hydrogen atmosphere to react for 4 hours. After completion of the reaction, the reaction mixture was filtered with suction, and the filtrate was concentrated under reduced pressure to give compound 17d (12.50g, 97.7%) as a dark blue oily liquid.

LC-MS：m/z 265.2[M+H] ⁺ 。

And 4, step 4: preparation of benzyl (1-acetamido-2-methylhexan-2-yl) carbamate (17 e)

Compound 17d (12.0g, 45.5 mmol) and triethylamine (9.18g, 90.9mmol) were dissolved in dichloromethane (150 mL) at room temperature, and acetyl chloride (3.90g, 50.0mmol) was slowly added dropwise at 0 ℃. The reaction solution was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was quenched with ice water (200 mL), and the mixture was extracted with ethyl acetate (3X 100 mL), and the combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting yellow crude product was isolated and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether = 1/1) to give compound 17e (8.73g, 62.8%) as a yellow solid.

LC-MS：m/z 307.2[M+H] ⁺ 。

And 5: preparation of N- (2-amino-2-methylhexyl) acetamide (17 f)

Compound 17e (4.0 g,13.1 mmol) was dissolved in methanol (50 mL) at room temperature, and 10% wet palladium on carbon (400 mg) was added. The reaction mixture was stirred at room temperature under hydrogen atmosphere for 4 hours. After the reaction, the reaction mixture was filtered under suction, and the filtrate was concentrated under reduced pressure to give compound 17f (1.55g, 68.9%) as a dark gray oily liquid.

LC-MS：m/z 173.2[M+H] ⁺ 。

And 6: preparation of ethyl 4- ((1-acetylamino-2-methylhexan-2-yl) amino) -2-chloro-1, 5-naphthyridine-3-carboxylate (17 g)

Compound 1d (180mg, 0.66mmol) and compound 17f (114mg, 0.66mmol) were dissolved in N-methylpyrrolidinone (3 mL) at room temperature under nitrogen and N, N-diisopropylethylamine (172mg, 1.33mmol) was added. The reaction was stirred at 100 ℃ under nitrogen for 4 hours. After cooling to room temperature, water (10 mL) was added, and ethyl acetate (3X 10 mL) was added to the system to extract, and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 17g (160mg, 59.2%) of a yellow oily liquid compound.

LC-MS：m/z 407.2[M+H] ⁺ 。

And 7: preparation of ethyl 4- ((1-acetylamino-2-methylhexan-2-yl) amino) -2- ((2, 4-dimethoxybenzyl) amino) -1, 5-naphthyridine-3-carboxylate (17 h)

Compound 17g (160mg, 0.39mmol) was dissolved in 2, 4-dimethoxybenzylamine (2 mL) at room temperature, and N, N-diisopropylethylamine (151mg, 1.17mmol) was added. The reaction solution was stirred at 100 ℃ for 1 hour. After completion of the reaction, the mixture was cooled to room temperature, saturated ammonium chloride solution (10 mL) was added, ethyl acetate (3X 10 mL) was added to the mixture, the mixture was extracted, the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 17h (150mg, 80.0%) as a yellow oily liquid.

LC-MS：m/z 538.3[M+H] ⁺ 。

And 8: preparation of 4- ((1-acetylamino-2-methylhexan-2-yl) amino) -2- ((2, 4-dimethoxybenzyl) amino) -1, 5-naphthyridine-3-carboxylic acid (17 i)

Compound 17h (150mg, 0.28mmol) was dissolved in absolute ethanol (1 mL) at room temperature, and aqueous sodium hydroxide (12.5 mol/L,1 mL) was added. The reaction mixture was stirred at 80 ℃ for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the resulting yellow crude product was added with water (20 mL) and 1mol/L dilute hydrochloric acid to adjust the pH to 5. Ethyl acetate (3X 20 mL) was added to the system for extraction, and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 17i (135mg, 95.0%) as a yellow oily liquid.

LC-MS：m/z 510.3[M+H] ⁺ 。

And step 9: preparation of N- (2- ((2, 4-dimethoxybenzyl) amino) -1, 5-naphthyridin-4-yl) amino) -2-methylhexyl) acetamide (17 j)

Compound 17i (135mg, 0.27mmol) was dissolved in diphenyl ether (1 mL) at room temperature. Stirred at 160 ℃ for 1 hour. After completion of the reaction, the reaction solution was cooled to room temperature, and the obtained crude product was purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether = 1/1) to obtain compound 17j (80mg, 64.9%) as a pale yellow oily liquid.

LC-MS：m/z 466.3[M+H] ⁺ 。

Step 10: preparation of N- (2- ((2-amino-1, 5-naphthyridin-4-yl) amino) -2-methylhexyl) acetamide (17)

Compound 17j (80mg, 0.17mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added while cooling on ice, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained crude product was separated and purified by means of preparative chromatography (column type: XBridge Prep C18 OBD column, 5. Mu.m, 19X 150mm; mobile phase A: water (10 mmol/L ammonium hydrogencarbonate), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 14% -56% acetonitrile in 8 minutes; detection wavelength: 254/220 nm) to obtain compound 17 (10.3 mg, 18.9%) as a white solid.

¹ H NMR (300 MHz, methanol-d ₄ )δ8.40(dd,J＝4.3,1.5Hz,1H),7.74(dd,J＝8.5,1.5Hz,1H),7.46(dd,J＝8.5,4.3Hz,1H),6.01(s,1H),3.77(d,J＝13.4Hz,1H),3.50(d,J＝13.4Hz,1H),2.17–1.99(m,1H),1.92(s,3H),1.66–1.50(m,1H),1.46–1.24(m,7H),0.95(t,J＝6.7Hz,3H)。

LC-MS：m/z 316.1[M+H] ⁺ 。

Example 18: preparation of (R) -6-amino-2-ethyl-2-methyl-2, 3-dihydro- [1,4] oxazepino [6,5-c ] [1,5] naphthyridin-5 (1H) -one (18)

Step 1: preparation of ethyl (R) -2-chloro-4- ((1-hydroxy-2-methylbut-2-yl) amino) -1, 5-naphthyridine-3-carboxylate (18 a) and (R) -6-chloro-2-ethyl-2-methyl-2, 3-dihydro- [1,4] oxazepino [6,5-c ] [1,5] naphthyridin-5 (1H) -one (18 b)

Compound 1d (370mg, 1.37mmol) and (R) -2 amino-2-methyl-1-butanol (169.0mg, 1.64mmol) were dissolved in N-methylpyrrolidone (2 mL) at room temperature, N-diisopropylethylamine (531mg, 4.11mmol) was then added, and the reaction mixture was stirred at 100 ℃ for 1.5 hours. After completion of the reaction, a saturated ammonium chloride solution (30 mL) was added to the reaction mixture, extraction was performed with ethyl acetate (3X 20 mL), and the combined organic phases were washed with a saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude mixtures 18a and 18b (350mg, 75.5%) as yellow viscous liquids.

LC-MS：m/z 18a 338.1[M+H] ⁺ ；LC-MS：m/z 18b 292.1[M+H] ⁺ 。

And 2, step: preparation of (R) -6- ((2, 4-dimethoxybenzyl) amino) -2-ethyl-2-methyl-2, 3-dihydro- [1,4] oxazepino [6,5-c ] [1,5] naphthyridin-5 (1H) -one (18 c)

To the mixtures 18a and 18b (350mg, 1.11mmol) was added 2, 4-dimethoxybenzylamine (2 mL) at room temperature, followed by N, N-diisopropylethylamine (430mg, 3.33mmol). The reaction was stirred at 100 ℃ overnight. After the reaction was completed, it was cooled to room temperature, and a saturated ammonium chloride solution (30 mL) was added, and extraction was performed with ethyl acetate (3X 20 mL), and the combined organic phases were washed with a saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude compound 18c (770 mg, crude) as a yellow viscous liquid. Used in the next step without purification.

LC-MS：m/z 423.2[M+H] ⁺ 。

And step 3: preparation of (R) -6-amino-2-ethyl-2-methyl-2, 3-dihydro- [1,4] oxazepino [6,5-c ] [1,5] naphthyridin-5 (1H) -one (18)

Crude compound 18c (50.0 mg, 0.12mmol) was dissolved in dichloromethane (2.5 mL) at room temperature, followed by the addition of trifluoroacetic acid (1.25 mL). The reaction solution was stirred at room temperature for 2 hours. After completion of the reaction, filtration was carried out, the filtrate was concentrated under reduced pressure, water (20 mL) was added to the residue, extraction was carried out with ethyl acetate (3X 20 mL), the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (mobile phase: methanol/dichloromethane = 0-10%) to obtain compound 18 (29.8mg, 92.5%) as a pale yellow solid.

¹ H NMR (300 MHz, methanol-d) ₄ )δ8.43(dd,J＝4.2,1.5Hz,1H),7.71(dd,J＝8.4,1.5Hz,1H),7.57(dd,J＝8.4,4.2Hz,1H),4.52–4.32(m,2H),1.95–1.77(m,2H),1.43(s,3H),1.07(t,J＝7.5Hz,3H)。

LC-MS：m/z 273.1[M+H] ⁺ 。

Example 19: preparation of 2- ((2-amino-1, 6-naphthyridin-4-yl) amino) hex-1-ol (19)

Step 1: preparation of methyl 4- (3-ethoxy-3-oxopropanamido) nicotinate (19 b)

Methyl 4-aminonicotinate 19a (1.0 g, 6.57mmol) and triethylamine (2.0 g, 19.74mmol) were dissolved in dichloromethane (20 mL) at room temperature, monoethyl malonyl chloride (1.19g, 7.89mmol) was slowly added dropwise at 0 deg.C, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was quenched by adding water (100 mL), and the system was extracted with dichloromethane (3X 60 mL), and the combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting yellow crude product was isolated and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether = 0-10%) to give compound 19b (350mg, 20.0%) as a yellow solid.

LC-MS：m/z 267.1[M+H] ⁺ 。

And 2, step: preparation of 2, 4-dioxo-1, 2,3, 4-tetrahydro-1, 6-naphthyridine-3-carboxylic acid ethyl ester (19 c)

Compound 19b (350mg, 1.31mmol) and sodium ethoxide (179mg, 2.63mmol) were dissolved in ethanol (10 mL) at room temperature, and the reaction solution was allowed to react at 80 ℃ for 1 hour. After the reaction, the reaction mixture was cooled to room temperature. The reaction was concentrated and filtered, the filter cake was collected, and the solid was washed with a small amount of cold ethanol to give compound 19c as a yellow solid (200mg, 65.0%).

LC-MS：m/z 235.1[M+H] ⁺ 。

And step 3: preparation of ethyl 2, 4-dichloro-1, 6-naphthyridine-3-carboxylate (19 d)

Compound 19c (200mg, 0.85mmol) was mixed with phosphorus oxychloride (10 mL) at 0 deg.C, and the reaction was stirred at 100 deg.C for 1.5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, quenched with ice water, extracted with ethyl acetate (3X 30 mL), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude compound 19d (184mg, 80.0%) as a brown oil. It was used in the next step without purification.

LC-MS：m/z 271.0[M+H] ⁺ 。

And 4, step 4: preparation of ethyl 2-chloro-4- ((1-hydroxyhex-2-yl) amino) -1, 6-naphthyridine-3-carboxylate (19 e) and 2-butyl-6-chloro-2, 3-dihydro- [1,4] oxazepino [6,5-c ] [1,6] naphthyridin-5 (1H) -one (19 f)

Compound 19d (184mg, 0.68mmol) and 2-amino-1-hexanol (92mg, 0.79mmol) were dissolved in N-methylpyrrolidone (6 mL) at room temperature under nitrogen and N, N-diisopropylethylamine (267mg, 2.05mmol) was added. The reaction was stirred at 100 ℃ under nitrogen for 4 hours. After cooling to room temperature, a saturated ammonium chloride solution (50 mL) was added, and ethyl acetate (3X 30 mL) was added to the system for extraction, and the combined organic phases were washed with a saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether = 0-20%) to give yellow oily mixtures 19e and 19f (153mg, 64.0%).

LC-MS：m/z 19e 352.1[M+H] ⁺ ；LC-MS：m/z 19f 306.1[M+H] ⁺ 。

And 5: preparation of 2-butyl-6- ((2, 4-dimethoxybenzyl) amino) -2, 3-dihydro- [1,4] oxazepino [6,5-c ] [1,6] naphthyridin-5 (1H) -one (19 g)

The mixtures 19e and 19f (153mg, 0.44mmol) were dissolved in 2, 4-dimethoxybenzylamine (3 mL) at RT, then N, N-diisopropylethylamine (1699 mg, 1.31mmol) was added and reacted at 100 ℃ for 4 hours. After the reaction was complete, it was cooled to room temperature. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (3X 30 mL), the organic phases were combined and washed successively with saturated ammonium chloride (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether = 0-40%) to obtain 19g (92mg, 35.0%) of a yellow solid compound.

LC-MS：m/z 437.2[M+H] ⁺ 。

Step 6: preparation of 6-amino-2-butyl-2, 3-dihydro- [1,4] oxazepino [6,5-c ] [1,6] naphthyridin-5 (1H) -one (19H)

Compound 19g (92mg, 0.21mmol) was dissolved in dichloromethane (4 mL) at room temperature. Trifluoroacetic acid (1 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained crude product was isolated and purified by silica gel column chromatography (mobile phase: methanol/dichloromethane = 0-6%) to obtain compound 19h (60mg, 99.0%) as a yellow solid.

LC-MS：m/z 287.1[M+H] ⁺ 。

And 7: preparation of 2- ((2-amino-1, 6-naphthyridin-4-yl) amino) hex-1-ol (19)

To compound 19h (60mg, 0.21mmol) was added aqueous sodium hydroxide (1.5mL, 12.5mol/L,18.75 mmol) at room temperature, and the mixture was stirred at 120 ℃ for 20 hours. After the reaction was completed, the reaction solution was cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the resulting crude product was separated and purified by preparative chromatography (column type: XBridge Prep C18 OBD column, 5um, 20X 250mm; mobile phase A: water (0.05% trifluoroacetic acid), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 15% -40% acetonitrile within 8 minutes; detection wavelength: 254/220 nm) to give compound 19 as a white solid (10.4 mg, 19.0%).

¹ H NMR (300 MHz, methanol-d ₄ )δ9.56(s,1H),8.73(d,J＝5.9Hz,1H),7.58(d,J＝6.0Hz,1H),6.12(s,1H),3.98–3.67(m,3H),2.00–1.69(m,2H),1.62–1.44(m,4H),1.14–0.89(m,3H)。

LC-MS：m/z 261.3[M+H] ⁺ 。

Example 20: preparation of (R) -2- ((2-amino-1, 5-naphthyridin-4-yl) amino) -2-methylbutan-1-ol (20)

Step 1: preparation of (R) -2- ((2-amino-1, 5-naphthyridin-4-yl) amino) -2-methylbutan-1-ol (20)

To compound 18 (200mg, 0.73mmol) was added sodium hydroxide solution (12.5M, 5 mL) at room temperature. The reaction was stirred at 120 ℃ overnight. After the reaction, 1mol/L diluted hydrochloric acid was added to adjust the pH of the reaction solution to 7, ethyl acetate (3X 15 mL) was added for extraction, the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting crude product was separated and purified by preparative chromatography (column: xbridge Prep C18 OBD column, 5um, 19X 150mm; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 5% -5% acetonitrile within 2 minutes; detection wavelength: 254/220 nm) to obtain 20 as a white solid compound (51.0mg, 28.2%).

¹ H NMR (400 MHz, methanol-d) ₄ )δ8.35(dd,J＝4.3,1.5Hz,1H),7.70(dd,J＝8.4,1.5Hz,1H),7.42(dd,J＝8.4,4.3Hz,1H),6.20(s,1H),3.78(d,J＝11.2Hz,1H),3.62(d,J＝11.2Hz,1H),2.00–1.76(m,2H),1.42(s,3H),0.92(t,J＝7.5Hz,3H)。

LC-MS：m/z 247.1[M+H] ⁺ 。

Example 21: preparation of 2-amino-N- (2-hydroxyethyl) -N-propylquinoline-4-carboxamide (21)

Step 1: preparation of 2- ((2, 4-dimethoxybenzyl) amino) quinoline-4-carboxylic acid (21 b)

2-chloroquinoline-4-carboxylic acid 21a (370mg, 1.78mmol) was dissolved in 1, 4-dioxane (6.0 mL) at room temperature. 2, 4-dimethoxybenzylamine (447.0 mg, 2.67mmol) and N, N-diisopropylethylamine (691mg, 5.35mmol) were added to the reaction mixture in this order, and the mixture was stirred at 100 ℃ under nitrogen for 2 hours. After the reaction was complete, it was cooled to room temperature. The reaction mixture was diluted with water (40 mL), extracted with ethyl acetate (3X 30 mL), and the combined organic phases were washed successively with saturated ammonium chloride (50 mL), saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was isolated and purified by silica gel column chromatography (mobile phase: methanol/dichloromethane = 0-8%) to obtain compound 21b (400mg, 64.3%) as a yellow solid.

LC-MS：m/z 339.1[M+H] ⁺ 。

Step 2: preparation of 2- ((2, 4-dimethoxybenzyl) amino) -N- (2-hydroxyethyl) -N-propylquinoline-4-carboxamide (21 c)

Compound 21b (400mg, 1.18mmol) was dissolved in dichloromethane (8.0 mL) at room temperature, the reaction solution was cooled to 0 ℃ and oxalyl chloride (1.0 mL) was slowly added dropwise, followed by one drop of N, N-dimethylformamide. And (3) heating the reaction solution to room temperature, continuing stirring for 1 hour, and then concentrating the reaction solution under reduced pressure to obtain crude acyl chloride.

In addition, 2- (propylamino) ethanol (366mg, 3.55mmol) and N, N-diisopropylethylamine (458mg, 3.55mmol) were dissolved in dichloromethane (6.0 mL), the reaction solution was cooled to 0 ℃ and the resulting crude acid chloride was dissolved in dichloromethane (3.0 mL) and slowly added dropwise to the reaction solution. After the reaction mixture was reacted at room temperature for 2 hours, water (40 mL) was added to quench the reaction, followed by extraction with dichloromethane (3X 30 mL), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (mobile phase: methanol/dichloromethane = 0-10%) to obtain compound 21c (300mg, 59.9%) as a white solid.

LC-MS：m/z 424.2[M+H] ⁺ 。

And 3, step 3: preparation of 2-amino-N- (2-hydroxyethyl) -N-propylquinoline-4-carboxamide (21)

Compound 21c (300mg, 0.71mmol) was dissolved in dichloromethane (4.0 mL) at room temperature. Trifluoroacetic acid (1.0 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained crude product was separated and purified by means of a preparative column (column type: xbridge Shield RP18 OBD column, 5. Mu.m, 19X 150mm; mobile phase A: water (10 mmoL/L ammonium hydrogencarbonate), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 15% -32% acetonitrile within 8 minutes; detection wavelength: 254 nm) to obtain compound 21 (103.2mg, 53.2%) as a white solid.

¹ H NMR (400 MHz, methanol-d) ₄ )δ7.63–7.47(m,3H),7.30–7.20(m,1H),6.78(d,J＝5.2Hz,1H),3.98–3.69(m,2H),3.65–3.45(m,2H),3.29–3.04(m,2H),1.89–1.75(m,1H),1.62–1.46(m,1H),1.10–0.61(m,3H)。

LC-MS:m/z 274.1[M+H] ⁺ 。

Example 22: n is a radical of ⁴ Preparation of (1-amino-2-methylhexan-2-yl) -1, 5-naphthyridine-2, 4-diamine (22)

Step 1: n is a radical of hydrogen ⁴ Preparation of (1-amino-2-methylhexan-2-yl) -1, 5-naphthyridine-2, 4-diamine (22)

Dilute hydrochloric acid (2 mol/L,0.5 mL) was added to compound 17 (8mg, 0.025mmol) at room temperature, and the reaction mixture was stirred at 100 ℃ for 8 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained crude product was separated and purified by means of a preparative column (column: gemini-NX C18 AXAI Packed column, 5um, 21.2X 150mm; mobile phase A: water (0.05% trifluoroacetic acid), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 8% -25% acetonitrile within 8 minutes; detection wavelength: 254 nm) to give a white solid compound 22 (4.0mg, 42.6%).

¹ H NMR (400 MHz, methanol-d) ₄ )δ8.60(dd,J＝4.4,1.4Hz,1H),7.86(dd,J＝8.4,1.5Hz,1H),7.65(dd,J＝8.5,4.4Hz,1H),6.12(s,1H),3.63–3.55(m,2H),1.75–1.62(m,2H),1.42–1.25(m,7H),0.89(t,J＝6.9Hz,3H)。

LC-MS：m/z 274.1[M+H] ⁺ 。

Example 23: preparation of 2- ((2-amino-1, 5-naphthyridin-4-yl) amino) heptan-1-ol (23)

Step 1: preparation of ethyl 2-chloro-4- ((1-hydroxyhept-2-yl) amino) -1, 5-naphthyridine-3-carboxylate (23 a)

Compound 1d (405mg, 1.49mol) was dissolved in N-methylpyrrolidone (5 mL) at room temperature, followed by addition of 2-amino-1-heptanol (254.8mg, 1.94mmol) and N, N-diisopropylethylamine (579.2mg, 4.48mmol). The reaction solution was stirred at 100 ℃ for 2 hours. After completion of the reaction, water (20 mL) was added for dilution, ethyl acetate (3X 20 mL) was extracted, and the combined organic phases were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether = 0-27%) to obtain compound 23a as a yellowish green oily liquid (350mg, 64.0%).

LC-MS：m/z 366.2[M+H] ⁺ 。

Step 2: preparation of ethyl 2- ((2, 4-dimethoxybenzyl) amino) -4- ((1-hydroxyhept-2-yl) amino) -1, 5-naphthyridine-3-carboxylate (23 b) and 6- ((2, 4-dimethoxybenzyl) amino) -2-pentyl-2, 3-dihydro- [1,4] oxazepino [6,5-c ] [1,5] naphthyridin-5 (1H) -one (23 c)

Compound 23a (350mg, 0.96mmol) and N, N-diisopropylethylamine (371mg, 2.87mmol) were dissolved in 2, 4-dimethoxybenzylamine (5 mL) at room temperature. The reaction mixture was stirred at 100 ℃ for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (30 mL) and extracted with ethyl acetate (3X 30 mL). The combined organic phases were washed with saturated ammonium chloride (2X 60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give yellow oily liquid mixtures 23b and 23c (260mg, 54.7%).

LC-MS：m/z 23b 497.3[M+H] ⁺ ；LC-MS：m/z 23c 451.2[M+H] ⁺ 。

And step 3: preparation of ethyl 2-amino-4- ((1-hydroxyhept-2-yl) amino) -1, 5-naphthyridine-3-carboxylate (23 d) and 6-amino-2-pentyl-2, 3-dihydro- [1,4] oxazepino [6,5-c ] [1,5] naphthyridin-5 (1H) -one (23 e)

Mixtures 23b and 23c (260mg, 0.52mmol) were dissolved in dichloromethane (2.5 mL) at room temperature, followed by addition of trifluoroacetic acid (2.5 mL) and reaction for 30 minutes at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (20 mL), adjusted to pH 7 by the addition of 2M sodium hydroxide solution, and extracted with ethyl acetate (3X 20 mL). The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give yellow solid mixtures 23d and 23e (175mg, 96.5%).

LC-MS：m/z 23d 347.2[M+H] ⁺ ；LC-MS：m/z 23e 301.2[M+H] ⁺ 。

And 4, step 4: preparation of 2- ((2-amino-1, 5-naphthyridin-4-yl) amino) heptan-1-ol (23)

To the mixtures 23d and 23e (175mg, 0.51mmol) was added an aqueous sodium hydroxide solution (10mL, 12.5mol/L,125 mmol) at room temperature, and the reaction was carried out at 120 ℃ for 24 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (10 mL), adjusted to pH 7 by addition of 2M dilute hydrochloric acid, and extracted with ethyl acetate (3X 30 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was isolated and purified by preparative chromatography (column type: xbridge Prep C18 OBD column, 19X 250mm,10um; mobile phase A: water (10 mmol/L ammonium hydrogencarbonate), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 35% -55% acetonitrile in 8 minutes; detection wavelength: 254/220 nm) to give compound 23 as a white solid (25mg, 18.0%).

¹ H NMR (300 MHz, methanol-d ₄ )δ8.41(dd,J＝4.3,1.5Hz,1H),7.76(dd,J＝8.5,1.5Hz,1H),7.48(dd,J＝8.5,4.3Hz,1H),6.01(s,1H),3.71(d,J＝4.9Hz,2H),3.68–3.58(m,1H),1.89–1.74(m,1H),1.75–1.58(m,1H),1.57–1.42(m,2H),1.43–1.27(m,4H),0.91(t,J＝6.5Hz,3H)。

LC-MS：m/z 275.1[M+H] ⁺ 。

Example 24: preparation of (1- (2-amino-1, 5-naphthyridin-4-yl) piperidin-2-yl) methanol (24)

Step 1: preparation of ethyl 2-chloro-4- (2- (hydroxymethyl) piperidin-1-yl) -1, 5-naphthyridine-3-carboxylate (24 a)

Compound 1d (649mg, 2.39mmol) was dissolved in N-methylpyrrolidone (8 mL) at room temperature, and 2-piperidinemethanol (303mg, 2.63mmol) and N, N-diisopropylethylamine (930mg, 7.21mmol) were added to the reaction solution in this order and reacted at 100 ℃ for 2 hours. After the reaction was complete, it was cooled to room temperature. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (3X 20 mL), the organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 1/1) to obtain compound 24a (364mg, 43.4%) as a yellow solid.

LC-MS：m/z 350.1[M+H] ⁺ 。

And 2, step: preparation of ethyl 2- ((2, 4-dimethoxybenzyl) amino) -4- (2- (hydroxymethyl) piperidin-1-yl) -1, 5-naphthyridin-3-carboxylate (24 b) and 6- ((2, 4-dimethoxybenzyl) amino) -9,9a,10,11,12, 13-hexahydro-7H-pyrido [2',1':3,4] [1,4] oxazepino [6,5-c ] [1,5] naphthyridin-7-one (24 c)

Compound 24a (364mg, 1.04mmol) was dissolved in 2, 4-dimethoxybenzylamine (2 mL) at room temperature. N, N-diisopropylethylamine (404mg, 3.13mmol) was added to the reaction mixture, and the mixture was reacted at 100 ℃ for 2 hours. After the reaction was complete, it was cooled to room temperature. The reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (3X 20 mL), the organic phases were combined and washed with saturated ammonium chloride (2X 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 1/1) to obtain yellow solid mixtures 24b and 24c (162.8mg, 36.0%).

LC-MS：m/z 24b 481.2[M+H] ⁺ ；LC-MS：m/z 24c 435.2[M+H] ⁺ 。

And step 3: preparation of 6-amino-9, 9a,10,11,12, 13-hexahydro-7H-pyrido [2',1':3,4] [1,4] oxazepino [6,5-c ] [1,5] naphthyridin-7-one (24 d)

Mixtures 24b and 24c (162.8mg, 0.38mmol) were dissolved in dichloromethane (2 mL) at room temperature. Trifluoroacetic acid (1 mL) was added to the reaction mixture, and the mixture was reacted at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (mobile phase: dichloromethane/methanol = 10/1) to obtain compound 24d (66mg, 61.9%) as a yellow solid.

LC-MS：m/z 285.1[M+H] ⁺ 。

And 4, step 4: preparation of 2-amino-4- (2- (hydroxymethyl) piperidin-1-yl) -1, 5-naphthyridine-3-carboxylic acid (24 e)

Compound 24d (66mg, 0.23mmol) was added to an ethanol-water solution (1ml, 1). The reaction mixture was reacted at 80 ℃ for 4 hours. After completion of the reaction, the reaction solution was cooled to room temperature, neutralized with 1M HCl to neutrality, and concentrated under reduced pressure to give crude yellow compound 24e (150 mg, crude). It was used in the next step without purification.

LC-MS：m/z 303.1[M+H] ⁺ 。

And 5: preparation of (1- (2-amino-1, 5-naphthyridin-4-yl) piperidin-2-yl) methanol (24)

Diphenyl ether (1 mL) was added to Compound 24e (150 mg, crude) at room temperature and reacted at 160 ℃ for 6 hours. After cooling, the reaction solution was directly separated and purified by silica gel column chromatography (mobile phase: dichloromethane/methanol = 10/1) to obtain crude product as a yellow solid. And then separated and purified by using a preparative chromatography column (column type: gemini-NX C18 OBD AXAI column, 5um,21.2 x 150mm; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 21% -33% acetonitrile within 8 minutes; detection wavelength: 254/220 nm) to obtain compound 24 (2.9 mg, 6.6%) as a white solid.

¹ H NMR (400 MHz, methanol-d) ₄ )δ8.40(dd,J＝4.3,1.6Hz,1H),7.82(dd,J＝8.5,1.6Hz,1H),7.46(dd,J＝8.4,4.2Hz,1H),6.48(s,1H),4.78–4.66(m,1H),4.09–4.00(m,1H),3.65(dd,J＝10.9,5.8Hz,1H),3.63–3.56(m,1H),3.53–3.43(m,1H),1.97–1.79(m,2H),1.78–1.62(m,4H)。

LC-MS：m/z 259.2[M+H] ⁺ 。

Example 25: preparation of N- (2- ((2-amino-1, 5-naphthyridin-4-yl) amino) -2-methylhexyl) methanesulfonamide (25)

Step 1: preparation of N- (2- ((2-amino-1, 5-naphthyridin-4-yl) amino) -2-methylhexyl) methanesulfonamide (25)

Compound 22 (20mg, 0.073mmol) and N, N-diisopropylethylamine (28.4mg, 0.22mmol) were dissolved in dichloromethane (1 mL) at 0 ℃. Methanesulfonyl chloride (9.2mg, 0.08mmol) was dissolved in dichloromethane (0.5 mL) and added dropwise slowly to the reaction over 10 min. The reaction solution was then allowed to cool to room temperature and the reaction was continued for 30 minutes. After completion of the reaction, the reaction mixture was quenched with methanol (2 mL) and concentrated to dryness under reduced pressure. The crude product was isolated and purified by preparative chromatography (column type: xbridge Prep C18 OBD column, 5um, 19X 150mm; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 20% -36% acetonitrile within 10 minutes; detection wavelength: 254/220 nm) to give compound 25 as a white solid (4.0 mg, 15.6%).

¹ H NMR (400 MHz, methanol-d) ₄ )δ8.42(dd,J＝4.3,1.5Hz,1H),7.75(dd,J＝8.5,1.5Hz,1H),7.47(dd,J＝8.4,4.3Hz,1H),6.02(s,1H),3.54–3.43(m,2H),3.02(s,3H),1.86–1.60(m,2H),1.57–1.30(m,7H),0.94(t,J＝7.1Hz,3H)。

LC-MS：m/z 352.2[M+H] ⁺ 。

Example 26: preparation of N- (2- ((2-amino-1, 5-naphthyridin-4-yl) amino) -2-methylhexyl) cyclopropanecarboxamide (26)

Compound 26 was obtained in the same manner as in the preparation of example 25, except that methanesulfonyl chloride was replaced with cyclopropylcarbonyl chloride.

¹ H NMR (400 MHz, methanol-d) ₄ )δ8.66(dd,J＝4.5,1.4Hz,1H),7.89(dd,J＝8.5,1.4Hz,1H),7.71(dd,J＝8.4,4.4Hz,1H),6.00(s,1H),3.87(d,J＝13.6Hz,1H),3.58(d,J＝13.6Hz,1H),2.19–2.04(m,1H),1.68–1.47(m,2H),1.47–1.25(m,7H),1.00–0.88(m,3H),0.86–0.77(m,2H),0.73–0.65(m,2H)。

LC-MS：m/z 342.3[M+H] ⁺ 。

Example 27 and example 28: preparation of (R) -2- ((2-amino-1, 5-naphthyridin-4-yl) amino) heptan-1-ol (27) and (S) -2- ((2-amino-1, 5-naphthyridin-4-yl) amino) heptan-1-ol (28)

Compound 23 (25mg, 0.09mmol) was subjected to chiral resolution at room temperature. Column type: CHIRAL ART Cellulose-SB,2 × 25cm,5um; mobile phase A: n-hexane (10 mM methanolic ammonia solution), mobile phase B: ethanol(ii) a Flow rate: 20mL/min; gradient: a constant gradient of 20% acetonitrile over 22 minutes; detection wavelength: 263/218nm; to give compound 27 (7.1mg, 28.4%) as a white solid, t _R =3.305min, ee value (enantiomeric excess): 97.5 percent; and white solid compound 28 (1.7mg, 6.8%), t _R =4.513min, ee value (enantiomeric excess): 99.1 percent; .

Compound 27

¹ H NMR (300 MHz, methanol-d ₄ )δ8.47(dd,J＝4.3,1.5Hz,1H),7.82(dd,J＝8.5,1.5Hz,1H),7.54(dd,J＝8.4,4.3Hz,1H),6.08(s,1H),3.77(d,J＝4.9Hz,2H),3.74–3.62(m,1H),1.95–1.82(m,1H),1.81–1.65(m,1H),1.65–1.49(m,2H),1.49–1.35(m,4H),0.98(t,J＝7.0Hz,3H)。

LC-MS：m/z 275.1[M+H] ⁺ 。

Compound 28

¹ H NMR (300 MHz, methanol-d ₄ )δ8.48(dd,J＝4.3,1.5Hz,1H),7.82(dd,J＝8.5,1.5Hz,1H),7.54(dd,J＝8.5,4.3Hz,1H),6.08(s,1H),3.77(d,J＝4.9Hz,2H),3.74–3.64(m,1H),1.96–1.81(m,1H),1.81–1.66(m,1H),1.65–1.49(m,2H),1.48–1.36(m,4H),0.98(d,J＝7.0Hz,3H)。

LC-MS：m/z 275.1[M+H] ⁺ 。

Example 29: preparation of (R) -2- ((2-amino-7- (6- (pyrrolidin-1-ylmethyl) pyridin-3-yl) -1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (29)

Step 1: preparation of methyl 3-amino-5-bromopicolinate (29 b)

3-amino-5-bromopicolinic acid 29a (20.0 g, 0.09mol) was dissolved in methanol (200 mL) at room temperature, followed by addition of concentrated sulfuric acid (20 mL). The reaction mixture was reacted at 70 ℃ for 72 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the residue was extracted with water (200 mL) and ethyl acetate (3X 150 mL), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained yellow crude product was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether = 0-5%) to obtain compound 29b (8.5g, 39.9%) as a pale yellow solid.

LC-MS：m/z 231.0[M+H] ⁺ 。

Step 2: preparation of methyl 5-bromo-3- (3-ethoxy-3-oxopropanoylamino) picolinate (29 c)

Compound 29b (8.5g, 36.9mmol) and triethylamine (11.2g, 110.6mmol) were dissolved in dichloromethane (100 mL) at room temperature, and malonic acid monoethyl ester acid chloride (6.6g, 44.3mmol) was slowly added dropwise at 0 ℃ and the reaction was reacted at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, quenched with water (100 mL), extracted with ethyl acetate (3X 100 mL), the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting yellow crude product was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether = 0-5%) to obtain compound 29c (6.8g, 53.5%) as a yellow solid.

LC-MS：m/z 345.0[M+H] ⁺ 。

And step 3: preparation of ethyl 7-bromo-2, 4-dioxo-1, 2,3, 4-tetrahydro-1, 5-naphthyridine-3-carboxylate (29 d)

Compound 29c (6.8g, 19.8mmol) and sodium ethoxide (3.4 g, 50mmol) were dissolved in ethanol (60 mL) at room temperature, and the reaction solution was allowed to stand at 80 ℃ for reaction for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, diluted with water (50 mL), and the pH of the reaction mixture was adjusted to 6 with 1mol/L dilute hydrochloric acid. The resulting mixture was concentrated under reduced pressure to give crude compound 29d (10.0 g, crude) as a yellow solid, which was used in the next step without purification.

LC-MS：m/z 313.0[M+H] ⁺ 。

And 4, step 4: preparation of ethyl 7-bromo-2, 4-dichloro-1, 5-naphthyridine-3-carboxylate (29 e)

At 0 deg.C, compound 29d (10.0 g, crude) and phosphorus oxychloride (50 mL) were added. The reaction mixture was reacted at 100 ℃ for 1.5 hours. After the reaction, the reaction mixture was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, quenched with ice water, and extracted with ethyl acetate (3 × 80 mL), the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting yellow crude product was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether = 0-3%) to obtain 29e (4.35 g, two-step yield 63.0%) as a yellow solid compound

LC-MS：m/z 348.9[M+H] ⁺ 。

And 5: preparation of ethyl (R) -7-bromo-4- ((1- ((tert-butyldimethylsilyl) oxy) -2-methylhexan-2-yl) amino) -2-chloro-1, 5-naphthyridine-3-carboxylate (29 f)

Compound 29e (4.35g, 12.4 mmol) and compound 11e (3.66g, 14.9 mmol) were dissolved in N-methylpyrrolidinone (40 mL) at room temperature under nitrogen and N, N-diisopropylethylamine (4.84g, 37.4 mmol) was added. The reaction was stirred at 100 ℃ under nitrogen for 4 hours. After cooling to room temperature, a saturated ammonium chloride solution (100 mL) was added, and ethyl acetate (3 × 80 mL) was added to the system to extract, and the combined organic phases were washed with a saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting yellow crude product was isolated and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether = 0-5%) to obtain compound 29f (5.1g, 73.7%) as a yellow oily liquid.

LC-MS：m/z 558.2[M+H] ⁺ 。

Step 6: preparation of ethyl (R) -7-bromo-4- ((1- ((tert-butyldimethylsilyl) oxy) -2-methylhexan-2-yl) amino) -2- ((2, 4-dimethoxybenzyl) amino) -1, 5-naphthyridine-3-carboxylate (29 g)

Compound 29f (5.1g, 9.1mmol) and N, N-diisopropylethylamine (3.5g, 27.3mmol) were dissolved in 2, 4-dimethoxybenzylamine (10 mL) at room temperature. The reaction mixture was reacted at 100 ℃ for 6 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, saturated ammonium chloride solution (100 mL) was added, ethyl acetate (3X 80 mL) was added to the reaction mixture to extract the mixture, and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting yellow crude product was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether = 0-3%) to obtain 29g (5.3g, 80.9%) of a yellow oily liquid compound.

LC-MS：m/z 689.3[M+H] ⁺ 。

And 7: preparation of (R) -7-bromo-4- ((1- ((tert-butyldimethylsilyl) oxy) -2-methylhexan-2-yl) amino) -2- ((2, 4-dimethoxybenzyl) amino) -1, 5-naphthyridine-3-carboxylic acid (29 h)

Compound 29g (5.3g, 7.7mmol) was dissolved in anhydrous ethanol (25 mL) at room temperature, and aqueous sodium hydroxide solution (12.5 mol/L,25 mL) was added. The reaction solution was stirred at 80 ℃ for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and water (100 mL) was added to the resulting yellow crude product, and 1mol/L diluted hydrochloric acid was added to adjust the pH to 6. Ethyl acetate (3X 80 mL) was added to the system for extraction, and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give yellow solid compound 29h (6.25 g, crude).

LC-MS：m/z 661.2[M+H] ⁺ 。

And 8: (R) -7-bromo-N ⁴ - (1- ((tert-butyldimethylsilyl) oxy) -2-methylhexan-2-yl) -N ² Preparation of- (2, 4-dimethoxybenzyl) -1, 5-naphthyridine-2, 4-diamine (29 i)

Compound 29h (6.25 g, crude) was dissolved in diphenyl ether (8 mL) at rt. The mixture was reacted at 160 ℃ for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature, and the obtained crude product was isolated and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether = 0-14%) to obtain 29i (2.31 g, two-step yield 48.7%) as a yellow viscous liquid.

LC-MS：m/z 617.24[M+H] ⁺ 。

And step 9: preparation of 5-bromo-2- (pyrrolidin-1-ylmethyl) pyridine (29 j)

5-bromo-2-pyridinecarboxaldehyde (200mg, 1.07mmol) was dissolved in methanol (4 mL) at room temperature. To the reaction mixture was added tetrahydropyrrole (97. Mu.L, 1.18 mmol). The reaction was carried out at room temperature for 0.5 hour. Sodium triacetoxyborohydride (228mg, 1.07mmol) was added to the reaction mixture, and the reaction was continued at room temperature for 12 hours. After the reaction is complete. The reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (3X 20 mL), the organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude yellow oil was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate/triethylamine = 1/1/0.01) to obtain compound 29j (130mg, 50.1%) as a yellow solid.

LC-MS：m/z 241.0[M+H] ⁺ 。

Step 10: (R) -N ⁴ - (1- ((tert-butyldimethylsilyl) oxy) -2-methylhexan-2-yl) -N ² Preparation of- (2, 4-dimethoxybenzyl) -7- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1, 5-naphthyridine-2, 4-diamine (29 k)

Compound 29i (100mg, 0.16mmol) was dissolved in 1, 4-dioxane (1 mL) at room temperature. Biborapinacol ester (62mg, 0.24mmol), potassium acetate (63mg, 0.64mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (13mg, 0.016 mmol) were added to the reaction solution in this order. The reaction solution was replaced with nitrogen three times, and reacted at 80 ℃ for 12 hours. After the reaction was complete, cool to room temperature. The reaction was diluted with water (30 mL), extracted with ethyl acetate (3X 20 mL), the organic phases combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give crude compound 29k (200 mg, crude) as a yellow oil. It was used in the next step without purification.

LC-MS：m/z 665.3[M+H] ⁺ 。

Step 11: (R) -N ⁴ - (1- ((tert-butyldimethylsilyl) oxy) -2-methylhexan-2-yl) -N ² Preparation of (2, 4-Dimethoxybenzyl) -7- (6- (pyrrolidin-1-ylmethyl) pyridin-3-yl) -1, 5-naphthyridine-2, 4-diamine (29 l)

Compound 29k (60mg, 0.25mmol) was dissolved in 1, 4-dioxane (3 mL) and water (0.75 mL) at room temperature. To the reaction solution were added potassium carbonate (69mg, 0.50mmol), compound 29j (200 mg, crude product) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (21mg, 0.025mmol) in this order. The reaction solution was replaced with nitrogen three times and reacted at 95 ℃ for 2 hours. After the reaction was complete, it was cooled to room temperature. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (3X 10 mL), the organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude yellow oil was isolated and purified by silica gel column chromatography (mobile phase: dichloromethane/methanol/triethylamine = 15/1/0.01) to give 29l (62 mg, two-step yield 54.9%) as a yellow solid compound.

LC-MS：m/z 699.4[M+H] ⁺ 。

Step 12: preparation of (R) -2- ((2-amino-7- (6- (pyrrolidin-1-ylmethyl) pyridin-3-yl) -1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (29)

Compound 29l (62mg, 0.088mmol) was dissolved in dichloromethane (1.5 mL) at room temperature. Trifluoroacetic acid (0.5 mL) was added to the reaction mixture. The reaction was carried out at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was isolated and purified by preparative chromatography (column type: XSelect CSH Prep C18 OBD column, 5. Mu.m, 19X 150mm; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 25% -44% acetonitrile over 8 min; detection wavelength: 254 nm) to give compound 29 (5.9 mg, 15.4%) as a colorless oil.

¹ H NMR (300 MHz, methanol-d ₄ )δ8.89(dd,J＝2.4,0.8Hz,1H),8.72(d,J＝2.1Hz,1H),8.20(dd,J＝8.2,2.4Hz,1H),7.95(d,J＝2.1Hz,1H),7.66(dd,J＝8.1,0.8Hz,1H),6.26(s,1H),3.97(s,2H),3.82(d,J＝11.2Hz,1H),3.65(d,J＝11.2Hz,1H),2.87–2.67(m,4H),1.99–1.80(m,4H),1.76–1.59(m,2H),1.47(s,3H),1.41–1.33(m,4H),0.93(t,J＝6.8Hz,3H)。

LC-MS：m/z 435.2[M+H] ⁺ 。

Example 30: preparation of (R) -2- ((2-amino-5, 6,7, 8-tetrahydro-1, 5-naphthyridin-4-yl) amino) -2-methylbutan-1-ol (30)

Step 1: preparation of (R) -2- ((2-amino-5, 6,7, 8-tetrahydro-1, 5-naphthyridin-4-yl) amino) -2-methylbutan-1-ol (30)

To a solution of compound 20 (25.0 mg, 0.101mmol) in methanol (3 mL) at room temperature under a nitrogen atmosphere was added platinum dioxide (10.0 mg). The reaction mixture was reacted overnight at 50 ℃ under a hydrogen atmosphere (10 atm). After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative chromatography (preparative column: XSelect CSH Prep C18 OBD column, 5um,19 x 150mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 5% -20% in 8 min; detection wavelength: 254 nm) to give off-white solid compound 30 (0.6 mg, 1.7%).

¹ H NMR (400 MHz, methanol-d) ₄ )δ6.01(s,1H),3.69(d,J＝11.2Hz,1H),3.51(d,J＝11.2Hz,1H),3.20–3.08(m,2H),2.63(t,J＝6.5Hz,2H),1.93–1.72(m,4H),1.35(s,3H),0.88(t,J＝7.5Hz,3H)。

LC-MS：m/z 251.0[M+H] ⁺ 。

Example 31: preparation of (R) -2- ((2-amino-7- (1 '-methyl-1', 2',3',6 '-tetrahydro- [2,4' -bipyridin ] -5-yl) -1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (31)

Step 1: preparation of 5-bromo-1 '-methyl-1', 2',3',6 '-tetrahydro-2, 4' -bipyridine (31 a)

1-methyl-1, 2,3, 6-tetrahydropyridine-4-boronic acid pinacol ester (300mg, 1.35mmol) was dissolved in 1, 4-dioxane (4 mL) and water (1 mL) at room temperature. Sodium carbonate (214mg, 2.02mmol), 2, 5-dibromopyridine (350mg, 1.48mmol) and tetrakis (triphenylphosphine) palladium (9mg, 0.011mmol) were added to the reaction solution in this order. The reaction solution was purged with nitrogen three times and reacted at 100 ℃ for 5 hours. After the reaction was complete, it was cooled to room temperature. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (3X 20 mL), and the organic phases were combined and washed with saturated brine (20 mL). Dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The crude yellow oil was isolated and purified by silica gel column chromatography (mobile phase: dichloromethane/methanol = 10/1) to give compound 31a as a yellow solid (60mg, 17.7%).

LC-MS：m/z 253.0[M+H] ⁺ 。

The remaining steps are the same as steps 10 to 12 of example 29, except that compound 31a is used instead of compound 29j to obtain compound 31.

¹ H NMR (300 MHz, methanol-d 4) δ 8.87 (dd, J =2.4,0.8hz, 1h), 8.70 (d, J =2.0hz, 1h), 8.15 (dd, J =8.4,2.4hz, 1h), 7.93 (d, J =2.1hz, 1h), 7.76-7.67 (m, 1H), 6.76 (d, J =3.6hz, 1h), 6.25 (s, 1H), 3.82 (d, J =11.2hz, 1h), 3.65 (d, J =11.1hz, 1h), 3.26 (d, J =3.4hz, 2h), 2.79 (s, 4H), 2.45 (s, 3H), 1.98-1.77 (m, 2H), 1.47 (s, 3H), 1.44-1.29 (m, 4H), 0.87, 99H, 0.87 (m, 0H).

LC-MS：m/z 447.2[M+H] ⁺ 。

Example 32: preparation of (R) -2- ((2-amino-7-methyl-1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (32)

Step 1: (R) -N ⁴ - (1- ((tert-butyldimethylsilyl) oxy) -2-methylhexan-2-yl) -N ² Preparation of- (2, 4-dimethoxybenzyl) -7-methyl-1, 5-naphthyridine-2, 4-diamine (32 a)

Compound 29i (70mg, 0.11mmol) was dissolved in 1, 4-dioxane (1.5 mL) and water (0.3 mL) at room temperature. Trimethylcyclotriboroxane (17.1mg, 0.14mmol), cesium carbonate (73.9mg, 0.23mmol) and tetrakis (triphenylphosphine) palladium (13.0mg, 0.01mmol) were sequentially added to the reaction solution. The reaction solution was replaced with nitrogen three times and reacted at 100 ℃ overnight. After the reaction was complete, cool to room temperature. The reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (3X 20 mL), the organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 32a (50mg, 47.9%) as a yellow oil.

LC-MS:m/z 553.3[M+H] ⁺ 。

And 2, step: preparation of (R) -2- ((2-amino-7-methyl-1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (32)

Compound 32a (30mg, 0.05mmol) was dissolved in dichloromethane (1.5 mL) at room temperature. Trifluoroacetic acid (0.5 mL) was added to the reaction mixture, and the mixture was reacted at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was separated and purified by preparative chromatography (column type: XSelect CSH Prep C18 OBD column, 5. Mu.m, 19X 150mm; mobile phase A: water (10 mmol/L ammonium hydrogencarbonate), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 20% to 40% acetonitrile in 8 minutes; detection wavelength: 254 nm) to obtain compound 32 (4.4mg, 28.1%) as a white solid.

¹ H NMR (400 MHz, methanol-d) ₄ )δ8.14(d,J＝1.9Hz,1H),7.41(d,J＝1.9Hz,1H),6.05(s,1H),3.68(d,J＝11.2Hz,1H),3.51(d,J＝11.2Hz,1H),2.33(s,3H),1.84–1.62(m,2H),1.32(s,3H),1.29–1.16(m,4H),0.80(t,J＝6.6Hz,3H)。

LC-MS:m/z 289.1[M+H] ⁺ 。

Example 33: preparation of (R) -2- ((2-amino-7-bromo-1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (33)

Step 1: preparation of (R) -2- ((2-amino-7-bromo-1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (33)

Compound 29i (30mg, 0.05mmol) was dissolved in dichloromethane (3.0 mL) at room temperature. Trifluoroacetic acid (1.5 mL) was added to the reaction mixture, and the mixture was reacted at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, diluted with a saturated sodium bicarbonate solution (20 mL), extracted with ethyl acetate (3X 20 mL), the organic phases were combined and washed with a saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was separated and purified by preparative chromatography (column type: XSelectCSH Prep C18 OBD column, 5um, 19X 150mm; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 35% -55% acetonitrile within 8 minutes; detection wavelength: 254 nm) to obtain compound 29 as a white solid (7.2mg, 54.0%).

¹ H NMR (400 MHz, methanol-d) ₄ )δ8.37(d,J＝2.1Hz,1H),7.84(d,J＝2.1Hz,1H),6.20(s,1H),3.77(d,J＝11.1Hz,1H),3.60(d,J＝11.1Hz,1H),1.95–1.70(m,2H),1.41(s,3H),1.39–1.27(m,4H),0.90(t,J＝6.7Hz,3H)。

LC-MS:m/z 354.1[M+H] ⁺ 。

Example 34: preparation of (R) -2- ((2-amino-7- (6- ((4-methylpiperazin-1-yl) methyl) pyridin-3-yl) -1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (34)

Step 1: preparation of 1- ((5-bromopyridin-2-yl) methyl) -4-methylpiperazine (34 a)

5-bromo-2-pyridinecarboxaldehyde (200mg, 1.07mmol) was dissolved in 1, 2-dichloroethane (2 mL) at room temperature. N-methylpiperazine (179. Mu.L, 1.61 mmol) was added to the reaction mixture. The reaction was carried out at room temperature for 0.5 hour. Sodium triacetoxyborohydride (342mg, 1.61mmol) was added to the reaction mixture, and the reaction was continued at room temperature for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting crude yellow oil was purified by silica gel column chromatography (mobile phase: dichloromethane/methanol/triethylamine = 10/1/0.01) to obtain compound 34a (240mg, 82.6%) as a yellow solid.

LC-MS：m/z 270.1[M+H] ⁺ 。

And 2, step: preparation of 1-methyl-4- ((5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridin-2-yl) methyl) piperazine (34 b)

Compound 34a (240mg, 0.89mmol) was dissolved in 1, 4-dioxane (4 mL) at room temperature. Biborapinacol ester (338mg, 0.24mmol), potassium acetate (348mg, 0.64mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (73mg, 0.089mmol) were sequentially added to the reaction solution. The reaction solution was replaced with nitrogen three times and reacted at 80 ℃ for 12 hours. After the reaction was complete, it was cooled to room temperature. The reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (3X 20 mL), the organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude compound 34b (400 mg, crude) as a yellow oil. It was used in the next step without purification.

LC-MS：m/z 318.4[M+H] ⁺ 。

And 3, step 3: (R) -N ⁴ - (1- ((tert-butyldimethylsilyl) oxy) -2-methylhexan-2-yl) -N ² Preparation of- (2, 4-dimethoxybenzyl) -7- (6- ((4-methylpiperazin-1-yl) methyl) pyridin-3-yl) -1, 5-naphthyridine-2, 4-diamine (34 c)

Compound 29i (70mg, 0.11mmol) was dissolved in 1, 4-dioxane (2 mL) and water (0.5 mL) at room temperature. To the reaction solution were added potassium carbonate (31mg, 0.23mmol), compound 34b (200 mg, crude product) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (9mg, 0.011mmol) in this order. The reaction solution was replaced with nitrogen three times and reacted at 95 ℃ for 2 hours. After the reaction was complete, cool to room temperature. The reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (3X 20 mL), the organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude yellow oil was isolated and purified by silica gel column chromatography (mobile phase: dichloromethane/methanol/triethylamine = 10/1/0.01) to give compound 34c (60mg, 72.8%) as a yellow solid.

LC-MS：m/z 728.4[M+H] ⁺ 。

And 4, step 4: preparation of (R) -2- ((2-amino-7- (6- ((4-methylpiperazin-1-yl) methyl) pyridin-3-yl) -1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (34)

Compound 34c (60mg, 0.082mmol) was dissolved in dichloromethane (1.5 mL) at room temperature. Trifluoroacetic acid (0.5 mL) was added to the reaction mixture, and the mixture was reacted at 40 ℃ for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained crude product was separated and purified by preparative chromatography (column type: XBridge Prep C18 OBD column, 5. Mu.m, 19X 150mm; mobile phase A: water (0.05% ammonia), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 25% -48% acetonitrile within 8 minutes; detection wavelength: 254/220 nm) to give off-white semi-solid semi-oily compound 34 (6.1mg, 16.0%).

¹ H NMR (400 MHz, methanol-d) ₄ )δ8.84(d,J＝2.3Hz,1H),8.66(d,J＝2.1Hz,1H),8.16(dd,J＝8.1,2.4Hz,1H),7.90(d,J＝2.1Hz,1H),7.66(d,J＝8.1Hz,1H),6.23(s,1H),3.80(d,J＝11.1Hz,1H),3.74(s,2H),3.63(d,J＝11.2Hz,1H),2.83–2.36(m,8H),2.29(s,3H),1.96–1.74(m,2H),1.44(s,3H),1.41–1.29(m,4H),0.96–0.85(m,3H)。

LC-MS：m/z 464.2[M+H] ⁺ 。

Example 35: preparation of (R) -2- ((2-amino-7- (2- (4-methylpiperazin-1-yl) pyrimidin-5-yl) -1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (35)

Compound 35 was obtained in the same manner as in step 3 and step 4 of example 34, except that compound 34b was replaced with 2- (4-methylpiperazin-1-yl) pyrimidine-5-boronic acid pinacol ester.

¹ H NMR (300 MHz, methanol-d ₄ )δ8.78–8.65(m,2H),8.65–8.55(m,1H),7.92–7.80(m,1H),6.28–6.14(m,1H),4.00–3.86(m,4H),3.81(d,J＝11.1Hz,1H),3.64 (d,J＝11.2Hz,1H),2.61–2.46(m,4H),2.37(s,3H),2.00–1.72(m,2H),1.45(s,3H),1.42–1.28(m,4H),1.03–0.83(m,3H)。

LC-MS：m/z 451.3[M+H] ⁺ 。

Example 36: preparation of (R) -2- ((2-amino-7- (2- (diethylamino) pyrimidin-5-yl) -1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (36)

Step 1: preparation of N, N-diethyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidin-2-amine (36 a)

5-bromo-2- (diethylamino) pyrimidine (50mg, 0.22mmol), pinacol diboron (83mg, 0.33mmol) and potassium acetate (64mg, 0.65mmol) were dissolved in 1, 4-dioxane (2 mL) at room temperature, then [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (33mg, 0.04mmol) was added, and the reaction solution was replaced three times with nitrogen and reacted at 80 ℃ overnight. After completion of the reaction, the reaction was quenched with water (30 mL), and ethyl acetate (3X 20 mL) was added to the system to extract, and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was isolated and purified by silica gel column chromatography (mobile phase: dichloromethane/methanol = 12/1) to give compound 36a as a yellow solid (70mg, 116.3%).

LC-MS：m/z 278.2[M+H] ⁺ 。

The remaining steps are the same as steps 3 and 4 of example 34, except that compound 34b is replaced with compound 36a to give compound 36.

¹ H NMR (400 MHz, methanol-d) ₄ )δ8.67(s,2H),8.63–8.56(m,1H),7.80(s,1H),6.20(s,1H),3.79(d,J＝11.1Hz,1H),3.70(q,J＝7.0Hz,4H),3.63(d,J＝11.2Hz,1H),1.96–1.73(m,2H),1.44(s,3H),1.40–1.29(m,4H),1.22(t,J＝7.0Hz,6H),0.96–0.86(m,3H)。

LC-MS：m/z 424.2[M+H] ⁺ 。

Example 37: preparation of (R) -2- ((2-amino-7- (2-morpholinopyrimidin-5-yl) -1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (37)

Compound 37 was obtained in the same manner as in step 3 and step 4 of example 34, except that compound 34b was replaced with 2- (4-morphinanyl) pyrimidine-5-boronic acid pinacol ester.

¹ H NMR (400 MHz, methanol-d) ₄ )δ8.84(d,J＝1.3Hz,1H),8.78(s,2H),7.97(s,1H),6.25(s,1H),3.92–3.85(m,4H),3.84–3.73(m,5H),3.62(d,J＝11.2Hz,1H),1.93–1.81(m,2H),1.47(s,3H),1.44–1.29(m,4H),0.97–0.88(m,3H)。

LC-MS：m/z 438.1[M+H] ⁺ 。

Example 38: preparation of (R) -2- ((2-amino-7- (6- (morpholinomethyl) pyridin-3-yl) -1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (38)

Compound 38 was obtained in the same manner as in step 3 and step 4 of example 34, except that compound 34b was replaced with 6- [ (4-morpholinyl) methyl ] pyridine-3-boronic acid pinacol ester.

¹ H NMR (400 MHz, methanol-d) ₄ )δ8.83(d,J＝2.3Hz,1H),8.68(d,J＝2.0Hz,1H),8.15(dd,J＝8.2,2.4Hz,1H),7.93(d,J＝2.1Hz,1H),7.66(d,J＝8.1Hz,1H),6.24(s,1H),3.82(d,J＝11.2Hz,1H),3.77–3.69(m,6H),3.65(d,J＝11.2Hz,1H),2.62–2.48(m,4H),1.97–1.74(m,2H),1.46(s,3H),1.42–1.30(m,4H),0.92(t,J＝6.8Hz,3H)。

LC-MS：m/z 451.1[M+H] ⁺ 。

Example 39: preparation of (R) -2- ((2-amino-7- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) -1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (39)

Compound 39 was prepared in the same manner as in step 3 and step 4 of example 34, except that compound 34b was replaced with 2- (4-methylpiperazin-1-yl) pyridine-5-boronic acid pinacol ester.

¹ H NMR (400 MHz, methanol-d) ₄ )δ8.63(t,J＝2.0Hz,1H),8.49(d,J＝2.6Hz,1H),7.99–7.89(m,1H),7.84–7.78(m,1H),6.97(d,J＝9.0Hz,1H),6.20(s,1H),3.79(d,J＝11.2Hz,1H),3.70–3.56(m,5H),2.58(t,J＝5.1Hz,4H),2.36(s,3H),1.97–1.73(m,2H),1.44(s,3H),1.40–1.30(m,4H),0.99–0.84(m,3H)。

LC-MS：m/z 450.2[M+H] ⁺ 。

Example 40: preparation of (R) -2- ((2-amino-7- (2- (pyrrolidin-1-yl) pyrimidin-5-yl) -1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (40)

Step 1: preparation of 5-bromo-2- (pyrrolidin-1-yl) pyrimidine (40 a)

5-bromo-2-chloropyrimidine (1.0 g, 5.17mmol) and tetrahydropyrrole (0.74g, 10.34mmol) were dissolved in anhydrous ethanol (10 mL) at room temperature. After the reaction mixture was stirred at 80 ℃ overnight, it was concentrated under reduced pressure, the residue was diluted with water (50 mL), ethyl acetate (3X 50 mL) was added and extracted, the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 40a (1.09g, 92.4%) as a white solid.

LC-MS：m/z 228.0[M+H] ⁺ 。

The remaining steps are the same as in step 2, step 3 and step 4 of example 34, except that compound 34a is replaced with 40a to give compound 40.

¹ H NMR (300 MHz, methanol-d ₄ )δ8.71(s,2H),8.62(d,J＝2.0Hz,1H),7.83(d,J＝2.1Hz,1H),6.23(s,1H),3.82(d,J＝11.0Hz,1H),3.70–3.60(m,5H),2.11–2.03(m,4H),1.96–1.78(m,2H),1.46(s,3H),1.43–1.33(m,4H),0.99–0.89(m,3H)。

LC-MS：m/z 422.1[M+H] ⁺ 。

Example 41: preparation of (2R) -2- ((2-amino-7- (2- (3-methylpyrrolidin-1-yl) pyrimidin-5-yl) -1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (41)

Step 1: preparation of 5-bromo-2- (3-methylpyrrolidin-1-yl) pyrimidine (41 a)

5-bromo-2-chloropyrimidine (477mg, 2.47mmol) and 3-methylpyrrolidine hydrochloride (300mg, 2.47mmol) were dissolved in absolute ethanol (8 mL) at room temperature. N, N-diisopropylethylamine (637mg, 4.93mmol) was added to the reaction mixture, and after stirring at 80 ℃ overnight, the mixture was concentrated under reduced pressure, the residue was diluted with water (30 mL), ethyl acetate (3X 20 mL) was added thereto for extraction, the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 41a (507mg, 84.9%) as a yellow solid.

LC-MS：m/z 242.0[M+H] ⁺ 。

The remaining steps are the same as in step 2, step 3 and step 4 of example 34, except that compound 34a is replaced with 41a to give compound 41.

¹ H NMR (300 MHz, methanol-d ₄ )δ8.68(s,2H),8.59(d,J＝2.0Hz,1H),7.80(d,J＝2.1Hz,1H),6.22(s,1H),3.91–3.71(m,3H),3.69–3.48(m,2H),3.12(dd,J＝11.0,8.0Hz,1H),2.53–2.33(m,1H),2.28–2.10(m,1H),2.01–1.76(m,2H),1.75–1.59(m,1H),1.46(s,3H),1.43–1.31(m,4H),1.17(d,J＝6.7Hz,3H),1.02–0.82(m,3H)。

LC-MS：m/z 436.1[M+H] ⁺ 。

Example 42: preparation of (R) -6-amino-8- ((1-hydroxy-2-methylhexan-2-yl) amino) -1, 5-naphthyridin-3-ol (42)

Step 1: preparation of (R) -8- ((1- ((tert-butyldimethylsilyl) oxy) -2-methylhexan-2-yl) amino) -6- ((2, 4-dimethoxybenzyl) amino) -1, 5-naphthyridin-3-ol (42 a)

Compound 29k (65mg, 0.098mmol) was dissolved in tetrahydrofuran (0.5 mL) and water (0.10 mL) at room temperature. To the reaction solution were added sodium hydroxide (3.1mg, 0.078mmol) and 30% hydrogen peroxide (22.2mg, 0.196mmol), and after stirring at room temperature for 2 hours, water (20 mL) was added for dilution, ethyl acetate (3 × 10 mL) was further added for extraction, the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting crude product was isolated and purified by preparative thin layer chromatography (mobile phase: dichloromethane/methanol = 12) to give compound 42a (20mg, 36.9%) as a brown oil.

LC-MS：m/z 555.3[M+H] ⁺ 。

Step 2: preparation of (R) -6-amino-8- ((1-hydroxy-2-methylhexan-2-yl) amino) -1, 5-naphthyridin-3-ol (42)

Compound 42a (30mg, 0.054 mmol) was dissolved in dichloromethane (1.5 mL) at room temperature. Trifluoroacetic acid (0.5 mL) was added to the reaction mixture, and the mixture was reacted at room temperature for 2 hours. After completion of the reaction, the reaction liquid was concentrated under reduced pressure, and the residue was separated and purified by preparative chromatography (column type: XBridge Prep C18 OBD column, 5um, 19X 150mm; mobile phase A: water (10 mmol/L ammonium hydrogencarbonate), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 6% -32% acetonitrile within 8 minutes; detection wavelength: 254 nm) to give a pale yellow solid compound 42 (5 mg, 30.0%).

¹ H NMR (400 MHz, methanol-d) ₄ )δ8.21(d,J＝2.2Hz,1H),7.14(s,1H),6.10(s,1H),3.78(d,J＝11.2Hz,1H),3.60(d,J＝11.2Hz,1H),1.94–1.76(m,2H),1.45(s,3H),1.41–1.24(m,4H),0.92(t,J＝6.8Hz,3H)。

LC-MS：m/z 291.1[M+H] ⁺ 。

Example 43: preparation of (R) -2- ((2-amino-7-methoxy-1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (43)

Step 1: (R) -N ⁴ - (1- ((tert-butyldimethylsilyl) oxy) -2-methylhexan-2-yl) -N ² Preparation of- (2, 4-dimethoxybenzyl) -7-methoxy-1, 5-naphthyridine-2, 4-diamine (43 a)

Compound 42a (55mg, 0.099mmol) was dissolved in acetone (2.0 mL) at room temperature. To the reaction mixture were added potassium carbonate (17.1mg, 0.14mmol) and methyl iodide (73.9mg, 0.23mmol) in this order, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (3 × 20 mL), the organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane/methanol/triethylamine = 15/1/0.01) to obtain compound 43a (35mg, 62.1%) as a brown oil.

LC-MS：m/z 569.3[M+H] ⁺ 。

And 2, step: preparation of (R) -2- ((2-amino-7-methoxy-1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (43)

Compound 43a (35mg, 0.06mmol) was dissolved in dichloromethane (2.0 mL) at room temperature. Trifluoroacetic acid (1.0 mL) was added to the reaction mixture, and the mixture was reacted at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by means of a preparative chromatography column (column type: XSelectric CSH Prep C18 OBD column, 5. Mu.m, 19X 150mm; mobile phase A: water (0.05% ammonia), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 30% -48% acetonitrile in 8 minutes; detection wavelength: 254 nm) to obtain compound 43 (5.8mg, 30.3%) as a white solid.

¹ H NMR (400 MHz, methanol-d) ₄ )δ8.09(d,J＝2.3Hz,1H),7.11(d,J＝2.6Hz,1H),6.08(s,1H),3.90(s,3H),3.77(d,J＝11.1Hz,1H),3.60(d,J＝11.1Hz,1H),1.94–1.69(m,2H),1.41(s,3H),1.38–1.25(m,4H),0.94–0.85(m,3H)。

LC-MS：m/z 305.2[M+H] ⁺ 。

Example 44: preparation of (R) -2- ((2-amino-7-fluoroquinolin-4-yl) amino) -2-methylhexan-1-ol (44)

Step 1: preparation of methyl 2- (3-ethoxy-3-oxopropanoylamino) -4-fluorobenzoate (44 b)

Methyl 2-amino-4-fluorobenzoate 44a (1.00g, 5.91mmol) and triethylamine (1.79g, 17.74mmol) were dissolved in dichloromethane (10 mL) at room temperature, malonic acid monoethyl ester acid chloride (0.98 g, 6.50mmol) was slowly added dropwise at 0 deg.C, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, water (50 mL) was added, ethyl acetate (3 × 50 mL) was further added for extraction, the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 44b (1.5g, 89.6%) as a yellow oily liquid.

LC-MS：m/z 284.1[M+H] ⁺ 。

Step 2: preparation of ethyl 7-fluoro-2, 4-dioxo-1, 2,3, 4-tetrahydroquinoline-3-carboxylate (44 c)

Compound 44b (1.5g, 5.30mmol) and sodium ethoxide (0.72g, 10.59mmol) were dissolved in ethanol (20 mL) at room temperature, and the reaction solution was stirred at 80 ℃ for 4 hours. After the reaction, the reaction solution was concentrated until a large amount of solid appeared, and then filtered under reduced pressure, and the filter cake was rinsed with cold ethanol (2X 10 mL). The resulting filter cake was dried under vacuum to give compound 44c as an orange solid (1.2g, 90.2%).

LC-MS：m/z 252.1[M+H] ⁺ 。

And step 3: preparation of ethyl 2, 4-dichloro-7-fluoroquinoline-3-carboxylate (44 d)

To compound 44c (1.2g, 4.78mol) was added phosphorus oxychloride (8 mL) at 0 ℃. The reaction mixture was reacted at 100 ℃ for 1.5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, the residue was quenched with ice water, ethyl acetate (3 × 50 mL) was added to the system for extraction, the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 44d (1.0 g, 72.7%) as a yellow-green solid.

LC-MS：m/z 288.0[M+H] ⁺ 。

And 4, step 4: preparation of ethyl (R) -4- ((1- ((tert-butyldimethylsilyl) oxy) -2-methylhexan-2-yl) amino) -2-chloro-7-fluoroquinoline-3-carboxylate (44 e)

Compound 44d (320mg, 1.11mmol) and compound 11e (327mg, 1.33mmol) were dissolved in N-methylpyrrolidone (5 mL) at room temperature under nitrogen and N, N-diisopropylethylamine (431mg, 3.34mmol) was added. The reaction was stirred at 100 ℃ under nitrogen for 4 hours. After cooling to room temperature, water (50 mL) was added, ethyl acetate (3X 30 mL) was added to the system for extraction, and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 44e (300mg, 54.3%) as a yellow oily liquid.

LC-MS：m/z 497.2[M+H] ⁺ 。

And 5: preparation of ethyl (R) -4- ((1- ((tert-butyldimethylsilyl) oxy) -2-methylhexan-2-yl) amino) -2- ((2, 4-dimethoxybenzyl) amino) -7-fluoroquinoline-3-carboxylate (44 f)

Compound 44e (300mg, 0.6 mmol) was dissolved in 2, 4-dimethoxybenzylamine (3.0 mL) at room temperature, and N, N-diisopropylethylamine (232mg, 1.8 mmol) was added. The reaction solution was stirred at 100 ℃ for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, saturated ammonium chloride solution (30 mL) was added thereto, ethyl acetate (3X 20 mL) was added thereto for extraction, and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 44f (300mg, 79.2%) as a yellow oily liquid.

LC-MS：m/z 628.4[M+H] ⁺ 。

And 6: preparation of (R) -4- ((1- ((tert-butyldimethylsilyl) oxy) -2-methylhexan-2-yl) amino) -2- ((2, 4-dimethoxybenzyl) amino) -7-fluoroquinoline-3-carboxylic acid (44 g)

Compound 44f (300mg, 0.48mmol) was dissolved in absolute ethanol (3 mL) at room temperature, and aqueous sodium hydroxide (12.5 mol/L,3 mL) was added. The reaction mixture was stirred at 80 ℃ for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the resulting yellow crude product was added with water (20 mL) and 1mol/L dilute hydrochloric acid to adjust the pH to 5. Ethyl acetate (3X 20 mL) was added to the system for extraction, and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 44g (260mg, 90.7%) of a yellow solid compound.

LC-MS：m/z 600.32[M+H] ⁺ 。

And 7: (R) -N ⁴ - (1- ((tert-butyldimethylsilyl) oxy) -2-methylhexan-2-yl) -N ² Preparation of- (2, 4-dimethoxybenzyl) -7-fluoroquinoline-2, 4-diamine (44 h)

44g (260mg, 0.43mmol) of compound are dissolved in diphenyl ether (2 mL) at room temperature. The reaction was carried out at 160 ℃ for 1 hour. After completion of the reaction, the reaction solution was cooled to room temperature, and the crude product obtained as a gray oil was purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether = 0-35%) to obtain compound 44h (180mg, 94.1%) as a pale yellow oil.

LC-MS：m/z 556.3[M+H] ⁺ 。

And 8: preparation of (R) -2- ((2-amino-7-fluoroquinolin-4-yl) amino) -2-methylhexan-1-ol (44)

Compound 44h (180mg, 0.41mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1.0 mL) was added while cooling on ice, followed by reaction at room temperature for 4 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained crude product was separated and purified by means of preparative chromatography (column type: XBridge Prep C18 OBD column, 5. Mu.m, 19X 150mm; mobile phase A: water (0.05% ammonia), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 25% -44% acetonitrile within 12 minutes; detection wavelength: 254/220 nm) to obtain compound 44 (3.9mg, 3.3%) as a white solid product.

¹ H NMR (300 MHz, methanol-d ₄ )δ7.89(dd,J＝9.1,6.0Hz,1H),7.12(dd,J＝10.9,2.6Hz,1H),7.01(ddd,J＝9.1,8.2,2.7Hz,1H),6.18(s,1H),3.88(d,J＝11.1Hz,1H),3.66(d,J＝11.1Hz,1H),2.01–1.86(m,2H),1.52(s,3H),1.48–1.36(m,4H),0.98(t,J＝6.8Hz,3H)。

LC-MS：m/z 292.2[M+H] ⁺ 。

Example 45: preparation of (R) -2- ((2-amino-7- (pyrrolidin-1-yl) -1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (45)

Step 1: (R) -N ⁴ - (1- ((tert-butyldimethylsilyl) oxy) -2-methylhexan-2-yl) -N ² Preparation of- (2, 4-dimethoxybenzyl) -7- (pyrrolidin-1-yl) -1, 5-naphthyridine-2, 4-diamine (45 a)

Compound 29i (40mg, 0.07mmol) was dissolved in toluene (1.5 mL) at room temperature. Tetrahydropyrrole (5 mg, 0.08mmol), sodium tert-butoxide (18mg, 0.19mmol) and [2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl ] (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (17mg, 0.01mmol) are added to the reaction solution in this order. The reaction solution was replaced with nitrogen three times and reacted at 100 ℃ for 4 hours. After the reaction was complete, it was cooled to room temperature. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (3 × 10 mL), the organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the crude brown oil was isolated and purified by silica gel column chromatography (mobile phase: dichloromethane/methanol = 12/1) to give compound 45a (50mg, 127.0%) as a brown solid.

LC-MS：m/z 608.2[M+H] ⁺ 。

And 2, step: preparation of (R) -2- ((2-amino-7- (pyrrolidin-1-yl) -1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (45)

Compound 45a (50mg, 0.08mmol) was dissolved in dichloromethane (2.0 mL) at room temperature. Trifluoroacetic acid (1.0 mL) was added to the reaction mixture, and the mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained crude product was separated and purified by preparative chromatography (column type: kinetex EVO Prep C18 OBD column, 5um,21.2 x 150mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 20% -40% acetonitrile within 8 minutes; detection wavelength: 254 nm) to give a pale yellow solid compound 45 (4.8mg, 16.9%).

¹ H NMR (300 MHz, methanol-d) ₄ )δ8.15(d,J＝2.5Hz,1H),6.65(d,J＝2.5Hz,1H),6.02(s,1H),3.79(d,J＝11.2Hz,1H),3.61(d,J＝11.2Hz,1H),3.51–3.42(m,4H),2.18–2.07(m,4H),1.92–1.81(m,2H),1.46(s,3H),1.42–1.33(m,4H),0.94(t,J＝6.7Hz,3H)。

LC-MS：m/z 344.2[M+H] ⁺ 。

Example 46: preparation of (R) -2- ((2-amino-7- (4-methylpiperazin-1-yl) -1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (46)

Compound 46 was obtained in the same manner as in step 1 and step 2 of example 45, except that the compound pyrrolidine was replaced with N-methylpiperazine.

¹ H NMR (400 MHz, methanol)-d ₄ )δ8.48(s,1H),8.25(s,br,1H,HCOOH),7.22–7.12(m,1H),6.09(s,1H),3.77(d,J＝11.2Hz,1H),3.69–3.53(m,5H),3.19–3.05(m,4H),2.80–2.66(m,3H),1.92–1.77(m,2H),1.44(s,3H),1.41–1.22(m,4H),0.92(t,J＝6.8Hz,3H)。

LC-MS：m/z 373.25[M+H] ⁺ 。

Example 47: preparation of (R) -2- ((2-amino-7- (4- (pyridin-2-yl) piperazin-1-yl) -1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (47)

Compound 47 is obtained in the same manner as in step 1 and step 2 of example 45, except that the compound tetrahydropyrrole is replaced with 1- (pyridin-2-yl) piperazine.

¹ H NMR (300 MHz, methanol-d ₄ )δ8.39–8.34(m,1H),8.14(dd,J＝5.1,1.9Hz,1H),7.65–7.58(m,1H),7.10(d,J＝2.6Hz,1H),6.91(d,J＝8.5Hz,1H),6.73(dd,J＝7.1,5.0Hz,1H),6.07(s,1H),3.79(d,J＝11.2Hz,1H),3.76–3.69(m,4H),3.63(d,J＝11.2Hz,1H),3.51–3.43(m,4H),1.91–1.75(m,2H),1.44(s,3H),1.40–1.33(m,4H),0.97–0.89(m,3H)。

LC-MS：m/z 436.2[M+H] ⁺ 。

Example 48: preparation of (R) -2- ((2-amino-7- (2- (1-methylpiperidin-4-yl) pyrimidin-5-yl) -1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (48)

Step 1: preparation of (2- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) pyrimidin-5-yl) boronic acid (48 a)

The compound 5-bromo-2- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) pyrimidine (450mg, 1.77mmol) was dissolved in 1, 4-dioxane (4.5 mL) at room temperature. Biborapinacol ester (674mg, 2.66mmol), potassium acetate (348mg, 3.54mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (144mg, 0.17mmol) were added to the reaction solution in this order. The reaction solution was replaced with nitrogen three times and reacted at 80 ℃ for 12 hours. After the reaction was complete, it was cooled to room temperature. The reaction was diluted with water (30 mL), extracted with ethyl acetate (3X 20 mL), the organic phases combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give crude compound 48a (400 mg, crude) as a black solid. It was used in the next step without purification.

LC-MS：m/z 220.0[M+H] ⁺ 。

Step 2: preparation of (2- (1-methylpiperidin-4-yl) pyrimidin-5-yl) boronic acid (48 b)

To a solution of compound 48a (400mg, 1.83mmol) in methanol (20 mL) under nitrogen at room temperature was added 10% palladium on carbon (100 mg). The reaction mixture was reacted under a hydrogen atmosphere (2 atm) at room temperature for 4 hours. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give crude compound 48b (430 mg, crude) as a yellow solid. It was used in the next step without purification.

LC-MS：m/z 222.1[M+H] ⁺ 。

The remaining steps are the same as steps 3 and 4 of example 34, except that compound 34b is replaced with compound 48b to give compound 48.

¹ H NMR (300 MHz, methanol-d ₄ )δ9.09(s,2H),8.67(d,J＝2.1Hz,1H),7.94(d,J＝2.1Hz,1H),6.26(s,1H),3.82(d,J＝11.1Hz,1H),3.65(d,J＝11.1Hz,1H),3.12–2.89(m,3H),2.36(s,3H),2.32–2.18(m,2H),2.17–1.99(m,4H),1.97–1.73(m,2H),1.46(s,3H),1.43–1.30(m,4H),0.99–0.86(m,3H)。

LC-MS：m/z 450.25[M+H] ⁺ 。

Example 49: preparation of (R) -2- ((2-amino-7- (2- (pyrrolidin-1-ylmethyl) pyrimidin-5-yl) -1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (49)

Step 1: preparation of 5-bromopyrimidine-2-carbaldehyde (49 a)

Methyl 5-bromo-2-pyrimidinecarboxylate (700mg, 3.225mmol) was dissolved in tetrahydrofuran (8.0 mL) at room temperature. Diisobutylaluminum hydride (4.8mL, 1M in tetrahydrofuran) was slowly added dropwise at 0 ℃ and the reaction was allowed to warm to room temperature slowly and stirred at room temperature overnight. After completion of the reaction, the reaction was quenched with water (20 mL), and ethyl acetate (3X 20 mL) was added to the system for extraction, and the combined organic phases were washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 49a (70mg, 11.6%) as a yellow liquid.

LC-MS：m/z 187.1[M+H] ⁺ 。

The remaining steps are the same as in step 1 to step 4 of example 34, except that the compound 5-bromo-2-pyridinecarboxaldehyde is replaced with 49a, to obtain compound 49.

¹ H NMR (300 MHz, methanol-d ₄ )δ9.18(s,2H),8.73(d,J＝2.1Hz,1H),8.00(d,J＝2.1Hz,1H),6.28(s,1H),4.07(s,2H),3.82(d,J＝10.9Hz,1H),3.65(d,J＝10.6Hz,1H),2.88–2.72(m,4H),1.95–1.83(m,6H),1.47(s,3H),1.42–1.36(m,4H),0.99–0.84(m,3H)。

LC-MS：m/z 436.2[M+H] ⁺ 。

Example 50: preparation of (R) -2- ((2-amino-7- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) -1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (50)

Compound 50 is obtained in the same manner as in step 3 and step 4 of example 34, except that compound 34b is replaced with 1-methyl-1, 2,3, 6-tetrahydropyridine-4-boronic acid pinacol ester.

¹ H NMR (400 MHz, methanol-d) ₄ )δ8.66(d,J＝1.8Hz,1H),7.74(d,J＝2.1Hz,1H),6.47–6.40(m,1H),6.21(s,1H),3.79(d,J＝11.2Hz,1H),3.62(d,J＝11.2Hz,1H),3.29–3.23(m,2H),2.83(t,J＝5.7Hz,2H),2.74–2.66(m,2H),2.46(s,3H),1.91–1.77(m,2H),1.45(s,3H),1.41–1.28(m,4H),0.97–0.85(m,3H)。

LC-MS：m/z 370.1[M+H] ⁺ 。

Example 51: preparation of (R) - (4- (6-amino-8- ((1-hydroxy-2-methylhexan-2-yl) amino) -1, 5-naphthyridin-3-yl) phenyl) (pyrrolidin-1-yl) methanone (51)

Compound 51 was obtained in the same manner as in step 3 and step 4 of example 34, except that compound 34b was replaced with pinacol 4- (pyrrolidine-1-carbonyl) phenylboronate.

¹ H NMR (300 MHz, methanol-d) ₄ )δ8.71(d,J＝1.9Hz,1H),7.94(d,J＝2.0Hz,1H),7.85(d,J＝8.2Hz,2H),7.70(d,J＝8.1Hz,2H),6.25(s,1H),3.82(d,J＝11.1Hz,1H),3.71–3.61(m,3H),3.55(t,J＝6.5Hz,2H),2.12–1.75(m,6H),1.47(s,3H),1.43–1.32(m,4H),1.00–0.86(m,3H)。

LC-MS：m/z 448.2[M+H] ⁺ 。

Example 52: preparation of (R) -2- ((2-amino-7- (2- (4-methylpiperazin-1-yl) pyrimidin-5-yl) quinolin-4-yl) amino) -2-methylhexan-1-ol (52)

Preparation of compound 52g was identical to example 44, steps 1 to 7 of preparation of compound 44h, except that compound 2-amino-4-fluorobenzoate 44a was replaced with 2-amino-4-bromobenzoate, to prepare compound 52g.

Compound 52 was prepared in the same manner as in step 3 and step 4 of example 34, except that compound 34b was replaced with 2- (4-methylpiperazin-1-yl) pyrimidine-5-boronic acid pinacol ester to prepare compound 52.

¹ H NMR (300 MHz, methanol-d) ₄ )δ8.79(s,2H),8.10(d,J＝8.4Hz,1H),7.76–7.60(m,2H),6.20(s,1H),4.15–3.98(m,4H),3.87(d,J＝11.3Hz,1H),3.64(d,J＝11.3Hz,1H),3.00–2.81(m,4H),2.62(s,3H),2.00–1.82(m,2H),1.51(s,3H),1.47–1.23(m,4H),1.05–0.83(m,3H)。

LC-MS：m/z 450.25[M+H] ⁺ 。

Example 53: preparation of (R) -2- ((2-amino-7-bromo-3-fluoro-1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (53)

Step 1: preparation of (R) -2- ((2-amino-7-bromo-3-fluoro-1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (53)

Compound 33 (80mg, 0.226mmol) was dissolved in acetonitrile (5.0 mL) at room temperature. The selective fluorine reagent (80.23mg, 0.226mmol) was added in portions at room temperature and the reaction was stirred at room temperature overnight. After completion of the reaction, concentration was carried out under reduced pressure, and the obtained residue was isolated and purified by preparative chromatography (column type: xbridge Shield RP18 OBD column, 5um, 19X 150mm; mobile phase A: water 0.05% ammonia), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 41% -58% acetonitrile within 8 minutes; detection wavelength: 254 nm) to give compound 53 (13.8mg, 16.4%) as a pale yellow solid.

¹ H NMR (400 MHz, methanol-d) ₄ )δ8.49(d,J＝2.0Hz,1H),7.97(d,J＝2.1Hz,1H),3.73(d,J＝11.2Hz,1H),3.65–3.60(m,1H),1.84–1.74(m,2H),1.40(d,J＝1.8Hz,3H),1.37–1.30(m,4H),0.94–0.86(m,3H)。

LC-MS：m/z 370.95[M+H] ⁺ 。

Example 54: preparation of 2- ((2-amino-3-fluoroquinolin-4-yl) amino) hex-1-ol (54)

Step 1: preparation of 2, 4-dichloro-3-fluoroquinoline (54 a)

The compound 2-fluoropropanedioic acid (4.72g, 38.7 mmol) was dissolved in phosphorus oxychloride (80.0 mL) at room temperature. After warming to 80 ℃ for 30 minutes, aniline (3.00g, 32.2mmol) was added and the reaction was allowed to proceed at 80 ℃ overnight. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the residue was quenched with ice water (100 mL), extracted with ethyl acetate (3 × 150 mL), the organic phases were combined and washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 10/1) to obtain 54a (1.60g, 23.0%) as a yellow solid.

LC-MS：m/z 216.2[M+H] ⁺ 。

And 2, step: preparation of 4-chloro-N- (2, 4-dimethoxybenzyl) -3-fluoroquinolin-2-amine (54 b)

Compound 54a (1.20g, 5.55mmol) was dissolved in dry 1, 4-dioxane (20.0 mL) at room temperature. 2, 4-dimethoxybenzylamine (1.39g, 8.31mmol), palladium acetate (0.12g, 0.534mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.32g, 0.553mmol), and cesium carbonate (4.52g, 13.9mmol) were added in this order. After three nitrogen replacements, the reaction was carried out at 70 ℃ for 2 hours. After completion of the reaction, the reaction solution was quenched with water (100 mL), extracted with ethyl acetate (3 × 60 mL), the organic phases were combined and washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 3/1) to obtain 54b (800mg, 41.5%) as a pale yellow solid.

LC-MS：m/z 347.1[M+H] ⁺ 。

And 3, step 3: preparation of 2- ((2, 4-dimethoxybenzyl) amino) -3-fluoroquinolin-4-yl) amino) hex-1-ol (54 c)

Compound 54b (400mg, 1.27mmol) was dissolved in dry 1, 4-dioxane (10.0 mL) at room temperature. 2-amino-1-hexanol (223mg, 1.91mmol), 2- (dicyclohexylphosphine) -3, 6-dimethoxy-2 '-4' -6 '-tri-I-propyl-11' -biphenyl (68.2mg, 0.127mmol), methanesulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (115mg, 0.127mmol), and sodium tert-butoxide (366mg, 3.81mmol) were added in this order. After the nitrogen substitution was carried out three times, the reaction was carried out at 100 ℃ for 2 hours. After completion of the reaction, the reaction solution was quenched with water (25 mL) and extracted with ethyl acetate (3 × 20 mL), the organic phases were combined and washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 1/1) to give a light brown oil 54c (80mg, 15.9%).

LC-MS：m/z 428.0[M+H] ⁺

And 4, step 4: preparation of 2- ((2-amino-3-fluoroquinolin-4-yl) amino) hex-1-ol (54)

Compound 54c (80mg, 0.187mmol) was dissolved in dichloromethane (1.0 mL) at room temperature. Trifluoroacetic acid (1.0 mL) was added to the reaction mixture, and the mixture was reacted at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by preparative chromatography (column type: XSelect CSH Prep C18 OBD column, 5. Mu.m, 19X 150mm; mobile phase A: water (10 mmol/L ammonium hydrogencarbonate), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 15% to 50% acetonitrile in 10 minutes; detection wavelength: 254 nm) to give compound 54 (31.3mg, 60.3%) as a white solid.

¹ H NMR (300 MHz, methanol-d) ₄ )δ7.82(d,J＝8.4Hz,1H),7.34(d,J＝3.6Hz,2H),7.13-7.08(m,1H),3.98-3.93(m,1H),3.65-3.53(m,2H),1.66-1.53(m,2H),1.38-1.34(m,4H),0.82(t,J＝7.2Hz,3H)。

LC-MS：m/z 278.2[M+H] ⁺ 。

Example 55: preparation of (R) -2- ((2-amino-7-cyclopropyl-1, 5-naphthyridin-4-yl) amino) -2-methylhexan-1-ol (55)

Compound 55 was prepared in the same manner as in step 3 and step 4 of example 34, except that compound 34b was replaced with cyclopropylboronic acid.

¹ H NMR (400 MHz, methanol-d) ₄ )δ8.36(d,J＝1.9Hz,1H),7.34(d,J＝2.0Hz,1H),6.11(s,1H),3.69(d,J＝11.3Hz,1H),3.51(d,J＝11.2Hz,1H),2.12–1.99(m,1H),1.83–1.68(m,2H),1.36(s,3H),1.33–1.16(m,4H),1.16–1.07(m,2H),0.89–0.74(m,5H)。

LC-MS：m/z 315.0[M+H] ⁺ 。

Biological assay

Test example 1: agonistic activity of compounds of the invention against hTLR8 and hTLR7

In vitro assays for receptor binding activity of compounds of the invention to hTLR8 and hTLR7 cells lines HEK-Bluen hTLR8 and HEK-Bluen hTLR7, purchased from Invivogen, inc. The cell is cotransfected with hTLR8 or hTLR7 gene and a reporter gene of secreted alkaline phosphatase (SEAP) in HEK293 cells. The SEAP gene is placed at the downstream of IFN-beta minimal promoter, and the IFN-beta minimal promoter is composed of 5 NF-movers and AP-1 binding sites. The stimulation agent of hTLR8 or hTLR7 can activate NF-agent and AP-1 promoter to produce SEAP, and the effect of said compound can be evaluated by detecting SEAP level.

Test reagents:

HEK-Blue hTLR8 cells and HEK-Blue hTLR7 cells (from Invivogen)

DMEM medium (from Gibco Co.)

Fetal bovine serum (from Gibco Corp.)

HEK-Blue ^TM Protection, normocino, zeocin and blasticidin (Bla)stinidine) (from Invivogen corporation)

The test process comprises the following steps:

1) Collecting cells from the cell culture flask, and adjusting the cell density to 2.2 × 10 ⁵ Per mL with HEK-Blue ^TM The Detection reagent resuspended the cells, 45. Mu.L of cell suspension was inoculated into 384-well plates, 10000 cells per well,

2) Compound plate preparation: test compounds were diluted 3-fold in DMSO from 2mM (or 18 mM) over 10 gradients. Adding 2 μ L diluted compound into 38 μ L HEK-Blue ^TM Detection reagents were diluted 20-fold intermediately. Cells plus 0.5% dmso wells served as low reading negative control wells. Cells were spiked with 1. Mu.M GS-9688 (see synthetic route WO2016141092A 1) as a positive control well for high reading.

3) 5 μ L of the intermediate diluted compound was added to a 384 well plate seeded with 45L cells and the drug was diluted 10 fold with a final DMSO concentration of 0.5%.

4) Placing 384-well plates containing cells and compounds at 37 deg.C, 5% ₂ The incubator of (2) was incubated for 16 hours.

5) After 16 hours, the plates were removed and the SEAP light absorption at 620nm was measured using the instrument VICTOR Nivo.

6) Data were analyzed using GraphPad Prism 8 software to obtain EC for each compound ₅₀ 。

The data for each concentration and positive and negative controls were averaged. The percent activity was calculated from the formula:

activity% = (compound read-negative well read)/(positive well read-negative well read) sexual well read.

Calculating IC of each compound by fitting the data to a nonlinear regression equation ₅₀ ：

Y = lowest value + (highest value-lowest value)/(1 +10^ ((LogEC) ₅₀ -X) hill slope));

wherein X is the logarithm of the concentration of the compound and Y is the percentage of activity.

The agonist activity of the compounds of the invention against TLR8/TLR7 is shown in table 1 below.

TABLE 1 agonism of the Compounds of the invention on TLR8/TLR7 EC ₅₀ Value of

And (4) conclusion: the compounds of the invention are capable of selectively activating TLR8.

Test example 2: pharmacokinetic study in rats

This experiment was conducted to evaluate the pharmacokinetic behavior of the compound of example 14 after intravenous drip or gavage administration in rats. Intravenous drip administration: test compounds were prepared as 0.5 mg/ml clear solution in 2% ethanol/40% polyethylene glycol 300/58%0.01 mol hydrochloric acid and plasma was collected at 0.25h, 0.5h, 0.583h, 0.75h, 1h, 2h, 4h, 6h, 8h and 24h after administration; intragastric administration: test compounds were formulated as 0.5 mg/ml clear solutions in 2% ethanol/40% polyethylene glycol 300/58%0.01 mol hydrochloric acid and plasma was collected at 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and 24h post-administration.

The concentration of the test compound in plasma was determined by high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Retention times of compounds and internal standards, chromatographic acquisitions and integrals of chromatograms were processed with a software Analyst (Applied Biosystems), statistics of the data were processed with a software Analyst (Applied Biosystems).

Plasma concentrations were processed using a non-compartmental model of WinNonlin Version 8.3 (Pharsight, mountain View, calif.) pharmacokinetic software and pharmacokinetic parameters were calculated using a linear log-trapezoidal method.

Compound example 14 rat pharmacokinetic related parameters at a dose of 1mg/kg given by intravenous drip at 0.5 hours and 5mg/kg administered orally by gavage are shown in Table 2 below.

Table 2 compound of example 14. Rat parameters relevant to intravenous drip and gavage pharmacokinetics

And (4) conclusion: the compounds of the present invention have low systemic oral bioavailability.

This experiment was conducted to evaluate the tissue distribution behavior of the compound of example 14 after intragastric gavage administration in rats. Intragastric administration: test compounds were formulated as a clear solution of 0.5 mg/ml, vehicle 2% ethanol/40% polyethylene glycol 300/58% hydrochloric acid 0.01 mole. Plasma, brain and liver were collected at 0.25h, 0.5h, 1h, 2h, 4h and 8h post-dose. The concentration of the test compound in plasma and tissues was determined by high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Retention times of compounds and internal standards, chromatographic acquisitions and integrals of chromatograms were processed with software analysis (Applied Biosystems) and statistics of data were processed with software analysis (Applied Biosystems). Plasma and tissue concentrations were processed using a non-compartmental model of WinNonlin Version 8.3 (Pharsight, mountain View, calif.) pharmacokinetic software and pharmacokinetic parameters were calculated using a linear log-trapezoidal method.

The parameters relevant to the study of the tissue distribution in rats given a 5mg/kg dose of the compound of example 14 by gavage are shown in Table 3 below.

Table 3 relevant parameters for study of gavage tissue distribution in rats for the compound of example 14

And (4) conclusion: the compound of the invention can be specifically enriched in liver tissues.

This experiment was conducted to evaluate the intestinal bioavailability and hepatic first-pass behavior of the compound of example 14 after intragastric administration in rats. Intragastric administration: test compounds were formulated as a clear solution of 0.5 mg/ml, vehicle 2% ethanol/40% polyethylene glycol 300/58% hydrochloric acid 0.01 mole. Portal vein and systemic plasma were collected at 0.25h, 0.5h, 1h, 2h, 4h and 8h post-dose. The concentration of the test compound in plasma was determined by high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Retention times of compounds and internal standards, chromatographic acquisitions and integrals of chromatograms were processed with software analysis (Applied Biosystems) and statistics of data were processed with software analysis (Applied Biosystems). Plasma concentrations were processed using a non-compartmental model of WinNonlin Version 8.3 (Pharsight, mountain View, calif.) pharmacokinetic software and pharmacokinetic parameters were calculated using a linear log-trapezoidal method.

The intestinal bioavailability and liver first-pass study related parameters of the compound of example 14 at the 5mg/kg gavage dose in rats are shown in table 4 below.

Table 4 example 14 compound rat gastrointestinal bioavailability and liver first pass study related parameters

And (4) conclusion: the compound of the invention has higher intestinal bioavailability.

This experiment was conducted to evaluate the excretory behavior of the compound of example 14 after intravenous drip administration in bile duct intubated rats. Intravenous drip administration: test compounds were formulated as a clear solution of 0.5 mg/ml, vehicle 2% ethanol/40% polyethylene glycol 300/58% hydrochloric acid 0.01 mole. Plasma was collected at 0.25h, 0.5h, 0.583h, 0.75h, 1h, 2h, 4h, 6h, 8h and 24h after administration, and bile, urine and feces were collected at 0-4h, 4-8h and 8-24 h. The concentration of the test compound in plasma, bile, urine and feces was determined by high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Retention times of compounds and internal standards, chromatographic acquisitions and integrals of chromatograms were processed with software analysis (Applied Biosystems) and statistics of data were processed with software analysis (Applied Biosystems). Plasma concentrations were processed using a non-compartmental model of WinNonlin Version 8.3 (Pharsight, mountain View, calif.) pharmacokinetic software and pharmacokinetic parameters were calculated using a linear log-trapezoidal method.

Compound example 14 intravenous drip the relevant parameters for the rat voiding study at the 1mg/kg dose administered at 0.5 hours are shown in table 4 below.

Table 5 example 14 parameters relevant to the study of intravenous drip voiding in rats

And (4) conclusion: the compounds of the present invention are excreted mainly through the intestinal tract.

Claims

A compound of formula (I) or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein, the first and the second end of the pipe are connected with each other,

x is a C atom or a N atom;

ring a is cycloalkyl, heterocycle, aromatic ring or heteroaromatic ring;

l is selected from a bond, - (CH) ₂ ) _t -、-C(O)(CH ₂ ) _t -or- (CH) ₂ ) _t C(O)-；

Each R is independently selected from hydrogen, halogen, cyano, oxo, alkyl, alkenyl, alkynyl, -OR ^a 、-SR ^a 、-NR ^a R ^b Cycloalkyl, heterocyclyl, aryl and heteroarylAryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted with one or more Q groups;

R ⁴ selected from hydrogen, halogen, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b (ii) a Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further substituted with one or more groups selected from halo, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁵ and R ⁶ Each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ^a R ^b 、-C(O)R ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-S(O) _n R ^a and-S (O) _n NR ^a R ^b (ii) a Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further selected from the group consisting of halogen, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b Substituted with one or more groups of (a);

or, R ⁵ And R ⁶ Together with the nitrogen atom to which it is attached, form a nitrogen-containing heterocycle optionally further containing one OR more heteroatoms selected from N, O, S in addition to N, said nitrogen-containing heterocycle optionally further selected from halogen, nitro, cyano, oxo, alkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b Substituted with one or more groups of (a);

or, R ⁴ And R ⁵ Or R ⁶ Together with the atoms to which they are attached form a nitrogen-containing heterocycle optionally further containing one OR more heteroatoms selected from N, O, S in addition to N, said nitrogen-containing heterocycle optionally further selected from halogen, nitro, cyano, oxo, alkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b Substituted with one or more groups of (a);

q is selected from the group consisting of halogen, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、-SR ^a 、-(CH ₂ ) _v -NR ^a R ^b 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ^a and R ^b Each independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, are optionally further substituted with one or more groups selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

or R ^a And R ^b Together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group optionally further containing one or more heteroatoms selected from N, O, S in addition to N, said nitrogen-containing heterocyclic group optionally further being selected from one of halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroarylOr a plurality of groups;

m is 0,1, 2,3 or 4;

n is 1 or 2;

v is 1 or 2;

t is 0,1, 2,3,4, 5 or 6.
A compound according to claim 1 of the general formula (I) or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

l is selected from a bond or-C (O) -; preferably a bond.
The compound of the general formula (I) according to claim 1 or 2, which is a compound of the general formula (II) or a stereoisomer, a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein, X, ring A, R ⁴ 、R ⁵ 、R ⁶ M is as defined in claim 1.
A compound of general formula (I) according to any one of claims 1 to 3, or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

ring a is a 5-to 7-membered heterocyclic ring, a benzene ring, or a 5-to 6-membered heteroaromatic ring.
The compound of the general formula (I) according to any one of claims 1 to 4, or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (III), or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

x is a C atom or a N atom;

y is a C atom or a N atom;

z is a C atom or a N atom;

s is 1 or 2;

each R is independently selected from hydrogen, halogen, oxo, C ₁ -C ₆ Alkyl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ Aryl and 5 to 10 membered heteroaryl, wherein said C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ Aryl, 5-to 10-membered heteroaryl optionally further substituted with one or more Q groups;

q is selected from the group consisting of halogen, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) ₂ ) _v -NR ^a R ^b 、-NR ^a R ^b 、-C(O)R ^a Wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, heteroaryl, and mixtures thereof,One or more substituents of cycloalkyl, heterocyclyl, aryl, heteroaryl;

R ^a and R ^b Each independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, are optionally further substituted with one or more groups selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

or R ^a And R ^b Together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group optionally further containing one or more heteroatoms selected from N, O, S in addition to N, said nitrogen-containing heterocyclic group optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl;

v is 1 or 2;

R ⁴ 、R ⁵ 、R ⁶ m is as defined in claim 1.
The compound of the general formula (I) according to any one of claims 1 to 5, or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (IV), or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

x is a C atom;

y is a C atom or a N atom;

R ¹ 、R ² 、R ³ each independently selected from hydrogen, halogen, C ₁ -C ₆ Alkyl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ Aryl and 5 to 10 membered heteroaryl, wherein said C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ Aryl, 5-to 10-membered heteroaryl optionally further substituted with one or more Q groups;

R ⁴ selected from hydrogen, halogen, nitro, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b (ii) a Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ⁵ and R ⁶ Each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ^a R ^b 、-C(O)R ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-S(O) _n R ^a and-S (O) _n NR ^a R ^b (ii) a Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further selected from the group consisting of halogen, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、 -SR ^a 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b Substituted with one or more groups;

or, R ⁵ And R ⁶ Together with the nitrogen atom to which it is attached, form a nitrogen-containing heterocycle optionally further containing one OR more heteroatoms selected from N, O, S in addition to N, the nitrogen-containing heterocycle optionally further selected from halogen, nitro, cyano, oxo, alkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b Substituted with one or more groups of (a);

or, R ⁴ And R ⁵ Or R ⁶ Together with the atoms to which they are attached form a nitrogen-containing heterocycle optionally further containing, in addition to N, one or more members selected from the group consisting of N, O, SA heteroatom, said nitrogen-containing heterocycle optionally further selected from halogen, nitro, cyano, oxo, alkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b Substituted with one or more groups;

q is selected from the group consisting of halogen, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、-SR ^a 、-(CH ₂ ) _v -NR ^a R ^b 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^a and R ^b Each independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further selected from the group consisting of halogenOne or more of amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

or R ^a And R ^b Together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group optionally further containing one or more heteroatoms selected from N, O, S in addition to N, said nitrogen-containing heterocyclic group optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl;

n is 1 or 2;

v is 1 or 2.
The compound of the general formula (I) according to any one of claims 1 to 6, or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R ⁵ and R ⁶ Each independently selected from hydrogen and C ₁ -C ₁₂ Alkyl radical, said C ₁ -C ₁₂ The alkyl group is optionally further selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、 -C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b Substituted with one or more groups of (a);

R ^a and R ^b Each independentlySelected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted with one or more groups selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

or R ^a And R ^b Together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group optionally further containing one or more heteroatoms selected from N, O, S in addition to N, said nitrogen-containing heterocyclic group optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl;

n is 1 or 2.
The compound of the general formula (I) according to any one of claims 1 to 7, or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R ⁵ and R ⁶ Each independently selected from hydrogen and C ₁ -C ₁₂ Alkyl radical, said C ₁ -C ₁₂ Alkyl is optionally further selected from-OR ^a 、-SR ^a 、-NR ^a R ^b 、-NR ^a C(O)R ^b and-NR ^a S(O) ₂ R ^b Substituted with one or more groups of (a);

R ^a selected from hydrogen, C ₁ -C ₆ An alkyl group;

R ^b selected from hydrogen, C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl and 5 to 7 membered heterocyclyl.
The compound of the general formula (I) according to any one of claims 1 to 6, or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (V), or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

x is a C atom;

y is a C atom or a N atom;

ring E is a nitrogen-containing heterocyclic group, preferably a 3-to 12-membered heterocyclic group, more preferably a 5-to 10-membered heterocyclic group, further preferably a 5-to 7-membered heterocyclic group, most preferably a 6-membered heterocyclic group; the nitrogen-containing heterocycle optionally further contains one or more heteroatoms selected from N, O, S in addition to N;

R ⁷ selected from hydrogen, halogen, cyano, oxo, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Hydroxyalkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₁₀ Cycloalkyl, 5-to 7-membered heterocyclyl, C ₅ -C ₁₀ Aryl, 5-to 10-membered heteroaryl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b (ii) a Preferably, R ⁷ Selected from hydrogen, halogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ A hydroxyalkyl group;

R ¹ 、R ² 、R ³ each independently selected from hydrogen, halogen, C ₁ -C ₆ Alkyl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ Aryl and 5 to 10 membered heteroaryl, wherein said C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ Aryl and 5-to 10-membered heteroaryl optionally further substituted with one or more Q groups;

R ⁴ selected from hydrogen, halogen, nitro, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b (ii) a Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

q is selected from halogen, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, and arylRadical, heteroaryl radical, -OR ^a 、-SR ^a 、-(CH ₂ ) _v -NR ^a R ^b 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ^a and R ^b Each independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, are optionally further substituted with one or more groups selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

or R ^a And R ^b Together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group optionally further containing one or more heteroatoms selected from N, O, S, in addition to N, said nitrogen-containing heterocyclic group optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl;

n is 1 or 2;

p is 1 or 2;

v is 1 or 2.
The compound of the general formula (I) according to any one of claims 1 to 9, or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R ⁴ selected from hydrogen, halogen, nitro, cyano, oxo, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Hydroxyalkyl, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₁₀ Cycloalkyl, 5-to 7-membered heterocyclyl, C ₅ -C ₁₀ Aryl, 5-to 10-membered heteroaryl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b (ii) a Wherein said C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Hydroxyalkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₁₀ Cycloalkyl, 5-to 7-membered heterocyclyl, C ₅ -C ₁₀ Aryl, 5-to 10-membered heteroaryl optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^a and R ^b Each independently selected from hydrogen, C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₁₀ Cycloalkyl, 5-to 7-membered heterocyclyl, C ₅ -C ₁₀ Aryl and 5 to 10 membered heteroaryl, wherein said C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₁₀ Cycloalkyl, 5-to 7-membered heterocyclyl, C ₅ -C ₁₀ Aryl, 5-to 10-membered heteroaryl optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

or R ^a And R ^b Together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group optionally further containing one or more heteroatoms selected from N, O, S, in addition to N, said nitrogen-containing heterocyclic group optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl;

preferably, R ⁴ Selected from hydrogen, halogen, nitro, cyano, C ₁ -C ₆ Alkyl, -C (O) R ^a and-C (O) OR ^a (ii) a And R is ^a Is C ₁ -C ₆ An alkyl group.
The compound of the general formula (I) according to any one of claims 1 to 6, or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (VI), or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

x is a C atom;

y is a C atom or a N atom;

ring G is a nitrogen-containing heterocycle, preferably a 3-to 12-membered heterocycle, more preferably a 5-to 10-membered heterocycle, further preferably a 5-to 7-membered heterocycle, most preferably a 7-membered heterocycle; the nitrogen-containing heterocycle optionally further contains one or more heteroatoms selected from N, O, S in addition to N;

R ⁸ selected from the group consisting of hydrogen, halogen, nitro, cyano, oxo, alkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b (ii) a Preferably, R ⁸ Is selected from C ₁ -C ₆ Alkyl or oxo;

R ¹ 、R ² 、R ³ each independently selected from hydrogen, halogen, C ₁ -C ₆ Alkyl, -OR ^a 、-SR ^a 、-NR ^a R ^b 、C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ Aryl and 5 to 10 membered heteroaryl, wherein said C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ Aryl, 5-to 10-membered heteroaryl optionallyFurther substituted by one or more Q groups;

q is selected from the group consisting of halogen, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^a 、-SR ^a 、-(CH ₂ ) _v -NR ^a R ^b 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁵ selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ^a R ^b 、-C(O)R ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-S(O) _n R ^a and-S (O) _n NR ^a R ^b ；

R ^a And R ^b Each independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, are optionally further substituted with one or more groups selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

or R ^a And R ^b Together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group optionally further containing one or more heteroatoms selected from N, O, S in addition to N, said nitrogen-containing heterocyclic group optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl;

n is 1 or 2;

q is 1,2,3 or 4;

v is 1 or 2.
The compound of the general formula (I) according to any one of claims 6 to 11, or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R ¹ and R ³ Is hydrogen;

R ² selected from hydrogen, halogen, hydroxy, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy radical, C ₃ -C ₆ Cycloalkyl, 5-to 6-membered heterocyclyl is preferably pyrrolidinyl, piperidinyl, piperazinyl, hydropyridyl, C ₆ -C ₁₀ Aryl is preferably phenyl, 5-to 10-membered heteroaryl is preferably pyridinyl, pyrimidinyl, wherein C ₁ -C ₆ Alkyl, 5-6 membered heterocyclic group, C ₆ -C ₁₀ Aryl, 5-to 10-membered heteroaryl optionally substituted with one or more Q groups;

q is as defined in claim 1.
The compound of general formula (I) according to any one of claims 1 to 12, or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

q is selected from halogen and C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, 4-to 6-membered heterocyclyl, C ₆ -C ₁₀ Aryl, 6-to 10-membered heteroaryl, -OR ^a 、-SR ^a 、-(CH ₂ ) _v -NR ^a R ^b 、-NR ^a R ^b 、-C(O)R ^a 、-O(O)CR ^a 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a C(O)R ^b 、-S(O) _n R ^a 、-S(O) _n NR ^a R ^b and-NR ^a S(O) _n R ^b Wherein said C is ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, 4-to 6-membered heterocyclyl, C ₆ -C ₁₀ Aryl, 6-to 10-membered heteroaryl optionally further selected from halogen, hydroxy, mercapto, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy radical, C ₃ -C ₆ Cycloalkyl, 4-to 6-membered heterocyclyl, C ₆ -C ₁₀ Aryl and 6 to 10 heteroaryl;

preferably, Q is selected from C ₁ -C ₆ Alkyl, 4-to 6-membered heterocyclyl, 6-membered heteroaryl, - (CH) ₂ ) _v -NR ^a R ^b 、-NR ^a R ^b 、-C(O)R ^a Wherein said C is ₁ -C ₆ Alkyl, 4 to 6 membered heterocyclyl is optionally further selected from C ₁ -C ₆ Alkyl, one or more groups of a 4-to 6-membered heterocyclyl;

R ^a and R ^b Each independently selected from hydrogen and C ₁ -C ₆ Alkyl, 4 to 6 membered heterocyclyl; or alternatively

R ^a And R ^b Together with the nitrogen atom to which they are attached form a 4-6 membered nitrogen containing heterocyclic group optionally further containing one or more heteroatoms selected from N, O, S in addition to N, said nitrogen containing heterocyclic group optionally further selected from C ₁ -C ₆ One or more groups of alkyl are substituted;

v is 1.
The compound of general formula (I) according to any one of claims 1 to 13, or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, selected from:
a process for the preparation of a compound of general formula (I) according to any one of claims 1 to 14 or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, which comprises the steps of:

1) When R is ⁴ In the case of hydrogen, the acid is,

firstly, compound Ia and DMB-NH are reacted under alkaline condition ₂ Reacting to obtain a compound Ib, wherein N, N-diisopropylethylamine is preferably selected as the basic condition; then, hydrolyzing the compound Ib under alkaline conditions, preferably NaOH, to obtain a compound Ic; then, carrying out decarboxylation on the compound Ic under high temperature conditions to obtain a compound Id, wherein the high temperature conditions are preferably 160 ℃; finally, carrying out deprotection reaction under acidic condition to obtain the compound shown in the general formula (I), wherein trifluoroacetic acid is preferred;

2) When R is ⁴ In the case of a halogen, the halogen is,

reacting the compound Ie with N-chlorosuccinimide or N-bromosuccinimide to obtain a compound in a general formula (I);

3) When R is ⁴ When the group is an ester group, a cyano group or a nitro group,

firstly, compound If and DMB-NH are reacted under alkaline condition ₂ Reacting to obtain a compound Ig, wherein the basic condition is preferably N, N-diisopropylethylamine; then, carrying out deprotection reaction under an acidic condition to obtain the compound shown in the general formula (I), wherein trifluoroacetic acid is preferred;

4) When R is ⁴ And R ⁵ When a nitrogen-containing heterocyclic ring is formed,

firstly, the compound Ih is reacted with H-L-N (R) under alkaline conditions ⁵ R ⁶ ) The reaction yields the compound Ia, preferably N, N-diisopropylethylamine under basic conditions; then, compound Ia and DMB-NH are reacted under alkaline condition ₂ Reacting to obtain a compound Ib, wherein N, N-diisopropylethylamine is preferably selected as the basic condition; finally, carrying out deprotection reaction under an acidic condition to obtain the compound shown in the general formula (I), wherein trifluoroacetic acid is preferred;

wherein, the first and the second end of the pipe are connected with each other,

DMB is 2, 4-dimethoxy benzyl,

ring A, X, L, R ⁵ 、R ⁶ M is as defined in claim 1.
A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 14 or a stereoisomer, a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
Use of a compound of general formula (I) according to any one of claims 1 to 14 or a stereoisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16 thereof, for the preparation of a TLR8 agonist medicament.
Use of a compound of general formula (I) according to any one of claims 1 to 14 or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, for the preparation of a medicament for the prophylaxis or treatment of TLR8 related diseases, preferably viral infectious diseases such as viral hepatitis b, HIV viral infection, and malignant tumors such as breast cancer, cervical cancer, colon cancer, lung cancer, gastric 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, melanoma, solid tumor, glioma, glioblastoma, hepatocellular carcinoma, papillary renal tumor, head and neck tumor, leukemia, lymphoma, myeloma and non-small cell lung cancer.