CN115362155B

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Publication number: CN115362155B
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: 2024-06-18
Anticipated expiration: 2041-07-21
Also published as: WO2022017408A1; CN115362155A

Abstract

Relates to arylamine derivatives, a preparation method and medical application thereof. In particular, it relates to compounds of formula (I), methods for their preparation, pharmaceutical compositions containing them and their use as Toll-like receptor (TLR) agonists for the treatment of diseases associated with TLR8 activity. Wherein each substituent in the general formula (I) is defined as the specification.

Description

Arylamine derivative, 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 compounds of formula (I), methods for their preparation, pharmaceutical compositions containing them and their use as Toll-like receptor (TLR) agonists for the treatment of diseases associated with 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, both as important elements involved in innate immunity and as a bridge linking innate immunity to specific immunity. The receptor can specifically recognize microorganisms and initiate an immune response.

TLRs are all type I transmembrane glycoproteins, consisting of an extracellular domain of a repeat sequence (LRR) rich in 16-28 leucine, a transmembrane domain, and a cytoplasmic Toll/IL-1 receptor (TIR) domain. X-ray crystallography analysis determined that the TLR LRR domains were horseshoe-like structures. To date 11 members have been found in humans, with TLR1, 2, 4, 5, 6, 10 and 11 located on the cell surface and TLR3, 7, 8, 9 located on the endosomal membrane. TLR8 and TLR7 are phylogenetically close to each other and have a high degree of sequence homology and are located on adjacent X chromosomes (Xp 22). When the LRR of TLRs binds to a ligand, the TIR domain conformation changes, which in turn triggers activation of TLR signaling pathways. The TIR domain of a TLR 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 depends on MyD88 signal path, induces activation of proteinase-1 (AP-1) and nuclear factor κB (NF- κB) to transfer into nucleus, induces expression of related genes in nucleus, secretes chemotactic factors and inflammatory factors, and plays a role in transcriptional regulation. In addition, TLR8 can activate mitogen-activated protein kinase (MAPK) signaling pathways, including p38, ERK, JNK, etc., mainly involved in the regulation of cell proliferation, cell differentiation, cell transformation, apoptosis, etc., and is closely related to various diseases such as inflammation and tumor (journal of immunology, 2017, 33, 813).

Hepatitis B Virus (HBV) is a particulate double stranded DNA virus. Activating TLR8 can effectively inhibit the replication of hepatitis B virus in vivo and in vitro, so that the TLR8 becomes a target for developing and treating chronic hepatitis B virus. The study shows that the TLR8 agonist ssRNA40 can selectively activate the innate immune cells around the liver to generate a large amount of IFN-gamma so as to inhibit the replication of hepatitis B virus, thereby having potential application as treatment of hepatitis virus infection. Stimulation of PBMCs with TLR8 agonists was found to induce high levels of IFN- γ and TNF- α production, thereby inhibiting HBV replication (Current Opinion in Virology,2018, 30,9).

TLRs are expressed not only on immune cells, but also in various tumor cells, participate in tumor immune monitoring, and play different roles in tumor growth. Wherein TLR8 enhances natural killer cell (NK cell) activity upon activation and enhances antibody-dependent cell-mediated cytotoxicity (ADCC) and induces Th1 polarization. TLR8 agonists are a potential adjuvant in cancer therapy, with the aim of inducing specific immune responses against tumor cells, improving the clinical efficacy of approved monoclonal antibody therapies, especially in individuals with reduced ADCC.

Given the important potential of TLR-8 agonists for the treatment of a variety of diseases, there is an urgent clinical need for novel TLR-8 agonists with potent activity and high selectivity.

Disclosure of Invention

Through intensive research, the inventor designs and synthesizes a series of aromatic amine compounds which show excellent TLR8 agonistic activity and can be developed into medicaments for treating diseases related to TLR 8.

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

Wherein,

X is a C atom or an N atom;

ring a is cycloalkyl, heterocycle, aromatic or heteroaromatic;

L is selected from a bond, - (CH₂)_t-、-C(O)(CH₂)_t -or- (CH₂)_t C (O) -;

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

R⁴ is selected from the group consisting of hydrogen, halogen, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-OR^a、-SR^a、-NR^aR^b、-C(O)R^a、-O(O)CR^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)_nR^a、-S(O)_nNR^aR^b, and-NR^aS(O)_nR^b; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is 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;

R⁵ and R⁶ are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-S(O)_nR^a, and-S (O)_nNR^aR^b; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further substituted with one or more groups selected from halogen, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-OR^a、-SR^a、-NR^aR^b、-C(O)R^a、-O(O)CR^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)_nR^a、-S(O)_nNR^aR^b, and-NR^aS(O)_nR^b;

Or R⁵ and R⁶ together with the nitrogen atom 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 being further substituted with one or more groups selected from halogen, nitro, cyano, oxo, alkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-OR^a、-SR^a、-NR^aR^b、-C(O)R^a、-O(O)CR^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)_nR^a、-S(O)_nNR^aR^b and-NR^aS(O)_nR^b;

Or R⁴ and R⁵ or R⁶ 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, the nitrogen-containing heterocycle optionally being further substituted with one or more groups selected from halogen, nitro, cyano, oxo, alkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-OR^a、-SR^a、-NR^aR^b、-C(O)R^a、-O(O)CR^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)_nR^a、-S(O)_nNR^aR^b and-NR^aS(O)_nR^b;

Q is selected from the group consisting of halogen, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-OR^a、-SR^a、-(CH₂)_v-NR^aR^b、-NR^aR^b、-C(O)R^a、-O(O)CR^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)_nR^a、-S(O)_nNR^aR^b, and-NR^aS(O)_nR^b, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is 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;

R^a and R^b are each independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is 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, the nitrogen-containing heterocyclic group optionally being 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 compounds of formula (I) according to the invention or stereoisomers, tautomers, meso, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein: l is selected from a bond or-C (O) -; preferably a key.

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

Wherein,

X is a C atom or an N atom;

ring a is cycloalkyl, heterocycle, aromatic or heteroaromatic;

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 a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

Wherein: ring a is a 5 to 7 membered heterocycle, benzene ring or 5 to 6 membered heteroaryl ring.

In another preferred embodiment, the compounds of formula (I) according to the invention or stereoisomers, tautomers, meso, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, are in the form of compounds of formula (III) or stereoisomers, tautomers, meso, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof,

Wherein,

X is a C atom or an N atom;

y is a C atom or an N atom;

Z is a C atom or an N atom;

s is 1 or 2;

Each R is independently selected from the group consisting of hydrogen, halogen, oxo, C₁-C₆ alkyl, -OR^a、-SR^a、-NR^aR^b、C₃-C₆ cycloalkyl, 4-6 membered heterocyclyl, C₆-C₁₀ aryl, and 5 to 10 membered heteroaryl, wherein the C₁-C₆ alkyl, C₃-C₆ cycloalkyl, 4-6 membered heterocyclyl, C₆-C₁₀ aryl, 5 to 10 membered heteroaryl are 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, - (CH₂)_v-NR^aR^b、-C(O)R^a), wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is 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;

v is 0, 1 or 2;

r⁴、R⁵、R⁶ and m are defined as in the general formula (I).

Wherein:

Each R is independently selected from the group consisting of hydrogen, halogen, oxo, C₁-C₆ alkyl, C₆-C₁₀ aryl, and 5 to 10 membered heteroaryl, wherein the alkyl, aryl, heteroaryl are 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, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is 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 compounds of formula (I) according to the invention or stereoisomers, tautomers, meso, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, are compounds of formula (IV) or stereoisomers, tautomers, meso, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof,

Wherein:

X is a C atom;

y is a C atom or an N atom;

R¹、R²、R³ is each independently selected from hydrogen, halogen, C₁-C₆ alkyl, -OR^a、-SR^a、-NR^aR^b、C₃-C₆ cycloalkyl, 4-6 membered heterocyclyl, C₆-C₁₀ aryl, and 5-to 10-membered heteroaryl, wherein the C₁-C₆ alkyl, C₃-C₆ cycloalkyl, 4-6 membered heterocyclyl, C₆-C₁₀ aryl, 5-to 10-membered heteroaryl are optionally further substituted with one OR more Q groups;

n is 1 or 2;

v is 1 or 2.

Wherein:

R⁵ and R⁶ are each independently selected from hydrogen and C₁-C₁₂ alkyl, said C₁-C₁₂ alkyl optionally being further substituted with one or more groups selected from halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-OR^a、-SR^a、-NR^aR^b、-C(O)R^a、-O(O)CR^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)_nR^a、-S(O)_nNR^aR^b and-NR^aS(O)_nR^b;

Or R^a and R^b together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group optionally containing one or more heteroatoms selected from N, O, S in addition to N, the nitrogen-containing heterocyclic group optionally being 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.

Wherein:

R⁵ and R⁶ are each independently selected from hydrogen and C₁-C₁₂ alkyl, said C₁-C₁₂ alkyl optionally further substituted with one OR more groups selected from-OR^a、-SR^a、-NR^aR^b、-NR^aC(O)R^b and-NR^aS(O)_nR^b;

R^a is selected from hydrogen, C₁-C₆ alkyl;

R^b is selected from hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl and 5 to 7 membered heterocyclyl.

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

Wherein:

X is a C atom;

y is a C atom or an N atom;

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

R⁷ is selected from the group consisting of hydrogen, halogen, cyano, oxo, C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5 to 7 membered heterocyclyl, C₅-C₁₀ aryl, 5 to 10 membered heteroaryl 、-OR^a、-SR^a、-NR^aR^b、-C(O)R^a、-O(O)CR^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)_nR^a、-S(O)_nNR^aR^b, and-NR^aS(O)_nR^b; preferably hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl;

R¹、R²、R³ is each independently selected from hydrogen, halogen, C₁-C₆ alkyl, -OR^a、-SR^a、-NR^aR^b、C₃-C₆ cycloalkyl, 4-6 membered heterocyclyl, C₆-C₁₀ aryl, and 5-to 10-membered heteroaryl, wherein the C₁-C₆ alkyl, C₃-C₆ cycloalkyl, 4-6 membered heterocyclyl, C₆-C₁₀ aryl, and 5-to 10-membered heteroaryl are optionally further substituted with one OR more Q groups;

R⁴ is selected from the group consisting of hydrogen, halogen, nitro, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-OR^a、-SR^a、-NR^aR^b、-C(O)R^a、-O(O)CR^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)_nR^a、-S(O)_nNR^aR^b, and-NR^aS(O)_nR^b; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is 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;

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 their stereoisomers, tautomers, meso, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof,

Wherein:

R⁷ is selected from the group consisting of hydrogen, halogen, cyano, oxo, C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5 to 7 membered heterocyclyl, C₅-C₁₀ aryl, 5 to 10 membered heteroaryl 、-OR^a、-SR^a、-NR^aR^b、-C(O)R^a、-O(O)CR^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)_nR^a、-S(O)_nNR^aR^b, and-NR^aS(O)_nR^b;

p is 1 or 2.

Wherein:

R⁴ is selected from the group consisting of hydrogen, halogen, nitro, cyano, oxo, C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5 to 7 membered heterocyclyl, C₅-C₁₀ aryl, 5 to 10 membered heteroaryl 、-OR^a、-SR^a、-NR^aR^b、-C(O)R^a、-O(O)CR^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)_nR^a、-S(O)_nNR^aR^b, and-NR^aS(O)_nR^b; wherein the C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5 to 7 membered heterocyclyl, C₅-C₁₀ aryl, 5 to 10 membered heteroaryl is 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 are each independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5 to 7 membered heterocyclyl, C₅-C₁₀ aryl, and 5 to 10 membered heteroaryl, wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5 to 7 membered heterocyclyl, C₅-C₁₀ aryl, 5 to 10 membered heteroaryl is 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;

Preferably, R⁴ is selected from hydrogen, halogen, nitro, cyano, C₁-C₆ alkyl, -C (O) R^a, and-C (O) OR^a; and R^a is C₁-C₆ alkyl.

In another preferred embodiment, the compounds of formula (I) according to the invention or stereoisomers, tautomers, meso, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, are in the form of compounds of formula (VI) or stereoisomers, tautomers, meso, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof,

Wherein:

X is a C atom;

y is a C atom or an 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;

R⁸ is selected from the group consisting of hydrogen, halogen, nitro, cyano, oxo, alkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-OR^a、-SR^a、-NR^aR^b、-C(O)R^a、-O(O)CR^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)_nR^a、-S(O)_nNR^aR^b, and-NR^aS(O)_nR^b; preferably, R⁸ is selected from C₁-C₆ alkyl or oxo;

R⁵ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-S(O)_nR^a, and-S (O)_nNR^aR^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 formulae (IV), (V), (VI) according to the invention or stereoisomers, tautomers, meso, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof,

Wherein:

R¹ and R³ are hydrogen;

R² is selected from hydrogen, halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, 5-6 membered heterocyclyl preferably pyrrolidinyl, piperidinyl, piperazinyl, hydropyridyl, C₆-C₁₀ aryl preferably phenyl, 5-10 membered heteroaryl preferably pyridinyl, pyrimidinyl, wherein the C₁-C₆ alkyl, 5-6 membered heterocyclyl, C₆-C₁₀ aryl, 5-10 membered heteroaryl is optionally substituted with one or more Q groups;

Q is defined as formula (I).

In another preferred embodiment, the compounds of the general formula according to the invention or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

Wherein:

Q is selected from halogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, 4 to 6 membered heterocyclyl, C₆-C₁₀ aryl, 6 to 10 membered heteroaryl 、-OR^a、-SR^a、-(CH₂)_v-NR^aR^b、-NR^aR^b、-C(O)R^a、-O(O)CR^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)_nR^a、-S(O)_nNR^aR^b, and-NR^aS(O)_nR^b, wherein the C₁-C₆ alkyl, C₃-C₆ cycloalkyl, 4 to 6 membered heterocyclyl, C₆-C₁₀ aryl, 6 to 10 membered heteroaryl is optionally further substituted with one or more groups selected from halogen, hydroxy, mercapto, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, 4 to 6 membered heterocyclyl, C₆-C₁₀ aryl, and 6 to 10 heteroaryl;

Preferably, Q is selected from C₁-C₆ alkyl, 4 to 6 membered heterocyclyl, 6 membered heteroaryl, - (CH₂)_v-NR^aR^b、-NR^aR^b、-C(O)R^a), wherein said C₁-C₆ alkyl, 4 to 6 membered heterocyclyl is optionally further substituted with one or more groups selected from C₁-C₆ alkyl, 4 to 6 membered heterocyclyl;

R^a and R^b are each independently selected from hydrogen, C₁-C₆ 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 heterocyclyl, optionally further containing one or more heteroatoms selected from N, O, S in addition to N, said nitrogen containing heterocyclyl optionally being further substituted with one or more groups selected from C₁-C₆ alkyl;

v is 1.

In another preferred embodiment, the compounds of formula (I) according to the invention or stereoisomers, tautomers, meso, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, are in the form of compounds of formula (VII) or stereoisomers, tautomers, meso, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof,

Wherein,

X is a C atom or an N atom;

y is a C atom or an N atom;

s is 1,2 or 3;

r, R⁴、R⁵、R⁶ and m are as defined in formula (I).

Wherein:

X is a C atom;

Y is an N atom.

In another preferred embodiment, the compounds of the general formula (I) according to the invention or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, are compounds of the general formula (VIII) or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

Wherein:

R¹、R²、R³ is each independently selected from hydrogen, halogen, cyano, oxo, alkyl, alkenyl, alkynyl, -OR^a、-SR^a、-NR^aR^b, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted with one OR more Q groups;

R⁴ is selected from the group consisting of hydrogen, halogen, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-OR^a、-SR^a、-(CH₂)_v-NR^aR^b、-NR^aR^b、-C(O)R^a、-O(O)CR^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)_nR^a、-S(O)_nNR^aR^b, and-NR^aS(O)_nR^b; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is 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 R⁵ and R⁶ together with the nitrogen atom 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 being further substituted with one or more groups selected from halogen, nitro, cyano, oxo, alkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-OR^a、-SR^a、-NR^aR^b、-C(O)R^a、-O(O)CR^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)_nR^a、-S(O)_nNR^aR^b、 and-NR^aS(O)_nR^b;

Or R⁴ and R⁵ or R^b 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, the nitrogen-containing heterocycle optionally being further substituted with one or more groups selected from halogen, nitro, cyano, oxo, alkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-OR^a、-SR^a、-NR^aR^b、-C(O)R^a、-O(O)CR^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)_nR^a、-S(O)_nNR^aR^b and-NR^aS(O)_nR^b;

Q is selected from the group consisting of halogen, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-OR^a、-SR^a、-NR^aR^b、-C(O)R^a、-O(O)CR^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)_nR^a、-S(O)_nNR^aR^b, and-NR^aS(O)_nR^b, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is 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;

n is 1 or 2;

v is 1.

In another preferred embodiment, the compounds of the general formula (VIII) according to the invention or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

Wherein:

R^a and R^b are each independently selected from hydrogen, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl and 5 to 7 membered heterocyclyl.

Wherein: r⁴ is selected from hydrogen, halogen, nitro, cyano, C₁-C₆ alkyl, -C (O) R^a, and-C (O) OR^a; and R^a is C₁-C₆ alkyl.

Wherein:

R¹ and R³ are hydrogen;

R² is selected from hydrogen, halogen, oxo, C₁-C₆ alkyl, C₆-C₁₀ aryl, and 6 to 10 membered heteroaryl, wherein the C₁-C₆ alkyl, C₆-C₁₀ aryl, 6 to 10 membered heteroaryl is optionally further substituted with one or more groups selected from Q;

Q is selected from halogen, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 5 to 7 membered heterocyclyl, C₆-C₁₀ aryl, 6 to 10 heteroaryl 、-OR^a、-SR^a、-NR^aR^b、-C(O)R^a、-O(O)CR^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aC(O)R^b、-S(O)_nR^a、-S(O)_nNR^aR^b, and-NR^aS(O)_nR^b, wherein the C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 5 to 7 membered heterocyclyl, C₆-C₁₀ aryl, 6 to 10 heteroaryl is 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 are each independently selected from hydrogen and C₁-C₆ alkyl;

preferably, R² is selected from hydrogen, halogen and C₁-C₆ alkyl.

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

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

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

(1) When R⁴ is hydrogen, the hydrogen atom,

Firstly, reacting a compound Ia with DMB-NH₂ under alkaline conditions to obtain a compound Ib, wherein the alkaline conditions are preferably N, N-diisopropylethylamine; then, compound Ib is hydrolyzed under alkaline conditions, preferably NaOH, to yield compound Ic; then, decarboxylating the compound Ic under high temperature conditions, preferably 160 ℃, to obtain a compound Id; finally, carrying out deprotection reaction under acidic conditions to obtain a compound of the general formula (I), wherein the acidic conditions are preferably trifluoroacetic acid;

(2) When R⁴ is a halogen atom, the halogen atom,

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

(3) When R⁴ is an ester group, a cyano group or a nitro group,

Firstly, reacting a compound If with DMB-NH₂ under alkaline conditions to obtain a compound Ig, wherein the alkaline conditions are preferably N, N-diisopropylethylamine; then, carrying out deprotection reaction under acidic conditions to obtain a compound of a general formula (I), wherein the acidic conditions are preferably trifluoroacetic acid;

(4) When R⁴ and R⁵ form a nitrogen-containing heterocycle,

Firstly, reacting a compound Ih with H-L-N (R⁵R⁶) under basic conditions to obtain a compound Ia, wherein the basic conditions are preferably N, N-diisopropylethylamine; then, reacting the compound Ia with DMB-NH₂ under alkaline conditions, preferably N, N-diisopropylethylamine, to obtain a compound Ib; finally, carrying out deprotection reaction under acidic conditions to obtain a compound of the general formula (I), wherein the acidic conditions are preferably trifluoroacetic acid;

Wherein,

DMB is 2, 4-dimethoxybenzyl,

The rings A, X, L, R, R⁵、R⁶ and m are defined as general formula (I).

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

(1) When R⁴ is hydrogen, the hydrogen atom,

Firstly, reacting a compound IIa with DMB-NH₂ under alkaline conditions to obtain a compound IIb, wherein the alkaline conditions are preferably N, N-diisopropylethylamine; then, hydrolyzing the compound IIb under alkaline conditions to obtain a compound IIc, wherein the alkaline conditions are preferably NaOH; then, decarboxylating the compound IIc under high temperature conditions, preferably 160 ℃, to obtain a compound IId; finally, carrying out deprotection reaction under acidic conditions to obtain a compound of a general formula (II), wherein the acidic conditions are preferably trifluoroacetic acid;

(2) When R⁴ is a halogen atom, the halogen atom,

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

(3) When R⁴ is an ester group, a cyano group or a nitro group,

Firstly, reacting a compound IIf with DMB-NH₂ under alkaline conditions to obtain a compound IIg, wherein the alkaline conditions are preferably N, N-diisopropylethylamine; then, carrying out deprotection reaction under acidic conditions to obtain a compound of a general formula (II), wherein the acidic conditions are preferably trifluoroacetic acid;

(4) When R⁴ and R⁵ form a nitrogen-containing heterocycle,

Firstly, reacting a compound IIh with H-L-N (R⁵R⁶) under alkaline conditions to obtain a compound IIa, wherein the alkaline conditions are preferably N, N-diisopropylethylamine; then, reacting the compound IIa with DMB-NH₂ under alkaline conditions, preferably N, N-diisopropylethylamine, to obtain a compound IIb; finally, carrying out deprotection reaction under acidic conditions to obtain a compound of a general formula (II), wherein the acidic conditions are preferably trifluoroacetic acid;

Wherein,

DMB is 2, 4-dimethoxybenzyl,

The rings A, X, R, R⁵、R⁶ and m are defined as general formula (II).

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

(1) When R⁴ is hydrogen, the hydrogen atom,

Firstly, reacting a compound IIIa with DMB-NH₂ under alkaline conditions to obtain a compound IIIb, wherein the alkaline conditions are preferably N, N-diisopropylethylamine; then, hydrolyzing the compound IIIb under alkaline conditions, preferably NaOH, to obtain a compound IIIc; then, decarboxylating the compound IIIc under high-temperature conditions, preferably 160 ℃, to obtain a compound IIId; finally, carrying out deprotection reaction under acidic conditions to obtain a compound of a general formula (III), wherein the acidic conditions are preferably trifluoroacetic acid;

(2) When R⁴ is a halogen atom, the halogen atom,

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

(3) When R⁴ is an ester group, a cyano group or a nitro group,

Firstly, reacting a compound IIIf with DMB-NH₂ under alkaline conditions to obtain a compound IIIg, wherein the alkaline conditions are preferably N, N-diisopropylethylamine; then, carrying out deprotection reaction under acidic conditions to obtain a compound of a general formula (III), wherein the acidic conditions are preferably trifluoroacetic acid;

(4) When R⁴ and R⁵ form a nitrogen-containing heterocycle,

Firstly, reacting a compound IIIh with HN (R⁵R⁶) under basic conditions, preferably N, N-diisopropylethylamine, to obtain a compound IIIa; then, reacting the compound IIIa with DMB-NH₂ under basic conditions, preferably N, N-diisopropylethylamine, to obtain a compound IIIb; finally, carrying out deprotection reaction under acidic conditions to obtain a compound of a general formula (III), wherein the acidic conditions are preferably trifluoroacetic acid;

Wherein,

DMB is 2, 4-dimethoxybenzyl,

X, Y, Z, R, R⁵、R⁶, m and s are defined as in the general formula (III).

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

(1) When R⁴ is hydrogen, the hydrogen atom,

Firstly, reacting a compound IVa with DMB-NH₂ under alkaline conditions to obtain a compound IVb, wherein the alkaline conditions are preferably N, N-diisopropylethylamine; then, hydrolyzing the compound IVb under alkaline conditions to obtain a compound IVc, wherein the alkaline conditions are preferably NaOH; then, carrying out decarboxylation reaction 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 conditions to obtain a compound of a general formula (IV), wherein the acidic conditions are preferably trifluoroacetic acid;

(2) When R⁴ is a halogen atom, the halogen atom,

Reacting compound IVe with N-chlorosuccinimide or N-bromosuccinimide to obtain a compound of formula (IV);

(3) When R⁴ is an ester group, a cyano group or a nitro group,

Firstly, reacting a compound IVf with DMB-NH₂ under alkaline conditions to obtain a compound IVg, wherein the alkaline conditions are preferably N, N-diisopropylethylamine; then, carrying out deprotection reaction under acidic conditions to obtain a compound of a general formula (IV), wherein the acidic conditions are preferably trifluoroacetic acid;

(4) When R⁴ and R⁵ form a nitrogen-containing heterocycle,

Firstly, reacting a compound IVh with HN (R⁵R⁶) under basic conditions to obtain a compound IVa, wherein the basic conditions are preferably N, N-diisopropylethylamine; then, reacting the compound IVa with DMB-NH₂ under alkaline conditions, preferably N, N-diisopropylethylamine, to obtain a compound IVb; finally, carrying out deprotection reaction under acidic conditions to obtain a compound of a general formula (IV), wherein the acidic conditions are preferably trifluoroacetic acid;

Wherein,

DMB is 2, 4-dimethoxybenzyl,

X, Y, R¹、R²、R³、R⁵、R⁶ is defined as formula (IV).

The invention further provides a pharmaceutical composition comprising a compound of formula (I) according to the invention or a meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

The invention further relates to the use of a compound of formula (I) according to the invention or a meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a TLR8 agonist.

The invention further relates to the use of a compound of formula (I) according to the invention or a meso-, racemate-, enantiomer-, diastereomer-or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the prevention or treatment of TLR 8-related diseases, which diseases may be viral infectious diseases or malignant tumors, such as viral hepatitis b, HIV viral infection, 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 tumors, ovarian tumors, peritoneal tumors, melanoma, solid tumors, glioma, glioblastoma, hepatocellular carcinoma, mastoid nephroma, head and neck tumors, leukemia, lymphoma, myeloma and non-small cell lung cancer.

The invention further relates to a compound of formula (I) or a meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, according to the invention, for use as a TLR8 agonist.

The invention further relates to a compound of formula (I) or a meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, according to the invention, for use as a medicament; the medicament is useful for preventing or treating TLR 8-related diseases, which 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, 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 tumors, ovarian tumors, peritoneal tumors, melanoma, solid tumors, glioma, glioblastoma, hepatocellular carcinoma, mastoid kidney tumor, head and neck tumor, leukemia, lymphoma, myeloma, and non-small cell lung cancer.

The 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 of formula (I) according to the invention or a meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, 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 tumors, ovarian tumors, peritoneal tumors, melanoma, solid tumors, glioma, neuroglioblastoma, hepatocellular carcinoma, mastoid kidney tumor, head and neck tumors, leukemia, lymphoma, myeloma, and non-small cell lung cancer.

The compounds of formula (I) of the present invention may form pharmaceutically acceptable base addition salts or acid addition salts with bases or acids according to methods conventional 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 acids 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, anti-cyclic acid, and the like.

Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, 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 preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweeteners, flavoring agents, coloring agents and preservatives to provide a pleasing 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, for example microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binders, such as starch, gelatin, polyvinylpyrrolidone or acacia; and lubricants such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or they may be coated by known techniques to 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 hydroxypropyl methylcellulose or hydroxypropyl cellulose, or extended time substances such as ethylcellulose, 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 carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone and acacia; the dispersing or wetting agent may be a naturally occurring phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain fatty alcohol such as heptadecaethyleneoxy cetyl alcohol (heptadeca ethyl ene oxy cetanol), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol such as polyethylene oxide sorbitol monooleate, or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride such as polyethylene oxide sorbitan monooleate. The aqueous suspension may also contain one or more preservatives such as ethyl or Jin Zhengbing-paraben, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, saccharin or aspartame.

Oily 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 suspension may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. The above-described sweeteners 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 use in the preparation of an aqueous suspension by the addition of water provide the active ingredient in combination 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 added. These compositions are preserved by the addition of an antioxidant such as ascorbic acid.

The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. 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 emulsifiers may be naturally occurring phospholipids, such as soy lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, such as 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 colorant and an antioxidant.

The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous solutions. Acceptable vehicles and solvents that may be used 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 an 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 or microemulsion may be injected into the patient's blood stream by local bolus injection. Or preferably the solution and microemulsion are administered in a manner that maintains a constant circulating concentration of the compound of the invention. To maintain this 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 known techniques using those suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension 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 stock oil may be used, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid may be used 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 will therefore 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 amount of drug administered depends on a variety of factors, including but not limited to the following: the activity of the particular compound used, 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 the drugs, etc. In addition, the optimal mode of treatment, such as the mode of treatment, the daily amount of the compound of formula (I) or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

The invention can contain the compound shown in the general formula (I) and pharmaceutically acceptable salt, hydrate or solvate thereof as active ingredients, and is mixed with pharmaceutically acceptable carriers or excipients to prepare a composition and 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 exert 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 drugs for the treatment of diseases associated with tyrosine kinase activity. Combination therapy is achieved by simultaneous, separate or sequential administration of the individual therapeutic components.

Detailed description of the invention

Unless stated to the contrary, the 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 from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 12 carbon atoms, more preferably an alkyl group containing from 1 to 6 carbon atoms. 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, n-heptyl, 2-methylhexyl 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof, and the like. More preferred are lower alkyl groups containing 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. The alkyl group 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, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl 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, such as vinyl, 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, such as 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 polycyclic group sharing one carbon atom (referred to as a spiro atom) between 5-to 20-membered monocyclic rings, which may contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multiple spirocycloalkyl group according to the number of common spiro atoms between rings, and preferably a single spirocycloalkyl group and a double spirocycloalkyl group. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monocyclocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

The term "fused ring alkyl" refers to a 5 to 20 membered, all carbon polycyclic group wherein each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group. Non-limiting examples of fused ring alkyl groups include:

The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Cycloalkyl groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, where the ring attached to the parent structure is cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, 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, carboxyl, or carboxylate groups.

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 ring atoms are heteroatoms selected from nitrogen, oxygen or S (O)_m (where m is an integer from 0 to 2), but excluding the ring portion of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably containing 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably from 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably from 5 to 7 ring atoms, of which 1 to 2 or 1 to 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 heterocyclyl groups include spiro, fused and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group having one atom (referred to as a spiro atom) shared between 5-to 20-membered monocyclic rings, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen or S (O)_m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. Which may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spiroheterocyclyl groups are classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a multiple spiroheterocyclyl group according to the number of common spiro atoms between rings, and preferably a single spiroheterocyclyl group and a double spiroheterocyclyl group. More preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro heterocyclic group. Non-limiting examples of spiroheterocyclyl 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 the other rings in the system, one or more of which may contain one or more double bonds, but none of which has a fully conjugated pi electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S (O)_m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:

The term "bridged heterocyclyl" refers to a5 to 14 membered, polycyclic heterocyclic group in which any two rings share two atoms which are not directly connected, which may contain one or more double bonds, but none of the rings has a fully conjugated pi electron system in which one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen or S (O)_m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Heterocyclic groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

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

Etc.

The heterocyclic group may be optionally 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, oxo, carboxyl, or carboxylate groups.

The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing 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:

Aryl 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, carboxyl, or carboxylate groups.

The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl groups are 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, hydroxy, 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, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy. The 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, carboxyl, or carboxylate groups.

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-NH₂.

The term "cyano" refers to-CN.

The term "nitro" refers to-NO₂.

The term "oxo" refers to = O.

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

The term "mercapto" refers to-SH.

The term "ester group" refers to a-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, wherein 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 group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

"Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.

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

By "pharmaceutically acceptable salts" is meant salts of the compounds of the present invention which are safe and effective when used in a mammal, and which possess the desired biological activity.

Synthesis method of compound of the invention

To accomplish the objects of the present invention, the compounds of the present invention are prepared using the following synthetic schemes.

The present invention provides a method for preparing a compound of formula (I) or a meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

(1) When R⁴ is hydrogen, the hydrogen atom,

Firstly, reacting a compound Ia with DMB-NH₂ under alkaline conditions to obtain a compound Ib, wherein the alkaline conditions are preferably N, N-diisopropylethylamine; then, compound Ib is hydrolyzed under alkaline conditions, preferably NaOH, to yield compound Ic; then, decarboxylating the compound Ic under high temperature conditions, preferably 160 ℃, to obtain a compound Id; finally, the deprotection reaction takes place under acidic conditions, preferably trifluoroacetic acid, to give the compounds of formula (I).

(2) When R⁴ is a halogen atom, the halogen atom,

And (3) obtaining the compound shown in the general formula (I) by mixing the compound Ie with N-chlorosuccinimide or N-bromosuccinimide.

(3) When R⁴ is an ester group, a cyano group or a nitro group,

Firstly, reacting a compound If with DMB-NH₂ under alkaline conditions to obtain a compound Ig, wherein the alkaline conditions are preferably N, N-diisopropylethylamine; deprotection reaction then takes place under acidic conditions, preferably trifluoroacetic acid, to give the compound of formula (I).

(4) When R⁴ and R⁵ form a nitrogen-containing heterocycle,

Wherein,

DMB is 2, 4-dimethoxybenzyl,

The rings A, X, L, R, R⁵、R⁶ and m are defined as general formula (I).

The present invention provides a method of preparing a compound of formula (II) or a meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

(1) When R⁴ is hydrogen, the hydrogen atom,

(2) When R⁴ is a halogen atom, the halogen atom,

(3) When R⁴ is an ester group, a cyano group or a nitro group,

(4) When R⁴ and R⁵ form a nitrogen-containing heterocycle,

Firstly, reacting a compound IIh with H-L-N (R⁵R⁶) under basic conditions, preferably N, N-diisopropylethylamine, to give a compound IIa; then, reacting the compound IIa with DMB-NH₂ under alkaline conditions, preferably N, N-diisopropylethylamine, to obtain a compound IIb; finally, carrying out deprotection reaction under acidic conditions to obtain a compound of a general formula (II), wherein the acidic conditions are preferably trifluoroacetic acid;

Wherein,

DMB is 2, 4-dimethoxybenzyl,

The rings A, X, R, R⁵、R⁶ and m are defined as general formula (II).

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

(1) When R⁴ is hydrogen, the hydrogen atom,

(2) When R⁴ is a halogen atom, the halogen atom,

(3) When R⁴ is an ester group, a cyano group or a nitro group,

(4) When R⁴ and R⁵ form a nitrogen-containing heterocycle,

Wherein,

DMB is 2, 4-dimethoxybenzyl,

X, Y, Z, R, R⁵、R⁶, m and s are defined as in the general formula (III).

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

(1) When R⁴ is hydrogen, the hydrogen atom,

(2) When R⁴ is a halogen atom, the halogen atom,

(3) When R⁴ is an ester group, a cyano group or a nitro group,

(4) When R⁴ and R⁵ form a nitrogen-containing heterocycle,

Wherein,

DMB is 2, 4-dimethoxybenzyl,

X, Y, R¹、R²、R³、R⁵、R⁶ is defined as formula (IV).

Detailed Description

The compounds of the present invention and their preparation are further understood by the examples which illustrate some 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 described and claimed herein.

The compounds of the present invention are prepared using convenient starting materials and general preparation procedures. Typical or preferential reaction conditions are given in the present invention, such as reaction temperature, time, solvent, pressure, molar ratio of reactants. But other reaction conditions can be adopted unless specifically stated. The optimization conditions may vary with the particular reactants or solvents used, but in general, both the 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 in organic preparation of protecting groups (3 rd edition, wiley, new York,1999 and literature citations) describe in detail the protection or deprotection of a large number of protecting groups.

The separation and purification of the compounds and intermediates may be carried out by any suitable method or procedure depending on the particular needs, such as filtration, extraction, distillation, crystallization, column chromatography, thin layer chromatography, high performance liquid chromatography or a combination thereof. The specific methods of use thereof may be found in the examples described herein. Of course, other similar isolation and purification means may be employed. It can be characterized using conventional methods, including physical constants and spectral data.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). The NMR shift is given in units of 10^-6 (ppm). NMR was performed using a Brukerdps model nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d₆), deuterated chloroform (CDCl₃), deuterated methanol (CD₃ OD) and Tetramethylsilane (TMS).

The MS was determined by LC (Waters 2695)/MS (Quattro Premier xE) mass spectrometer (manufacturer: watt) (Photodiode Array Detector).

The preparation liquid chromatography used an lc6000 high performance liquid chromatograph (manufacturer: innovative). The column was Daisogel C, 10 μm 100A (30 mm. Times.250 mm), mobile phase: acetonitrile/water.

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

The silica gel column chromatography uses Qingdao ocean silica gel 100-200 mesh, 200-300 mesh and 300-400 mesh silica gel as carrier.

The known starting materials of the present invention may be synthesized using or according to methods known in the art or may be purchased from commercial establishments, beijing couplings, sigma, carbofuran, yi Shiming, shanghai Shuya, shanghai Enoki, an Naiji chemistry, shanghai Pico, and the like.

The examples are not particularly described, and the reactions can all be carried out under nitrogen atmosphere.

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

The reaction solvent, the organic solvent or the inert solvent are each expressed as the solvent used which does not participate in the reaction under the described reaction conditions, and include, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, methylene chloride, diethyl ether, methanol, N-methylpyrrolidone (NMP), pyridine, etc. The examples are not specifically described, and the solution refers to an aqueous solution.

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, between-78 ℃ and 200 ℃ at one atmosphere, completed in about 1 to 24 hours. If the reaction is overnight, the reaction time is typically 16 hours. The reaction temperature is room temperature and is 20-30 deg.c without specific explanation in the examples.

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

ΜΙ = microliter;

μΜ=micromolar;

NMR = nuclear magnetic resonance;

Boc=tert-butoxycarbonyl group

Br=broad peak

D=bimodal

Delta = chemical shift

C = degrees celsius

Dd = double bipeak

DIPEA = diisopropylethylamine

Dmb=2, 4-dimethoxybenzyl group

Dmf=n, N-dimethylformamide

DMSO = dimethylsulfoxide

Dcm=dichloromethane

Ea=ethyl acetate

HATU = 2- (7-azobenzotriazole) -N, N' -tetramethylurea hexafluorophosphate

HPLC = high performance liquid phase

Hz = Hz

IC₅₀ = concentration inhibiting 50% of activity

J=coupling constant (Hz)

LC-ms=liquid chromatography-mass spectrometry combination

M = multiple peaks

M+h⁺ =parent compound mass+proton

M/z = mass to charge ratio

Nm=nanomole

Pe=petroleum ether

Ppm = parts per million

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-oxopropanamido) picolinate (1 b)

Methyl 3-aminopicolinate 1a (15.6 g,0.10 mol), triethylamine (31.1 g,0.31 mol) are dissolved in dichloromethane (150 mL) at room temperature. Monoethyl malonate acyl chloride (18.5 g,0.12 mol) was slowly added dropwise at 0℃and the reaction stirred at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was quenched with water (100 mL), dichloromethane (3×100 mL) was added to the reaction mixture, 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, and the obtained yellow crude product was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether=0 to 10%) to give 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 (15.3 g,57.5 mmol) and sodium ethoxide (7.82 g,114.9 mmol) were dissolved in ethanol (150 mL) at room temperature, and the reaction 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]⁺。

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

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

LC-MS：m/z 271.0[M+H]⁺。

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

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

LC-MS：m/z 352.1[M+H]⁺。

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

Compound 1e (129 mg,0.37 mmol) was dissolved in 2, 4-dimethoxybenzylamine (2.5 mL) at room temperature. N, N-diisopropylethylamine (142.2 mg,1.10 mmol) was added to the reaction mixture, and the mixture was reacted at 100℃overnight. After the reaction was completed, 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, and concentrated under reduced pressure. The crude product was isolated and purified by preparative thin layer chromatography (mobile phase: ethyl acetate/petroleum ether=1:1) to give compound 1f (100 mg, 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 (100 mg,0.21 mmol) 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 hydrogencarbonate solution (20 mL), extracted with ethyl acetate (3X 30 mL), and the organic phases were combined, 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=1:1) to give compound 1 (8 mg, 11.6%) as a yellow oil.

¹ H NMR (400 MHz, methanol -d₄)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) hexan-1-ol (2)

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

To compound 1 (85 mg,0.26 mmol) was added aqueous sodium hydroxide (2 mL,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 then added, ethyl acetate (3X 10 mL) was added, 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 silica gel column chromatography (mobile phase: methanol/dichloromethane=0-10%) to give compound 2 (22.5 mg, 32.6%) as a white solid.

¹ H NMR (300 MHz, meOH -d₄)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 (300 mg,1.28 mmol) was mixed with cyclohexylamine (6.0 mL) at room temperature. The reaction was stirred overnight at 110℃under nitrogen. After the reaction was completed, 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, 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 (315 mg, 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 (100 mg,0.35 mmol) was mixed with phosphorus oxychloride (2.0 mL) at 0 ℃. Triethylamine (140.9 mg,1.39 mmol) was added to the reaction solution, and the mixture was stirred overnight at 120℃under nitrogen. After the completion of the reaction, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and after the reaction was quenched with ice water, the ph=7 was adjusted with saturated sodium bicarbonate solution, ethyl acetate (2×30 mL) was added to the system to extract, 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 3b (78 mg, 100.0%) as a brown oil, which was used in the next step without purification.

LC-MS：m/z 224.0[M+H]⁺。

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

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

LC-MS：m/z 305.1[M+H]⁺。

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

Compound 3c (105 mg,0.35 mmol) was dissolved in 2, 4-dimethoxybenzylamine (2.0 mL) at room temperature. N, N-diisopropylethylamine (178 mg,1.38 mmol) was added to the reaction mixture, and the mixture was stirred under a nitrogen atmosphere at 100℃for 2 hours. After the reaction was completed, 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 3d (47 mg, 31.3%) as a pale brown semi-solid compound.

LC-MS：m/z 436.2[M+H]⁺。

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

Compound 3d (47 mg,0.11 mmol) 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 hydrogencarbonate solution (20 mL), extracted with ethyl acetate (3X 30 mL), and the organic phases were combined, washed with saturated brine (40 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: dichloromethane/methanol=10:1) to give compound 3 (15.7 mg, 51.0%) as a pale yellow solid.

¹ H NMR (400 MHz, methanol -d₄)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 (50 mg,0.21 mmol) was dissolved in N, N-dimethylformamide (1.5 mL) at room temperature. To the reaction solution were added 3-amino-1-hexylhydrochloride (31.6 mg,0.21 mmol) and N, N-diisopropylethylamine (106.4 mg,0.82 mmol) in this order, and the mixture was stirred under nitrogen at 80℃for 2 hours. After the reaction was completed, it was cooled to room temperature. The reaction mixture was diluted with water (40 mL), extracted with ethyl acetate (3X 30 mL), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 4b (66 mg, 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]⁺。

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

Compound 4b (66 mg,0.20 mmol) was dissolved in 1, 4-dioxane (2.0 mL) at room temperature. To the reaction mixture was added 2, 4-dimethoxybenzylamine (170.4 mg,1.02 mmol) and N, N-diisopropylethylamine (52.7 mg,0.41 mmol) in this order, and the mixture was stirred under nitrogen at 100℃for 3 hours. After the reaction was completed, 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 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 crude product was isolated and purified by preparative thin layer chromatography (mobile phase: ethyl acetate/petroleum ether=2:3) to give compound 4c (24 mg, 25.9%) as an orange semi-solid.

LC-MS：m/z 455.2[M+H]⁺。

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

Compound 4c (24 mg,0.053 mmol) was dissolved in dichloromethane (2.0 mL) at room temperature. Trifluoroacetic acid (0.8 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the crude product obtained was purified by preparative chromatography (column: sunFire 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: 9% -27% acetonitrile within 8 minutes; detection wavelength: 254 nm) to give orange solid compound 4 (10 mg, 62.2%).

¹ H NMR (400 MHz, methanol -d₄)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) hexan-1-ol (5) and (S) -3- ((2-amino-1, 5-naphthyridin-4-yl) amino) hexan-1-ol (6)

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

Compound 5:

¹ H NMR (300 MHz, meOH -d₄)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, meOH -d₄)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) hexan-1-ol (7 b)

5, 7-Dichloropyrazolo [1,5-a ] pyrimidine 7a (120 mg,0.64 mmol), (R) -2-amino-1-hexanoic acid hydrochloride (98.1 mg,0.64 mmol) was dissolved in N-butanol (5 mL) at room temperature, followed by the addition of N, N-diisopropylethylamine (247 mg,1.91 mmol). The reaction mixture was reacted at 100℃for 2 hours. After the completion of the reaction, the mixture was concentrated under reduced pressure, a saturated ammonium chloride solution (20 mL) was added to the residue, ethyl acetate (3X 15 mL) was extracted, 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 7b (150 mg, 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 (150 mg,0.56 mmol) was mixed with 2, 4-dimethoxybenzylamine (2.0 mL) at room temperature, followed by the addition of N, N-diisopropylethylamine (216 mg,1.67 mmol). The reaction mixture was reacted at 100℃for 6 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, a saturated ammonium chloride solution (30 mL), ethyl acetate (3×20 mL) was added to the reaction mixture, 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, and the obtained residue was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether=0 to 50%) to give yellow viscous liquid 7c (200 mg, 89.7%).

LC-MS：m/z 400.2[M+H]⁺。

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

Compound 7c (200 mg,0.50 mmol) was dissolved in dichloromethane (5.0 mL) at room temperature, followed by the addition of trifluoroacetic acid (2.5 mL). The reaction solution was stirred at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, water (20 mL) was added thereto, ethyl acetate (3X 20 mL) was extracted, 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 obtained residue was separated and purified by preparative chromatography (column: XSelect CSH Prep C 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 in 8 minutes; detection wavelength: 254 nm), to give compound 7 (17.2 mg, 13.8%) as a white solid.

¹ H NMR (400 MHz, methanol -d₄)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) hexan-1-ol (8)

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

Compound 1d (200 mg,0.74 mmol) and (R) -2-amino-1-hexanoic acid hydrochloride (124 mg,0.81 mmol) were dissolved in N-butanol (3 mL) at room temperature, followed by the addition of N, N-diisopropylethylamine (284 mg,2.21 mmol). The reaction solution was stirred at 100℃for 2 hours. After the completion of the reaction, the filtrate was filtered, concentrated under reduced pressure, a saturated ammonium chloride solution (30 mL), ethyl acetate (3X 20 mL) was added to the reaction mixture, the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 8a (200 mg, 77.0%) as a yellow viscous liquid. It was used in the next step without purification.

LC-MS：m/z 352.1[M+H]⁺。

Step 2: preparation of (R) -2- ((2, 4-dimethoxybenzyl) amino) -4- ((1-hydroxyhex-2-yl) amino) -1, 5-naphthyridine-3-carboxylic acid ethyl ester (8 b) and (R) -2-butyl-N- (2, 4-dimethoxybenzyl) -1,2,3, 5-tetrahydro- [1,4] oxaazepino [6,5-c ] [1,5] naphthyridine-6-amine (8 c)

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

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

Step 3: preparation of (R) -2-amino-4- ((1-hydroxyhex-2-yl) amino) -1, 5-naphthyridine-3-carboxylic acid ethyl ester (8 d) and (R) -2-butyl-1, 2,3, 5-tetrahydro- [1,4] oxaazepino [6,5-c ] [1,5] naphthyridine-6-amine (8 e)

The mixtures 8b and 8c (239.3 mg,0.50 mmol) 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 completion of the reaction, filtration, concentration of the filtrate under reduced pressure, addition of water (30 mL), extraction of ethyl acetate (3×20 mL) and washing of the combined organic phases with saturated brine (30 mL), drying over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, separation and purification of the crude yellow viscous liquid by silica gel column chromatography (mobile phase: methanol/dichloromethane=0-10%) gave yellow oily liquid mixtures 8d and 8e (118 mg, 71.5%).

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

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

To the mixtures 8d and 8e (118 mg,0.35 mmol) was added sodium hydroxide solution (12.5M, 5 mL) at room temperature. The reaction solution was stirred at 120℃for 24 hours. After the reaction, 1mol/L dilute hydrochloric acid is added to adjust the pH of the reaction solution to 7. To the reaction solution was added water (30 mL), 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 crude product was purified by preparative chromatography (column: YMC-Actus Triart C 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 in 8 min; detection wavelength: 254/220 nm) to give compound 8 (4.6 mg, 5.0%) as a white solid.

¹ H NMR (400 MHz, methanol -d₄)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 (R) -2-chloro-4- ((1-hydroxypentan-2-yl) amino) -1, 5-naphthyridine-3-carboxylic acid ethyl ester (9 a)

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

LC-MS：m/z 338.1[M+H]⁺。

Step 2: preparation of (R) -2- ((2, 4-dimethoxybenzyl) amino) -4- ((1-hydroxypentan-2-yl) amino) -1, 5-naphthyridine-3-carboxylic acid ethyl ester (9 b) and (R) -6- ((2, 4-dimethoxybenzyl) amino) -2-propyl-2, 3-dihydro- [1,4] oxaazepino [6,5-c ] [1,5] naphthyridin-5 (1H) -one (9 c)

Compound 9a (233 mg,0.69 mmol) 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 completed, 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, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (mobile phase: petroleum ether/ethyl acetate=2/1) to give yellow solid mixtures 9b and 9c (42 mg, 15.0%).

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

Step 3: preparation of (R) -2-amino-4- ((1-hydroxypentan-2-yl) amino) -1, 5-naphthyridine-3-carboxylic acid ethyl ester (9 d)

The mixtures 9b and 9c (42 mg,0.101 mmol) 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 obtained crude product was purified by silica gel column chromatography (mobile phase: dichloromethane/methanol=12/1) to give compound 9d (20 mg, 62.1%) as a yellow solid.

LC-MS：m/z 319.2[M+H]⁺。

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

To compound 9d (20 mg,0.062 mmol) was added aqueous sodium hydroxide (0.5 mL,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 crude product obtained was purified by preparative chromatography (column: XB ridge Prep C18 OBD column, 5um,19 x 150mm; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 17% -37% acetonitrile in 8 min; detection wavelength: 254/220 nm) to give white solid compound 9 (7.3 mg, 47.8%).

¹ H NMR (300 MHz, meOH -d₄)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) hexan-1-ol (10)

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

Compound 1d (200 mg,0.74 mmol) and (S) -2-amino-1-hexanol (95 mg,0.81 mmol) were dissolved in N, N-dimethylformamide (10 mL) at room temperature under nitrogen, followed by the addition of N, N-diisopropylethylamine (284 mg,2.21 mmol). The reaction was stirred at 80℃under nitrogen for 6 hours. After cooling to room temperature, water (50 mL) was added, and ethyl acetate (3×50 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 to give compound 10a (160 mg, 61.6%) as a yellow oily liquid.

LC-MS：m/z 352.1[M+H]⁺。

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

Compound 10a (160 mg,0.46 mmol) was dissolved in 2, 4-dimethoxybenzylamine (2.0 mL) at room temperature, and N, N-diisopropylethylamine (178 mg,1.38 mmol) was added. The reaction solution was stirred at 100℃for 1 hour. After the completion of the reaction, cooled to room temperature, saturated ammonium chloride solution (30 mL) was added, and ethyl acetate (3×20 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 yellow oily liquid mixtures 10b and 10c (150 mg, 75.6%).

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

Step 3: preparation of (S) -2-amino-4- ((1-hydroxyhex-2-yl) amino) -1, 5-naphthyridine-3-carboxylic acid ethyl ester (10 d) and (S) -6-amino-2-butyl-2, 3-dihydro- [1,4] oxaazepino [6,5-c ] [1,5] naphthyridine-5 (1H) -one (10 e)

The mixtures 10b and 10c (150 mg,0.34 mmol) were dissolved in dichloromethane (2.0 mL) and trifluoroacetic acid (1.0 mL) was added under ice-bath and stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, followed by addition of water (30 mL) and extraction 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 resulting yellow crude product was purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether=1/1) to give yellow oily liquid mixtures 10d and 10e (65 mg, 66.1%).

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

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

The mixtures 10d and 10e (65 mg,0.23 mmol) were added to aqueous sodium hydroxide (2 mL,12.5 mol/L) and stirred at 120℃for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature, water (30 mL) was then added, ethyl acetate (3X 20 mL) was added, 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 obtained was purified by separation using a preparative chromatography column (column: XBridge Shield RP OBD column, 5um,19 x 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 (11.9 mg, 20.1%) as a white solid.

¹ H NMR (300 MHz, meOH -d₄)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-methylhex-1-ol (11)

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

Hydroxyacetone 11a (100 g,1.35 mol) was dissolved in dichloromethane (1L) at room temperature. The solution was cooled to 0deg.C and imidazole (175 g,2.57 mol) and tert-butyldimethylchlorosilane (245 g,1.63 mol) were added sequentially. The reaction solution was stirred at 0℃for 1 hour, then slowly warmed to room temperature, and stirring was continued for 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 (200 g, 78.7%) as a pale yellow liquid.

¹H-NMR(CDCl₃)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-methylpropane-2-sulfonamide (11 c)

Compound 11b (200 g,1.06 mol) and S-tert-butylsulfinamide (129 g,1.06 mol) were dissolved in tetrahydrofuran (3.6L) at room temperature. The reaction was added dropwise to tetraisopropyl orthotitanate (800 mL,2.66 mol). The reaction solution was stirred at 70℃for 12 hours. After the reaction was completed, it was cooled to room temperature. The reaction solution was concentrated under reduced pressure, the resulting brown liquid was added to ice water (1L), the resulting solid was removed by filtration, ethyl acetate (3X 500 mL) was added 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. The crude brown oil was purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether=3% -20%) to give compound 11c (50 g, 16.1%) as a tan 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 ]⁺.

Step 3: preparation of (S) -N- ((R) -1- ((tert-butyldimethylsilyl) oxy) -2-methylhex-2-yl) -2-methylpropane-2-sulfonamide (11 d)

Compound 11c (50 g,0.171 mol) was dissolved in toluene (500 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was added dropwise to a heptanes solution of trimethylaluminum (207 mL,1mol/L,0.21 mol) at-78℃and, after completion of the addition, stirring was continued for 0.5 hours. Then, n-hexane solution (102 mL,2.5mol/L,0.26 mol) of n-butylaluminum was added dropwise thereto at-78℃and, after completion of the addition, the mixture was stirred at-78℃for 4 hours. After completion of the reaction, water (500 mL) was added thereto, followed by quenching, filtration, extraction with ethyl acetate (3X 200 mL) was performed, 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 purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether=7% -10%) to give compound 11d (26 g, 43.4%) as a yellow liquid.

¹ H NMR (400 MHz, chloroform -d)δ3.66(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),0.05(s,3H).)

LC-MS：m/z 350.3[M+H]⁺。

Step 4: preparation of (R) -1- ((tert-butyldimethylsilyl) oxy) -2-methylhex-2-amine hydrochloride (11 e)

Compound 11d (26 g,0.074 mol) was dissolved in methanol (260 mL) at room temperature, and a1, 4-dioxane solution (55.5 mL,4mol/L,0.222 mol) of hydrogen chloride was added. The reaction solution was stirred at room temperature for 3 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to give compound 11e (15 g, 71.9%) as a pale yellow liquid.

¹ H NMR (400 MHz, chloroform-d) delta 3.30 (q, j=9.4 hz, 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]⁺。

Step 5: preparation of (R) -4- ((1- ((tert-butyldimethylsilyl) oxy) -2-methylhex-2-yl) amino) -2-chloro-1, 5-naphthyridine-3-carboxylic acid ethyl ester (11 f)

Compound 1d (120 mg,0.44 mmol) and compound 11e (150 mg,0.53 mmol) were dissolved in N-methylpyrrolidone (5 mL) at room temperature under nitrogen, and N, N-diisopropylethylamine (172 mg,1.33 mmol) was added. The reaction was stirred for 4 hours at 100℃under nitrogen. After cooling to room temperature, a saturated ammonium chloride solution (30 mL) was added, and ethyl acetate (3×20 mL) was added to the system for extraction, and 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. The crude product was purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether=0-20%) to give compound 11f (80.0 mg, 37.6%) as a yellow oily liquid.

LC-MS：m/z 480.2[M+H]⁺。

Step 6: preparation of (R) -4- ((1- ((tert-butyldimethylsilyl) oxy) -2-methylhex-2-yl) amino) -2- ((2, 4-dimethoxybenzyl) amino) -1, 5-naphthyridine-3-carboxylic acid ethyl ester (11 g)

Compound 11f (80.0 mg,0.17 mmol) and N, N-diisopropylethylamine (64.6 mg,0.50 mmol) 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 completed, 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 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether=0-40%) to give 11g (60.0 mg, 58.8%) of a yellow oily liquid compound.

LC-MS：m/z 611.4[M+H]⁺。

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

11G (20 mg,0.033 mmol) of the compound was dissolved in absolute ethanol (2 mL) at room temperature, and an aqueous sodium hydroxide solution (12.5 mol/L,2 mL) was added. The reaction solution was stirred at 80℃for 2 hours. After the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting yellow crude product was added with water (20 mL), and 1mol/L diluted hydrochloric acid was added to adjust the pH to 5. Ethyl acetate (3×20 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 a yellow solid compound 11h (18.0 mg, 94.7%).

LC-MS：m/z 583.3[M+H]⁺。

Step 8: preparation of (R) -N⁴ - (1- ((tert-butyldimethylsilyl) oxy) -2-methylhex-2-yl) -N² - (2, 4-dimethoxybenzyl) -1, 5-naphthyridine-2, 4-diamine (11 i)

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

LC-MS：m/z 539.33[M+H]⁺。

Step 9: preparation of (R) -2- ((2-amino-1, 5-naphthyridin-4-yl) amino) -2-methylhex-1-ol (11)

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

¹ H NMR (400 MHz, methanol -d₄)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 (S) -2-chloro-4- ((1-hydroxypentan-2-yl) amino) -1, 5-naphthyridine-3-carboxylic acid ethyl ester (12 a)

Compound 1d (289 mg,1.07 mmol) and (S) -2-amino-1-pentanol (110.0 mg,1.07 mmol) were dissolved in N, N-dimethylformamide (3 mL) at room temperature followed by the addition of N, N-diisopropylethylamine (413.3 mg,3.20 mmol). The reaction solution 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 (3×20 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]⁺。

Step 2: preparation of (S) -2- ((2, 4-dimethoxybenzyl) amino) -4- ((1-hydroxypentan-2-yl) amino) -1, 5-naphthyridine-3-carboxylic acid ethyl ester (12 b) and (S) -6- ((2, 4-dimethoxybenzyl) amino) -2-propyl-2, 3-dihydro- [1,4] oxaazepino [6,5-c ] [1,5] naphthyridin-5 (1H) -one (12 c)

Compound 12a (560 mg, crude) was mixed with 2, 4-dimethoxybenzyl amine (2 mL) at room temperature, followed by the addition of N, N-diisopropylethylamine (640 mg,4.98 mmol). The reaction solution was stirred at 100℃for 3 hours. After completion of the reaction, the 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 saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude yellow viscous liquid was 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 mg, 19.2%).

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

Step 3: preparation of (S) -2-amino-4- ((1-hydroxypentan-2-yl) amino) -1, 5-naphthyridine-3-carboxylic acid ethyl ester (12 d) and (S) -2-propyl-1, 2,3, 5-tetrahydro- [1,4] oxazepino [6,5-c ] [1,5] naphthyridine-6-amine (12 e)

The mixtures 12b and 12c (154.2 mg,0.33 mmol) 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, the mixture was filtered, and the filtrate was concentrated 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 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 (61.5 mg, 58.6%).

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

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, 1mol/L dilute hydrochloric acid is added to adjust the pH to 7. To the reaction solution was added water (20 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 yellow viscous liquid was purified by preparative chromatography (column: XBridge Prep C18 OBD column, 5um,20 x 250mm; mobile phase A: water (0.05% trifluoroacetic acid), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 17% -40% acetonitrile in 2 min; detection wavelength: 254/220 nm) to give white solid compound 12 (15.3 mg, 34.0%).

¹ H NMR (400 MHz, methanol -d₄)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,0.041 mmol) was added. After the reaction solution was stirred at room temperature for 2 hours under a nitrogen atmosphere, it was diluted with water (20 mL) and extracted with ethyl acetate (2X 20 mL). 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 crude product was purified using preparative chromatography (preparative column: XBridge Prep C18 OBD column, 5um,19 x 150mm; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 24% -36% within 8 min; detection wavelength: 254/220 nm) to give compound 13 as a white solid (2 mg, 30.3%).

¹ H NMR (400 MHz, methanol -d₄)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-methylhex-1-ol (14) and (S) -2- ((2-amino-7-fluoro-1, 5-naphthyridin-4-yl) amino) -2-methylhex-1-ol (15)

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

2-Bromo-5-fluoropyridin-3-amine 14a (5.0 g,26.3 mmol) was dissolved in methanol (250 mL) at room temperature, and triethylamine (5.32 g,52.6 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (1.07 g,1.3 mmol) were added. The reaction mixture was reacted overnight at 80℃under carbon monoxide (10 atm). After completion of the reaction, the reaction mixture was concentrated, water (200 mL) was added, extraction was performed 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 purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether=0-20%) to give compound 14b (4.3 g, 96.2%) as a white solid.

LC-MS：m/z 171.1[M+H]⁺。

Step 2: preparation of methyl 3- (3-ethoxy-3-oxopropanamido) -5-fluoropyridine carboxylate (14 c)

Compound 14b (1.0 g,5.88 mmol) and triethylamine (1.78 g,17.6 mmol) were dissolved in dichloromethane (100 mL) at room temperature, and monoethyl malonate acyl chloride (1.06 g,7.05 mmol) was slowly added dropwise at 0deg.C and the reaction stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was quenched with water (100 mL), 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 concentrated under reduced pressure. The resulting yellow crude product was purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether=0-35%) to give compound 14c (0.45 g, 26.9%) as a yellow solid.

LC-MS：m/z 285.1[M+H]⁺。

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

LC-MS：m/z 253.1[M+H]⁺。

Step4: preparation of ethyl 2, 4-dichloro-7-fluoro-1, 5-naphthyridine-3-carboxylate (14 e)

To compound 14d (0.19 g,0.75 mmol) was added phosphorus oxychloride (2.0 mL) at 0deg.C. The reaction solution was stirred at 100℃for 1.5 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. Ice water was added to the residue, the pH was adjusted to 7 with saturated sodium bicarbonate solution, ethyl acetate (3×20 mL) was added to the system 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 purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether=0-7%) to give compound 14e (0.19 g, 87.2%) as a yellow solid.

LC-MS：m/z 289.0[M+H]⁺。

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

Compound 14e (0.19 g,0.66 mmol) and compound 1- ((tert-butyldimethylsilyl) oxy) -2-methylhex-2-amine hydrochloride (204 mg,0.72 mmol) were dissolved in N-methylpyrrolidone (NMP) (2 mL) and N, N-Diisopropylethylamine (DIEA) (254 mg,1.97 mmol) was added under a nitrogen atmosphere at room temperature. The reaction was stirred for 4 hours at 100℃under nitrogen. After cooling to room temperature, a saturated ammonium chloride solution (20 mL) was added, and ethyl acetate (3×20 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 separated and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether=0-20%) to give compound 14f (88 mg, 26.9%) as a yellow oily liquid.

LC-MS：m/z 498.2[M+H]⁺。

Step 6: preparation of 4- ((1- ((tert-butyldimethylsilyl) oxy) -2-methylhex-2-yl) amino) -2- ((2, 4-dimethoxybenzyl) amino) -7-fluoro-1, 5-naphthyridine-3-carboxylic acid ethyl ester (14 g) and N⁴ - (1- ((tert-butyldimethylsilyl) oxy) -2-methylhex-2-yl) -N² - (2, 4-dimethoxybenzyl) -7-fluoro-1, 5-naphthyridine-2, 4-diamine (14 h)

Compound 14f (88 mg,0.18 mmol) and N, N-diisopropylethylamine (68.5 mg,0.53 mmol) were dissolved in 2, 4-dimethoxybenzylamine (2 mL) at room temperature. The reaction solution was stirred at 100℃for 6 hours. After the completion of the reaction, the mixture was cooled to room temperature, a saturated ammonium chloride solution (20 mL) was added, ethyl acetate (3X 20 mL) was added to the system, 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 silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether=0-40%) to give 14g (22 mg, 19.8%) and 14h (0.033 g, 33.6%) of a yellow oily liquid compound.

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

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

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

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

Compound 14i was further subjected to chiral resolution. Column type: CHIRAL ART cell-SB, 2 x 25cm,5um; 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; compound 14 was obtained as a white solid, t_R = 17.6min, ee value (enantiomeric excess): 98.3%; and white solid compound 15, t_R =16.5 min, ee value (enantiomeric excess): 85.0%.

Compound 14

¹ H NMR (300 MHz, meOH -d₄)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, meOH -d₄)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)

Step1: preparation of (S) -2- ((2-amino-3-chloro-1, 5-naphthyridin-4-yl) amino) pentan-1-ol (16)

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

¹ H NMR (300 MHz, meOH -d₄)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 ammonia (60 mL) at room temperature followed by 2-hexanone 17a (10.0 g,0.1 mol) and ammonium chloride (5.35 g,0.1 mol) in that order. The reaction solution was stirred at room temperature overnight, then dichloromethane (4×50 mL) was added, the combined organic phases were washed with saturated ferrous sulfate, water and saturated brine in this order, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 17b (11.28 g, 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 (18.65 g,174 mmol) were dissolved in water (50 mL) and tetrahydrofuran (50 mL) at room temperature, and benzoyl chloride (16.36 g,95.88 mmol) was slowly added dropwise at 0deg.C. The reaction solution 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) and ethyl acetate (3X 50 mL) were added to the residue to extract. The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate 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 compound 17c (12.60 g, 55.5%) as a colorless oily liquid.

LC-MS：m/z 261.2[M+H]⁺。

Step 3: preparation of benzyl (1-amino-2-methylhex-2-yl) carbamate (17 d)

Compound 17c (12.60 g,48.40 mmol) 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 (2.07 g,24.20 mmol) was added. The reaction solution was allowed to react under a hydrogen atmosphere for 4 hours. After the completion of the reaction, the reaction mixture was filtered under suction, and the filtrate was concentrated under reduced pressure to give compound 17d (12.50 g, 97.7%) as a dark blue oily liquid.

LC-MS：m/z 265.2[M+H]⁺。

Step 4: preparation of benzyl (1-acetamido-2-methylhex-2-yl) carbamate (17 e)

Compound 17d (12.0 g,45.5 mmol) and triethylamine (9.18 g,90.9 mmol) were dissolved in dichloromethane (150 mL) at room temperature, and acetyl chloride (3.90 g,50.0 mmol) was slowly added dropwise at 0deg.C. The reaction solution was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was quenched with ice water (200 mL), ethyl acetate (3X 100 mL) was added to the reaction mixture, 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 (8.73 g, 62.8%) as a yellow solid.

LC-MS：m/z 307.2[M+H]⁺。

Step 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 solution was stirred at room temperature under a hydrogen atmosphere for 4 hours. After the completion of the reaction, the reaction mixture was filtered under suction, and the filtrate was concentrated under reduced pressure to give compound 17f (1.55 g, 68.9%) as a dark gray oily liquid.

LC-MS：m/z 173.2[M+H]⁺。

Step 6: preparation of 4- ((1-acetamido-2-methylhex-2-yl) amino) -2-chloro-1, 5-naphthyridine-3-carboxylic acid ethyl ester (17 g)

Compound 1d (180 mg,0.66 mmol) and compound 17f (114 mg,0.66 mmol) were dissolved in N-methylpyrrolidone (3 mL) at room temperature under nitrogen, and N, N-diisopropylethylamine (172 mg,1.33 mmol) was added. The reaction was stirred for 4 hours at 100℃under nitrogen. 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 give 17g (160 mg, 59.2%) of a yellow oily liquid compound.

LC-MS：m/z 407.2[M+H]⁺。

Step 7: preparation of ethyl 4- ((1-acetamido-2-methylhex-2-yl) amino) -2- ((2, 4-dimethoxybenzyl) amino) -1, 5-naphthyridine-3-carboxylate (17 h)

17G (160 mg,0.39 mmol) of the compound was dissolved in 2, 4-dimethoxybenzylamine (2 mL) at room temperature, and N, N-diisopropylethylamine (151 mg,1.17 mmol) was added. The reaction solution was stirred at 100℃for 1 hour. After the completion of the reaction, the reaction mixture was cooled to room temperature, saturated ammonium chloride solution (10 mL) was added, ethyl acetate (3X 10 mL) was added to the reaction mixture, 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 a yellow oily liquid compound 17h (150 mg, 80.0%).

LC-MS：m/z 538.3[M+H]⁺。

Step 8: preparation of 4- ((1-acetamido-2-methylhex-2-yl) amino) -2- ((2, 4-dimethoxybenzyl) amino) -1, 5-naphthyridine-3-carboxylic acid (17 i)

Compound 17h (150 mg,0.28 mmol) was dissolved in absolute ethanol (1 mL) at room temperature, and aqueous sodium hydroxide (12.5 mol/L,1 mL) was added. The reaction solution was stirred at 80℃for 2 hours. After the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting yellow crude product was added with water (20 mL), and 1mol/L diluted hydrochloric acid was added to adjust the pH to 5. Ethyl acetate (3×20 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 (135 mg, 95.0%) as a yellow oily liquid.

LC-MS：m/z 510.3[M+H]⁺。

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

Compound 17i (135 mg,0.27 mmol) was dissolved in diphenyl ether (1 mL) at room temperature. Stirred at 160℃for 1 hour. After the completion of the reaction, the reaction mixture was cooled to room temperature, and the crude product obtained was purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether=1/1) to give compound 17i (80 mg, 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 (80 mg,0.17 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added under ice-bath, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the crude product obtained was purified by preparative chromatography (column: XBRID Prep C18 OBD column, 5um,19 x 150mm; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 14% -56% acetonitrile in 8 minutes; detection wavelength: 254/220 nm) to give 17 (10.3 mg, 18.9%) as a white solid compound.

¹ H NMR (300 MHz, meOH -d₄)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 (R) -2-chloro-4- ((1-hydroxy-2-methylbutan-2-yl) amino) -1, 5-naphthyridine-3-carboxylic acid ethyl ester (18 a) and (R) -6-chloro-2-ethyl-2-methyl-2, 3-dihydro- [1,4] oxaazepino [6,5-c ] [1,5] naphthyridin-5 (1H) -one (18 b)

Compound 1d (370 mg,1.37 mmol) and (R) -2-amino-2-methyl-1-butanol (169.0 mg,1.64 mmol) were dissolved in N-methylpyrrolidone (2 mL) at room temperature, then N, N-diisopropylethylamine (531 mg,4.11 mmol) was added, and the reaction was stirred at 100℃for 1.5 hours. After the completion of the reaction, a saturated ammonium chloride solution (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 yellow viscous liquid mixtures 18a and 18b (350 mg, 75.5%).

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

Step 2: 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 mixtures 18a and 18b (350 mg,111 mmol) was added 2, 4-dimethoxybenzylamine (2 mL) at room temperature followed by N, N-diisopropylethylamine (430 mg,3.33 mmol). The reaction was stirred at 100℃overnight. After the completion of the reaction, the mixture was cooled to room temperature, saturated ammonium chloride solution (30 mL) was added, ethyl acetate (3X 20 mL) was extracted, 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 18c (770 mg, crude) as a yellow viscous liquid. It was used in the next step without purification.

LC-MS：m/z 423.2[M+H]⁺。

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)

The crude compound 18c (50.0 mg,0.12 mmol) 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 performed, the filtrate was concentrated under reduced pressure, water (20 mL) was added to the residue, ethyl acetate (3×20 mL) was extracted, 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 silica gel column chromatography (mobile phase: methanol/dichloromethane=0-10%) to give compound 18 (29.8 mg, 92.5%) as a pale yellow solid.

¹ H NMR (300 MHz, meOH -d₄)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) hexan-1-ol (19)

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

Methyl 4-aminonicotinate 19a (1.0 g,6.57 mmol) and triethylamine (2.0 g,19.74 mmol) were dissolved in dichloromethane (20 mL) at room temperature, and monoethyl malonate acyl chloride (1.19 g,7.89 mmol) was slowly added dropwise thereto at 0℃and the reaction solution was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was quenched with water (100 mL), dichloromethane (3X 60 mL) was added to the reaction mixture, 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 separated and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether=0-10%) to give compound 19b (350 mg, 20.0%) as a yellow solid.

LC-MS：m/z 267.1[M+H]⁺。

Step 2: preparation of ethyl 2, 4-dioxo-1, 2,3, 4-tetrahydro-1, 6-naphthyridine-3-carboxylate (19 c)

Compound 19b (350 mg,1.31 mmol) and sodium ethoxide (178 mg,2.63 mmol) were dissolved in ethanol (10 mL) at room temperature, and the reaction solution was reacted at 80℃for 1 hour. After the reaction was completed, the reaction mixture was cooled to room temperature. The reaction solution was concentrated and filtered, and the filter cake was collected, and the solid was washed with a small amount of cold ethanol to give compound 19c (200 mg, 65.0%) as a yellow solid.

LC-MS：m/z 235.1[M+H]⁺。

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

Compound 19c (200 mg,0.85 mmol) was mixed with phosphorus oxychloride (10 mL) at 0deg.C, and the reaction was stirred at 100deg.C for 1.5 hours. After the 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), 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 a brown oily crude compound 19d (184 mg, 80.0%). It was used in the next step without purification.

LC-MS：m/z 271.0[M+H]⁺。

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 (184 mg,0.68 mmol) and 2-amino-1-hexanol (92 mg,0.79 mmol) were dissolved in N-methylpyrrolidone (6 mL) at room temperature under a nitrogen atmosphere, and N, N-diisopropylethylamine (267 mg,2.05 mmol) was added. The reaction was stirred for 4 hours at 100℃under nitrogen. After cooling to room temperature, a saturated ammonium chloride solution (50 mL) was added, and ethyl acetate (3×30 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. The crude product was purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether=0-20%) to give yellow oily mixtures 19e and 19f (153 mg, 64.0%).

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

Step 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 (153 mg,0.44 mmol) were dissolved in 2, 4-dimethoxybenzylamine (3 mL) at room temperature, then N, N-diisopropylethylamine (169 mg,1.31 mmol) was added and reacted at 100℃for 4 hours. After the reaction was completed, it was cooled to room temperature. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (3X 30 mL), and the organic phases were combined, 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 purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether=0-40%) to give 19g (92 mg, 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 (92 mg,0.21 mmol) 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 the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (mobile phase: methanol/dichloromethane=0 to 6%), to obtain a yellow solid compound 19h (60 mg, 99.0%).

LC-MS：m/z 287.1[M+H]⁺。

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

To compound 19h (60 mg,0.21 mmol) was added aqueous sodium hydroxide (1.5 mL,12.5mol/L,18.75 mmol) at room temperature and stirred at 120℃for 20 h. After the reaction was completed, the reaction solution was cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the crude product obtained was purified by preparative chromatography (column: XB ridge Prep C18 OBD column, 5um,20 x 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 white solid compound 19 (10.4 mg, 19.0%).

¹ H NMR (300 MHz, meOH -d₄)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 (200 mg,0.73 mmol) was added sodium hydroxide solution (12.5M, 5 mL) at room temperature. The reaction was stirred at 120℃overnight. After the reaction, 1mol/L of diluted hydrochloric acid was added to adjust the pH of the reaction solution to 7, ethyl acetate (3X 15 mL) was added to extract, the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained 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 in 2 minutes; detection wavelength: 254/220 nm), to obtain a white solid compound 20 (51.0 mg, 28.2%).

¹ H NMR (400 MHz, methanol -d₄)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 (370 mg,1.78 mmol) was dissolved in 1, 4-dioxane (6.0 mL) at room temperature. To the reaction mixture was added, in order, 2, 4-dimethoxybenzylamine (447.0 mg,2.67 mmol) and N, N-diisopropylethylamine (691 mg,5.35 mmol), and the mixture was stirred at 100℃under nitrogen for 2 hours. After the reaction was completed, 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 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 crude product was purified by silica gel column chromatography (mobile phase: methanol/dichloromethane=0-8%) to give compound 21b (400 mg, 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 (400 mg,118 mmol) was dissolved in dichloromethane (8.0 mL) at room temperature, the reaction liquid cooled to 0deg.C, oxalyl chloride (1.0 mL) was slowly added dropwise, followed by one drop of N, N-dimethylformamide. The reaction solution was warmed to room temperature, stirred for 1 hour, and then concentrated under reduced pressure to obtain crude acid chloride.

2- (Propylamino) ethanol (365 mg,3.55 mmol) and N, N-diisopropylethylamine (458 mg,3.55 mmol) were dissolved in dichloromethane (6.0 mL), the reaction liquid was cooled to 0℃and the obtained crude acid chloride was dissolved in dichloromethane (3.0 mL) and the reaction liquid was slowly added dropwise. After the reaction mixture was reacted at room temperature for 2 hours, the reaction was quenched with water (40 mL), extracted 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 crude product was purified by silica gel column chromatography (mobile phase: methanol/dichloromethane=0-10%) to give compound 21c (300 mg, 59.9%) as a white solid.

LC-MS：m/z 424.2[M+H]⁺。

Step 3: preparation of 2-amino-N- (2-hydroxyethyl) -N-propylquinoline-4-carboxamide (21)

Compound 21c (300 mg,0.71 mmol) 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 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 Shield RP OBD column, 5um,19 x 150mm; mobile phase A: water (10 mmoL/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 15% -32% acetonitrile in 8 minutes; detection wavelength: 254 nm), to obtain white solid compound 21 (103.2 mg, 53.2%).

¹ H NMR (400 MHz, methanol -d₄)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: preparation of N⁴ - (1-amino-2-methylhex-2-yl) -1, 5-naphthyridine-2, 4-diamine (22)

Step 1: preparation of N⁴ - (1-amino-2-methylhex-2-yl) -1, 5-naphthyridine-2, 4-diamine (22)

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

¹ H NMR (400 MHz, methanol -d₄)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 (405 mg,1.49 mol) was dissolved in N-methylpyrrolidone (5 mL) at room temperature, followed by the addition of 2-amino-1-heptanol (254.8 mg,1.94 mmol) and N, N-diisopropylethylamine (579.2 mg,4.48 mmol). The reaction solution was stirred at 100℃for 2 hours. After completion of the reaction, water (20 mL) was added thereto for dilution, ethyl acetate (3X 20 mL) was used for extraction, 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 purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether=0-27%) to give compound 23a (350 mg, 64.0%) as a yellowish green oil.

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] oxaazepino [6,5-c ] [1,5] naphthyridin-5 (1H) -one (23 c)

Compound 23a (350 mg,0.96 mmol) and N, N-diisopropylethylamine (371 mg,2.87 mmol) were dissolved in 2, 4-dimethoxybenzylamine (5 mL) at room temperature. The reaction solution was stirred at 100℃for 1 hour. After the reaction was completed, 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 concentrated under reduced pressure to give yellow oily liquid mixtures 23b and 23c (260 mg, 54.7%).

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

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] naphthyridine-5 (1H) -one (23 e)

The mixtures 23b and 23c (260 mg,0.52 mmol) were dissolved in dichloromethane (2.5 mL) at room temperature, then trifluoroacetic acid (2.5 mL) was added and reacted at room temperature for 30 min. After completion of the reaction, the mixture was concentrated under reduced pressure, the residue was diluted with water (20 mL), 2M sodium hydroxide solution was added to adjust pH to 7, and ethyl acetate (3X 20 mL) was used for extraction. 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 (175 mg, 96.5%).

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

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

To the mixtures 23d and 23e (175 mg,0.51 mmol) was added aqueous sodium hydroxide (10 mL,12.5mol/L,125 mmol) at room temperature and reacted 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 adding 2M diluted 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 obtained was purified by preparative chromatography (column: XBridge Prep C18 OBD column, 19X 250mm,10um; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 35% -55% acetonitrile in 8 min; detection wavelength: 254/220 nm) to give white solid compound 23 (25 mg, 18.0%).

¹ H NMR (300 MHz, meOH -d₄)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 (649 mg,2.39 mmol) was dissolved in N-methylpyrrolidone (8 mL) at room temperature, 2-piperidinemethanol (303 mg,2.63 mmol) and N, N-diisopropylethylamine (930 mg,7.21 mmol) were added to the reaction solution in this order, and the mixture was reacted at 100℃for 2 hours. After the reaction was completed, 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, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate=1/1) to give compound 24a (264 mg, 43.4%) as a yellow solid.

LC-MS：m/z 350.1[M+H]⁺。

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

Compound 24a (264 mg,1.04 mmol) was dissolved in 2, 4-dimethoxybenzylamine (2 mL) at room temperature. N, N-diisopropylethylamine (404 mg,3.13 mmol) was added to the reaction mixture, and the mixture was reacted at 100℃for 2 hours. After the reaction was completed, it was cooled to room temperature. The reaction solution was diluted with water (30 mL), extracted with ethyl acetate (3X 20 mL), and the organic phases were combined, 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 purified by column chromatography on silica gel (mobile phase: petroleum ether/ethyl acetate=1/1) to give yellow solid mixtures 24b and 24c (162.8 mg, 36.0%).

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

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

The mixtures 24b and 24c (162.8 mg,0.38 mmol) 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 the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained crude yellow oil was purified by silica gel column chromatography (mobile phase: dichloromethane/methanol=10/1) to obtain 24d (66 mg, 61.9%) as a yellow solid.

LC-MS：m/z 285.1[M+H]⁺。

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

Compound 24d (66 mg,0.23 mmol) was added to an ethanol-water solution (1 mL, 1:1) at room temperature, followed by sodium hydroxide (46.4 mg,1.16 mmol). The reaction solution 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 compound 24e (150 mg, crude) as yellow color. It was used in the next step without purification.

LC-MS：m/z 303.1[M+H]⁺。

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

To compound 24e (150 mg, crude) was added diphenyl ether (1 mL) at room temperature and reacted at 160℃for 6 hours. After cooling, the reaction mixture was directly purified by silica gel column chromatography (mobile phase: dichloromethane/methanol=10/1) to give crude yellow solid. Then the mixture was separated and purified by preparative chromatography (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 in 8 minutes; detection wavelength: 254/220 nm), to give white solid compound 24 (2.9 mg, 6.6%).

¹ H NMR (400 MHz, methanol -d₄)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 (20 mg,0.073 mmol) and N, N-diisopropylethylamine (28.4 mg,0.22 mmol) were dissolved in dichloromethane (1 mL) at 0deg.C. Methanesulfonyl chloride (9.2 mg,0.08 mmol) was dissolved in dichloromethane (0.5 mL) and slowly added dropwise to the reaction solution over 10 minutes. The reaction was then allowed to warm to room temperature for a further 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 obtained was 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: 20% -36% acetonitrile in 10 min; detection wavelength: 254/220 nm) to give compound 25 as a white solid (4.0 mg, 15.6%).

¹ H NMR (400 MHz, methanol -d₄)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 produced in the same manner as in the production method of example 25, except that cyclopropylchloride was used instead of methanesulfonylchloride.

¹ H NMR (400 MHz, methanol -d₄)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]⁺。

Examples 27 and 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)

Chiral resolution of compound 23 (25 mg,0.09 mmol) was performed at room temperature. Column type: CHIRAL ART cell-SB, 2 x 25cm,5um; mobile phase a: n-hexane (10 mM methanolic ammonia solution), mobile phase B: ethanol; flow rate: 20mL/min; gradient: a constant gradient of 20% acetonitrile over 22 minutes; detection wavelength: 263/218nm; compound 27 (7.1 mg, 28.4%) was obtained as a white solid, t_R = 3.305min, ee (enantiomeric excess): 97.5%; and white solid compound 28 (1.7 mg, 6.8%), t_R = 4.513min, ee value (enantiomeric excess): 99.1%; .

Compound 27

¹ H NMR (300 MHz, meOH -d₄)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, meOH -d₄)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-methylhex-1-ol (29)

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

3-Amino-5-bromopicolinic acid 29a (20.0 g,0.09 mol) 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 mixture was concentrated under reduced pressure, water (200 mL) was added to the residue, the mixture was extracted with 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 resulting yellow crude product was purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether=0-5%) to give compound 29b (8.5 g, 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-oxopropanamido) picolinate (29 c)

Compound 29b (8.5 g,36.9 mmol) and triethylamine (11.2 g,110.6 mmol) were dissolved in dichloromethane (100 mL) at room temperature, and monoethyl malonate acyl chloride (6.6 g,44.3 mmol) was slowly added dropwise at 0deg.C and the reaction solution was reacted at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, quenched with water (100 mL), 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 resulting yellow crude product was purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether=0-5%) to give compound 29c (6.8 g, 53.5%) as a yellow solid.

LC-MS：m/z 345.0[M+H]⁺。

Step 3: preparation of 7-bromo-2, 4-dioxo-1, 2,3, 4-tetrahydro-1, 5-naphthyridine-3-carboxylic acid ethyl ester (29 d)

Compound 29c (6.8 g,19.8 mmol) and sodium ethoxide (3.4 g,50 mmol) were dissolved in ethanol (60 mL) at room temperature, and the reaction solution was allowed to react 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 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]⁺。

Step 4: preparation of 7-bromo-2, 4-dichloro-1, 5-naphthyridine-3-carboxylic acid ethyl ester (29 e)

Compound 29d (10.0 g, crude) and phosphorus oxychloride (50 mL) were added at 0deg.C. The reaction mixture was reacted at 100℃for 1.5 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and after quenching the reaction with ice water, ethyl acetate (3X 80 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 obtained yellow crude product was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether=0 to 3%) to obtain yellow solid compound 29e (4.35 g, two-step yield 63.0%)

LC-MS：m/z 348.9[M+H]⁺。

Step 5: preparation of (R) -7-bromo-4- ((1- ((tert-butyldimethylsilyl) oxy) -2-methylhex-2-yl) amino) -2-chloro-1, 5-naphthyridine-3-carboxylic acid ethyl ester (29 f)

Compound 29e (4.35 g,12.4 mmol) and compound 11e (3.66 g,14.9 mmol) were dissolved in N-methylpyrrolidone (40 mL) at room temperature under nitrogen, and N, N-diisopropylethylamine (4.84 g,37.4 mmol) was added. The reaction was stirred for 4 hours at 100℃under nitrogen. 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 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. The resulting yellow crude product was purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether=0-5%) to give compound 29f (5.1 g, 73.7%) as a yellow oily liquid.

LC-MS：m/z 558.2[M+H]⁺。

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

Compound 29f (5.1 g,9.1 mmol) and N, N-diisopropylethylamine (3.5 g,27.3 mmol) were dissolved in 2, 4-dimethoxybenzylamine (10 mL) at room temperature. The reaction mixture was reacted at 100℃for 6 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, a saturated ammonium chloride solution (100 mL) was added, ethyl acetate (3X 80 mL) was added to the reaction mixture, 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 purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether=0-3%) to give 29g (5.3 g, 80.9%) of a yellow oily liquid compound.

LC-MS：m/z 689.3[M+H]⁺。

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

29G (5.3 g,7.7 mmol) of the compound was dissolved in absolute 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 mixture was concentrated under reduced pressure, and the resulting yellow crude product was added with water (100 mL), and 1mol/L diluted hydrochloric acid was added to adjust the pH to 6. Ethyl acetate (3×80 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 a yellow solid compound 29h (6.25 g, crude).

LC-MS：m/z 661.2[M+H]⁺。

Step 8: preparation of (R) -7-bromo-N⁴ - (1- ((tert-butyldimethylsilyl) oxy) -2-methylhex-2-yl) -N² - (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 room temperature. The mixture was reacted at 160℃for 1 hour. After the completion of the reaction, the reaction mixture was cooled to room temperature, and the crude product obtained was purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether=0 to 14%) to give compound 29i as a yellow viscous liquid (2.31 g, two-step yield 48.7%).

LC-MS：m/z 617.24[M+H]⁺。

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

5-Bromo-2-pyridinecarboxaldehyde (200 mg,1.07 mmol) was dissolved in methanol (4 mL) at room temperature. To the reaction mixture was added tetrahydropyrrole (97. Mu.L, 118 mmol). The reaction was carried out at room temperature for 0.5 hours. Sodium triacetoxyborohydride (228 mg,1.07 mmol) was further added to the reaction mixture, and the reaction was continued at room temperature for 12 hours. After the reaction was completed. The reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (3X 20 mL), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product obtained was isolated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate/triethylamine=1/1/0.01) to give compound 29j (130 mg, 50.1%) as a yellow solid.

LC-MS：m/z 241.0[M+H]⁺。

Step 10: preparation of (R) -N⁴ - (1- ((tert-butyldimethylsilyl) oxy) -2-methylhex-2-yl) -N² - (2, 4-dimethoxybenzyl) -7- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1, 5-naphthyridine-2, 4-diamine (29 k)

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

LC-MS：m/z 665.3[M+H]⁺。

Step 11: preparation of (R) -N⁴ - (1- ((tert-butyldimethylsilyl) oxy) -2-methylhex-2-yl) -N² - (2, 4-dimethoxybenzyl) -7- (6- (pyrrolidin-1-ylmethyl) pyridin-3-yl) -1, 5-naphthyridine-2, 4-diamine (291)

Compound 29k (60 mg,0.25 mmol) was dissolved in 1, 4-dioxane (3 mL) and water (0.75 mL) at room temperature. To the reaction solution were added potassium carbonate (69 mg,0.50 mmol), compound 29j (200 mg, crude) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (21 mg,0.025 mmol) in this order. The reaction mixture was replaced with nitrogen three times and reacted at 95℃for 2 hours. After the reaction was completed, it was cooled to room temperature. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (3X 10 mL), and the organic phases were combined, 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 purified by silica gel column chromatography (mobile phase: dichloromethane/methanol/triethylamine=15/1/0.01) to give 291 (62 mg, two-step yield 54.9%) as a yellow solid.

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-methylhex-1-ol (29)

Compound 291 (62 mg,0.088 mmol) 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 crude product was purified by preparative chromatography (column: XSelect CSH Prep C OBD column, 5um,19 x 150mm; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 25% -44% acetonitrile in 8 min; detection wavelength: 254 nm) to give compound 29 (5.9 mg, 15.4%) as a colorless oil.

¹ H NMR (300 MHz, meOH -d₄)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,0.101 mmol) in methanol (3 mL) at room temperature under nitrogen atmosphere was added platinum dioxide (10.0 mg). The reaction solution 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 C 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 -d₄)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-methylhex-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 (300 mg,1.35 mmol) was dissolved in 1, 4-dioxane (4 mL) and water (1 mL) at room temperature. To the reaction solution were added sodium carbonate (214 mg,2.02 mmol), 2, 5-dibromopyridine (350 mg,1.48 mmol) and tetrakis (triphenylphosphine) palladium (9 mg,0.01 mmol) in this order. The reaction mixture was replaced with nitrogen three times and reacted at 100℃for 5 hours. After the reaction was completed, 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 was concentrated under reduced pressure. The resulting crude yellow oil was purified by silica gel column chromatography (mobile phase: dichloromethane/methanol=10/1) to give compound 31a (60 mg, 17.7%) as a yellow solid.

LC-MS：m/z 253.0[M+H]⁺。

The remaining steps were the same as steps 10 to 12 of example 29, except that compound 31a was used instead of compound 29j, to prepare compound 31.

¹ H NMR (300 MHz, meOH -d4)δ8.87(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),0.99-0.87(m,3H).)

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-methylhex-1-ol (32)

Step 1: preparation of (R) -N⁴ - (1- ((tert-butyldimethylsilyl) oxy) -2-methylhex-2-yl) -N² - (2, 4-dimethoxybenzyl) -7-methyl-1, 5-naphthyridine-2, 4-diamine (32 a)

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

LC-MS：m/z 553.3[M+H]⁺。

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

Compound 32a (30 mg,0.05 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 the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained residue was separated and purified by preparative chromatography (column type: XSelect CSH Prep C OBD column, 5um,19 x 150mm; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 20% -40% acetonitrile in 8 minutes; detection wavelength: 254 nm), to obtain white solid compound 32 (4.4 mg, 28.1%).

¹ H NMR (400 MHz, methanol -d₄)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-methylhex-1-ol (33)

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

Compound 29i (30 mg,0.05 mmol) 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 saturated sodium hydrogencarbonate solution (20 mL), extracted with ethyl acetate (3X 20 mL), the organic phases were combined, 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 purified by separation through preparative chromatography (column: XSelect CSH Prep C 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 in 8 minutes; detection wavelength: 254 nm) to give compound 29 (7.2 mg, 54.0%) as a white solid.

¹ H NMR (400 MHz, methanol -d₄)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-methylhex-1-ol (34)

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

5-Bromo-2-pyridinecarbaldehyde (200 mg,1.07 mmol) was dissolved in1, 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 hours. To the reaction mixture was added sodium triacetoxyborohydride (348 mg,1.61 mmol), 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 obtained crude yellow oil was purified by silica gel column chromatography (mobile phase: dichloromethane/methanol/triethylamine=10/1/0.01) to obtain compound 34a (240 mg, 82.6%) as a yellow solid.

LC-MS：m/z 270.1[M+H]⁺。

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

Compound 34a (240 mg,0.89 mmol) was dissolved in 1, 4-dioxane (4 mL) at room temperature. To the reaction solution were added, successively, biborofenamate (338 mg,0.24 mmol), potassium acetate (348 mg,0.64 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (73 mg,0.089 mmol). The reaction mixture was replaced with nitrogen three times and reacted at 80℃for 12 hours. After the reaction was completed, it was cooled to room temperature. The reaction solution was diluted with water (30 mL), extracted with ethyl acetate (3×20 mL), and the organic phases were combined, 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]⁺。

Step 3: preparation of (R) -N⁴ - (1- ((tert-butyldimethylsilyl) oxy) -2-methylhex-2-yl) -N² - (2, 4-dimethoxybenzyl) -7- (6- ((4-methylpiperazin-1-yl) methyl) pyridin-3-yl) -1, 5-naphthyridine-2, 4-diamine (34 c)

Compound 29i (70 mg,0.11 mmol) was dissolved in 1, 4-dioxane (2 mL) and water (0.5 mL) at room temperature. To the reaction solution were added, in order, potassium carbonate (31 mg,0.23 mmol), compound 34b (200 mg, crude product), and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (9 mg,0.01 mmol). The reaction mixture was replaced with nitrogen three times and reacted at 95℃for 2 hours. After the reaction was completed, it was cooled to room temperature. The reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (3X 20 mL), and the organic phases were combined, 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 purified by silica gel column chromatography (mobile phase: dichloromethane/methanol/triethylamine=10/1/0.01) to give compound 34c (60 mg, 72.8%) as a yellow solid.

LC-MS：m/z 728.4[M+H]⁺。

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-methylhex-1-ol (34)

Compound 34c (60 mg,0.082 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 40℃for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product obtained was purified by preparative chromatography (column: XBRID Prep C18 OBD column, 5um,19 x 150mm; mobile phase A: water (0.05% ammonia water), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 25% -48% acetonitrile in 8 minutes; detection wavelength: 254/220 nm) to give off-white semi-oily compound 34 (6.1 mg, 16.0%).

¹ H NMR (400 MHz, methanol -d₄)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-methylhex-1-ol (35)

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

¹ H NMR (300 MHz, meOH -d₄)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-methylhex-1-ol (36)

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

5-Bromo-2- (diethylamino) pyrimidine (50 mg,0.22 mmol), pinacol biborate (83 mg,0.33 mmol) and potassium acetate (64 mg,0.65 mmol) were dissolved in 1, 4-dioxane (2 mL) at room temperature, and then [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (33 mg,0.04 mmol) was added, the reaction solution was replaced with nitrogen three times, and reacted overnight at 80 ℃. After completion of the reaction, the reaction mixture was quenched with 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 concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase: dichloromethane/methanol=12/1) to give compound 36a (70 mg, 116.3%) as a yellow solid.

LC-MS：m/z 278.2[M+H]⁺。

The remaining steps were the same as step 3 and step 4 of example 34, except that compound 34b was replaced with compound 36a, to prepare compound 36.

¹ H NMR (400 MHz, methanol -d₄)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-morpholinpyrimidin-5-yl) -1, 5-naphthyridin-4-yl) amino) -2-methylhex-1-ol (37)

Compound 37 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-morpholinyl) pyrimidine-5-boronic acid pinacol ester.

¹ H NMR (400 MHz, methanol -d₄)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-methylhex-1-ol (38)

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

¹ H NMR (400 MHz, methanol -d₄)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-methylhex-1-ol (39)

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, compound 39 was produced.

¹ H NMR (400 MHz, methanol -d₄)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-methylhex-1-ol (40)

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

5-Bromo-2-chloropyrimidine (1.0 g,5.17 mmol) and tetrahydropyrrole (0.74 g,10.34 mmol) were dissolved in absolute ethanol (10 mL) at room temperature. After stirring overnight at 80 ℃, the reaction mixture was concentrated under reduced pressure, the residue was diluted with water (50 mL), ethyl acetate (3×50 mL) was added to the diluted mixture, 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 40a (1.09 g, 92.4%) as a white solid.

LC-MS：m/z 228.0[M+H]⁺。

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

¹ H NMR (300 MHz, meOH -d₄)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-methylhex-1-ol (41)

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

5-Bromo-2-chloropyrimidine (477 mg,2.47 mmol) and 3-methylpyrrolidine hydrochloride (300 mg,2.47 mmol) were dissolved in absolute ethanol (8 mL) at room temperature. N, N-diisopropylethylamine (637 mg,4.93 mmol) was added to the reaction mixture, stirred at 80℃overnight, concentrated under reduced pressure, the residue was diluted with water (30 mL), ethyl acetate (3X 20 mL) was added to the diluted solution, 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 (507 mg, 84.9%) as a yellow solid.

LC-MS：m/z 242.0[M+H]⁺。

The remaining steps were the same as step 2, step 3 and step 4 of example 34, except that compound 34a was replaced with 41a, to prepare compound 41.

¹ H NMR (300 MHz, meOH -d₄)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-methylhex-2-yl) amino) -1, 5-naphthyridin-3-ol (42)

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

Compound 29k (65 mg,0.098 mmol) was dissolved in tetrahydrofuran (0.5 mL) and water (0.10 mL) at room temperature. Sodium hydroxide (3.1 mg,0.078 mmol) and 30% hydrogen peroxide (22.2 mg,0.196 mmol) were added to the reaction solution, stirred at room temperature for 2 hours, diluted with water (20 mL), extracted with ethyl acetate (3×10 mL), the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the crude product was isolated and purified by preparative thin layer chromatography (mobile phase: dichloromethane/methanol=12:1) to give compound 42a (20 mg, 36.9%) as a brown oil.

LC-MS：m/z 555.2[M+H]⁺。

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

Compound 42a (30 mg,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 the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by preparative chromatography (column: XBRID Prep C18 OBD column, 5um,19 x 150mm; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 6% -32% acetonitrile in 8 minutes; detection wavelength: 254 nm) to give compound 42 (5 mg, 30.0%) as pale yellow solid.

¹ H NMR (400 MHz, methanol -d₄)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-methylhex-1-ol (43)

Step 1: preparation of (R) -N⁴ - (1- ((tert-butyldimethylsilyl) oxy) -2-methylhex-2-yl) -N² - (2, 4-dimethoxybenzyl) -7-methoxy-1, 5-naphthyridine-2, 4-diamine (43 a)

Compound 42a (55 mg,0.099 mmol) was dissolved in acetone (2.0 mL) at room temperature. To the reaction solution were successively added potassium carbonate (17.1 mg,0.14 mmol) and methyl iodide (73.9 mg,0.23 mmol), 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), and the organic phases were combined, 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 give compound 43a (35 mg, 62.1%) as a brown oil.

LC-MS：m/z 569.3[M+H]⁺。

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

Compound 43a (35 mg,0.06 mmol) 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 the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by preparative chromatography (column: XSelect CSH Prep C OBD column, 5um,19 x 150mm; mobile phase A: water (0.05% ammonia water), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 30% -48% acetonitrile in 8 minutes; detection wavelength: 254 nm), to give compound 43 (5.8 mg, 30.2%) as a white solid.

¹ H NMR (400 MHz, methanol -d₄)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-methylhex-1-ol (44)

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

Methyl 2-amino-4-fluorobenzoate 44a (1.00 g,5.91 mmol) and triethylamine (1.79 g,17.74 mmol) were dissolved in dichloromethane (10 mL) at room temperature, and monoethyl malonate acyl chloride (0.98 g,6.50 mmol) was slowly added dropwise thereto at 0℃and the reaction solution was stirred at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, then water (50 mL) was added, ethyl acetate (3X 50 mL) was added, and extracted, 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 44b (1.5 g, 89.6%) as a yellow oily liquid.

LC-MS：m/z 284.1[M+H]⁺。

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

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

LC-MS：m/z 252.1[M+H]⁺。

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

To compound 44c (1.2 g,4.78 mol) was added phosphorus oxychloride (8 mL) at 0deg.C. The reaction mixture was reacted at 100℃for 1.5 hours. After the completion of the reaction, the reaction solution 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, 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 a yellowish green solid compound 44d (1.0 g, 72.7%).

LC-MS：m/z 288.0[M+H]⁺。

Step 4: preparation of (R) -4- ((1- ((tert-butyldimethylsilyl) oxy) -2-methylhex-2-yl) amino) -2-chloro-7-fluoroquinoline-3-carboxylic acid ethyl ester (44 e)

Compound 44d (320 mg,1.11 mmol) and compound 11e (327 mg,1.33 mmol) were dissolved in N-methylpyrrolidone (5 mL) at room temperature under nitrogen, and N, N-diisopropylethylamine (431 mg,3.34 mmol) was added. The reaction was stirred for 4 hours at 100℃under nitrogen. After cooling to room temperature, water (50 mL) was added, and ethyl acetate (3×30 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 give compound 44e (300 mg, 54.3%) as a yellow oily liquid.

LC-MS：m/z 497.2[M+H]⁺。

Step 5: preparation of (R) -4- ((1- ((tert-butyldimethylsilyl) oxy) -2-methylhex-2-yl) amino) -2- ((2, 4-dimethoxybenzyl) amino) -7-fluoroquinoline-3-carboxylic acid ethyl ester (44 f)

Compound 44e (300 mg,0.6 mmol) was dissolved in 2, 4-dimethoxybenzylamine (3.0 mL) at room temperature and N, N-diisopropylethylamine (232 mg,1.8 mmol) was added. The reaction solution was stirred at 100℃for 1 hour. After the completion of the reaction, the reaction mixture was cooled to room temperature, saturated ammonium chloride solution (30 mL) was added, ethyl acetate (3X 20 mL) was added to the reaction mixture, 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 44f (300 mg, 79.2%) as a yellow oily liquid.

LC-MS：m/z 628.4[M+H]⁺。

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

Compound 44f (300 mg,0.48 mmol) was dissolved in absolute ethanol (3 mL) at room temperature, and aqueous sodium hydroxide solution (12.5 mol/L,3 mL) was added. The reaction solution was stirred at 80℃for 2 hours. After the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting yellow crude product was added with water (20 mL), and 1mol/L diluted hydrochloric acid was added to adjust the pH to 5. 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 to give 44g (260 mg, 90.7%) of a yellow solid compound.

LC-MS：m/z 600.32[M+H]⁺。

Step 7: preparation of (R) -N⁴ - (1- ((tert-butyldimethylsilyl) oxy) -2-methylhex-2-yl) -N² - (2, 4-dimethoxybenzyl) -7-fluoroquinoline-2, 4-diamine (44 h)

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

LC-MS：m/z 556.3[M+H]⁺。

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

Compound 44h (180 mg,0.41 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1.0 mL) was added under ice-bath and reacted at room temperature for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the crude product obtained was purified by preparative chromatography (column: XBRID Prep C18 OBD column, 5um,19 x 150mm; mobile phase A: water (0.05% ammonia water), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 25% -44% acetonitrile in 12 minutes; detection wavelength: 254/220 nm) to give compound 44 (3.9 mg, 3.3%) as a white solid product.

¹ H NMR (300 MHz, meOH -d₄)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-methylhex-1-ol (45)

Step 1: preparation of (R) -N⁴ - (1- ((tert-butyldimethylsilyl) oxy) -2-methylhex-2-yl) -N² - (2, 4-dimethoxybenzyl) -7- (pyrrolidin-1-yl) -1, 5-naphthyridine-2, 4-diamine (45 a)

Compound 29i (40 mg,0.07 mmol) was dissolved in toluene (1.5 mL) at room temperature. To the reaction solution were successively added tetrahydropyrrole (5 mg,0.08 mmol), sodium t-butoxide (18 mg,0.19 mmol) and methanesulfonic acid [2,2 '-bis (diphenylphosphine) -1,1' -binaphthyl ] (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (17 mg,0.01 mmol). The reaction mixture was replaced with nitrogen three times and reacted at 100℃for 4 hours. After the reaction was completed, it was cooled to room temperature. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (3×10 mL), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting crude brown oil was separated and purified by silica gel column chromatography (mobile phase: dichloromethane/methanol=12/1) to give compound 45a (50 mg, 127.0%) as a brown solid.

LC-MS：m/z 608.2[M+H]⁺。

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

Compound 45a (50 mg,0.08 mmol) 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 crude product was purified by preparative chromatography (column: kinetex EVO Prep C 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 in 8 min; detection wavelength: 254 nm) to give compound 45 (4.8 mg, 16.9%) as pale yellow solid.

¹ H NMR (300 MHz, meOH -d₄)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 produced in the same manner as in step 1 and step 2 of example 45, except that the compound tetrahydropyrrole was replaced with N-methylpiperazine.

¹ H NMR (400 MHz, methanol -d₄)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-methylhex-1-ol (47)

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

¹ H NMR (300 MHz, meOH -d₄)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-methylhex-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 (450 mg,1.77 mmol) was dissolved in 1, 4-dioxane (4.5 mL) at room temperature. To the reaction solution were added successively, bisboropinacol ester (674 mg,2.66 mmol), potassium acetate (348 mg,3.54 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (144 mg,0.17 mmol). The reaction mixture was replaced with nitrogen three times and reacted at 80℃for 12 hours. After the reaction was completed, it was cooled to room temperature. The reaction solution was diluted with water (30 mL), extracted with ethyl acetate (3×20 mL), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a 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 (400 mg,1.83 mmol) in methanol (20 mL) was added 10% palladium on carbon (100 mg) at room temperature under nitrogen. The reaction solution was reacted at room temperature under a hydrogen atmosphere (2 atm) for 4 hours. After the 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 were the same as step 3 and step 4 of example 34, except that compound 34b was replaced with compound 48b, to prepare compound 48.

¹ H NMR (300 MHz, meOH -d₄)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-methylhex-1-ol (49)

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

Methyl 5-bromo-2-pyrimidinecarboxylate (700 mg,3.225 mmol) was dissolved in tetrahydrofuran (8.0 mL) at room temperature. Diisobutylaluminum hydride (4.8 mL,1M tetrahydrofuran solution) was slowly added dropwise at 0℃and the reaction solution was slowly warmed to room temperature and stirred at room temperature overnight. After completion of the reaction, the reaction mixture was quenched with water (20 mL), ethyl acetate (3X 20 mL) was added to the reaction mixture, 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 (70 mg, 11.6%) as a yellow liquid.

LC-MS：m/z 187.1[M+H]⁺。

The remaining procedures were the same as in step 1 to step4 of example 34, except that compound 5-bromo-2-pyridinecarboxaldehyde was replaced with 49a, to obtain compound 49.

¹ H NMR (300 MHz, meOH -d₄)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-methylhex-1-ol (50)

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

¹ H NMR (400 MHz, methanol -d₄)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-methylhex-2-yl) amino) -1, 5-naphthyridin-3-yl) phenyl) (pyrrolidin-1-yl) methanone (51)

In the same manner as in step 3 and step 4 of example 34 except that the compound 34b was replaced with 4- (pyrrolidine-1-carbonyl) phenylboronic acid pinacol ester, the compound 51 was produced.

¹ H NMR (300 MHz, meOH -d₄)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-methylhex-1-ol (52)

Preparation of Compound 52g in the same manner as in step 1 to step 7 of preparing Compound 44h in example 44 except that Compound 2-amino-4-fluorobenzoate 44a was replaced with 2-amino-4-bromobenzoate, compound 52g was obtained.

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.

¹ H NMR (300 MHz, meOH -d₄)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-methylhex-1-ol (53)

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

Compound 33 (80 mg,0.226 mmol) was dissolved in acetonitrile (5.0 mL) at room temperature. The selective fluororeagent (80.23 mg,0.226 mmol) was added portionwise at room temperature and the reaction stirred at room temperature overnight. After the reaction was completed, the residue was concentrated under reduced pressure and purified by preparative chromatography (column: XBridge Shield RP OBD column, 5um,19 x 150mm; mobile phase a: aqueous 0.05% ammonia), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 41% -58% acetonitrile in 8 minutes; detection wavelength: 254 nm) to give compound 53 (13.8 mg, 16.4%) as a pale yellow solid.

¹ H NMR (400 MHz, methanol -d₄)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)

Compound 2-fluoromalonic acid (4.72 g,38.7 mmol) was dissolved in phosphorus oxychloride (80.0 mL) at room temperature. After reaction at 80℃for 30 minutes, aniline (3.00 g,32.2 mmol) was added and reacted overnight at 80 ℃. 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, washed with saturated brine (200 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: petroleum ether/ethyl acetate=10/1) to give yellow solid 54a (1.60 g, 23.0%).

LC-MS：m/z 216.2[M+H]⁺。

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

Compound 54a (1.20 g,5.55 mmol) was dissolved in dry 1, 4-dioxane (20.0 mL) at room temperature. 2, 4-Dimethoxybenzylamine (1.39 g,8.31 mmol), palladium acetate (0.12 g,0.534 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.32 g,0.553 mmol), cesium carbonate (4.52 g,13.9 mmol) were added sequentially. After three nitrogen substitutions, the reaction was carried out at 70℃for 2 hours. After completion of the reaction, the reaction mixture was quenched with water (100 mL), extracted with ethyl acetate (3×60 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, and the resulting residue was purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate=3/1) to give 54b (800 mg, 41.5%) as a pale yellow solid.

LC-MS：m/z 347.1[M+H]⁺。

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

Compound 54b (400 mg,1.27 mmol) was dissolved in dry 1, 4-dioxane (10.0 mL) at room temperature. 2-amino-1 hexanol (223 mg,1.91 mmol), 2- (dicyclohexylphosphine) -3, 6-dimethoxy-2 '-4' -6 '-tri-I-propyl-11' -biphenyl (68.2 mg,0.127 mmol), methanesulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (115 mg,0.127 mmol), sodium t-butoxide (366 mg,3.81 mmol) were added sequentially. After three nitrogen substitutions, the reaction was carried out at 100℃for 2 hours. After completion of the reaction, the reaction mixture was quenched with water (25 mL), extracted with ethyl acetate (3×20 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, and the resulting residue was purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate=1/1) to give a light brown oil 54c (80 mg, 15.9%).

LC-MS：m/z 428.0[M+H]⁺

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

Compound 54c (80 mg,0.187 mmol) 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 the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by preparative chromatography (column: XSelect CSH Prep C OBD column, 5um,19 x 150mm; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 15% -50% acetonitrile in 10 minutes; detection wavelength: 254 nm) to give compound 54 (31.3 mg, 60.3%) as a white solid.

¹ H NMR (300 MHz, meOH -d₄)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-methylhex-1-ol (55)

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

¹ H NMR (400 MHz, methanol -d₄)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 the compounds of the invention on hTLR8 and hTLR7

In vitro assays of the receptor binding activity of the compounds of the invention on hTLR8 and hTLR7 using HEK-Bluen hTLR and HEK-Bluen hTLR cell lines purchased from Invivogen. The cell is a reporter gene for hTLR8 or hTLR7 gene and a secreted alkaline phosphatase (SEAP) co-transfected in HEK293 cells. Wherein the gene for SEAP is placed downstream of the IFN- β minimal promoter, which consists of 5 NF-promoters and AP-1 binding sites. The stimulation agent of hTLR8 or hTLR7 can activate NF-agent and AP-1 promoter to generate SEAP, and the effect of the compound is evaluated by detecting the SEAP level, and the detection method is a one-step detection method, is convenient to use and is often applied to high-throughput screening.

Test reagent:

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

DMEM medium (from Gibco company)

Fetal bovine serum (from Gibco company)

HEK-Blue^TM Detection, normocino, zeocin and blasticidin (Blasticidine) (from Invivogen Inc.)

The test process comprises the following steps:

1) Collecting cells in a cell culture flask, adjusting cell density to 2.2X10⁵/mL, resuspending cells with HEK-Blue^TM Detection reagent, inoculating 45 μl of cell suspension into 384 well plates, 10000 cells per well,

2) Compound plate preparation: test compounds were diluted 3-fold with DMSO from 2mM (or 18 mM) for 10 gradients. mu.L of diluted compound was added to 38. Mu.L of HEK-Blue^TM Detection reagent for 20-fold intermediate dilution. Cells were plated in 0.5% dmso wells as negative control wells for low reading. Cells were added with 1. Mu.M GS-9688 (cf. WO2016141092A1 synthetic route) as positive control wells for high read-out.

3) 5. Mu.L of the intermediate diluted compound was added to 384-well plates in which 45L of cells had been inoculated, and the drug was 10-fold diluted to give a final DMSO concentration of 0.5%.

4) 384-Well plates containing cells and compounds were placed in an incubator at 37℃with 5% CO₂ for 16 hours.

5) After 16 hours, the plates were removed and the SEAP absorbance at 620nm was measured using instrument VICTORNivo.

6) Data were analyzed using GRAPHPAD PRISM software to give EC₅₀ for each compound.

The average of the data for each concentration and positive and negative controls was determined. The percent activity was calculated from the formula:

Activity% = (compound reading-negative well reading)/(positive well reading-negative well reading) sex well reading.

IC₅₀ for each compound was calculated by fitting the data to a nonlinear regression equation:

Y=lowest+ (highest-lowest)/(1+10 ++logec₅₀ -X schl slope);

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

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

TABLE 1 agonist EC₅₀ values of compounds of the invention on TLR8/TLR7

Conclusion: the compounds of the invention are capable of selectively activating TLR8.

Test example 2: pharmacokinetic study in rats

This experiment was intended to evaluate the pharmacokinetic behavior of the compound of example 14 following intravenous drip or intragastric administration in rats. Intravenous drip administration: the tested compound is prepared into a clear solution with the concentration of 0.5 mg/ml, the solvent is 2% ethanol/40% polyethylene glycol 300/58%0.01 mol hydrochloric acid, and plasma is collected at 0.25h, 0.5h, 0.583h, 0.75h, 1h, 2h, 4h, 6h, 8h and 24h after administration; gastric lavage administration: the test compound was formulated as a clear solution of 0.5 mg/ml with a vehicle of 2% ethanol/40% polyethylene glycol 300/58%0.01 mole hydrochloric acid and plasma was collected at 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and 24h after dosing.

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

Plasma concentrations were processed using a non-compartmental model of WinNonlinTM Version 8.3.3 (Pharsight, mountain View, calif.) pharmacokinetic software and pharmacokinetic parameters were calculated using a linear log trapezoidal method.

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

Table 2 example 14 compound rat intravenous drip and lavage pharmacokinetic parameters

Conclusion: the compound of the invention has lower systemic oral bioavailability.

This experiment was intended to evaluate the tissue distribution behavior of the compound of example 14 following intragastric administration in rats. Gastric lavage administration: the test compound was formulated as a clear solution of 0.5 mg/ml with a vehicle of 2% ethanol/40% polyethylene glycol 300/58%0.01 mole hydrochloric acid. Plasma, brain and liver were collected at 0.25h, 0.5h, 1h, 2h, 4h and 8h after dosing. The concentration of the test compounds in plasma and tissues was determined by high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Retention times, chromatographic acquisitions and chromatograms of the compounds and internal standards were processed using software Analyst (Applied Biosystems) and statistics of the data were processed using software Analyst (Applied Biosystems). Plasma and tissue concentrations were processed using a non-compartmental model of WinNonlinTM Version 8.3.3 (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 of the compound of example 14 in rats at a dose of 5mg/kg administered by gavage are shown in table 3 below.

TABLE 3 study of the comparative parameters of the gastric lavage tissue distribution of Compound example 14 in rats

Conclusion: the compounds of the invention can be specifically enriched in liver tissue.

This experiment was designed to evaluate the intestinal bioavailability and liver first pass behavior of the compound of example 14 following intragastric administration in rats. Gastric lavage administration: the test compound was formulated as a clear solution of 0.5 mg/ml with a vehicle of 2% ethanol/40% polyethylene glycol 300/58%0.01 mole hydrochloric acid. Portal vein and systemic plasma were collected at 0.25h, 0.5h, 1h, 2h, 4h and 8h after dosing. The concentration of the test compound in the plasma was determined by high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Retention times, chromatographic acquisitions and chromatograms of the compounds and internal standards were processed using software Analyst (Applied Biosystems) and statistics of the data were processed using software Analyst (Applied Biosystems). Plasma concentrations were processed using a non-compartmental model of WinNonlinTM Version 8.3.3 (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 parameters of the compound of example 14 at 5mg/kg administered by gavage are shown in table 4 below.

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

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 following intravenous drip administration in bile duct intubated rats. Intravenous drip administration: the test compound was formulated as a clear solution of 0.5 mg/ml with a vehicle of 2% ethanol/40% polyethylene glycol 300/58%0.01 mole hydrochloric acid. Plasma was collected at 0.25h, 0.5h, 0.583h, 0.75h, 1h, 2h, 4h, 6h, 8h and 24h, and bile, urine and faeces were collected at 0-4h, 4-8h and 8-24h after dosing. The concentration of the test compounds in plasma, bile, urine and feces was determined by high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Retention times, chromatographic acquisitions and chromatograms of the compounds and internal standards were processed using software Analyst (Applied Biosystems) and statistics of the data were processed using software Analyst (Applied Biosystems). Plasma concentrations were processed using a non-compartmental model of WinNonlinTM Version 8.3.3 (Pharsight, mountain View, calif.) pharmacokinetic software and pharmacokinetic parameters were calculated using a linear log trapezoidal method.

Compound example 14 relevant parameters for rat excretion studies at a dose of 1mg/kg administered for 0.5 hour intravenous drip are shown in table 4 below.

TABLE 5 example 14 rat intravenous drip excretion study parameters

Conclusion: the compounds of the present invention are excreted primarily through the intestinal tract.

Claims

1. A compound of formula (IV) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

Wherein,

X is a C atom;

y is an N atom;

R¹ and R³ are hydrogen;

R² is selected from hydrogen, halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5 to 10 membered heteroaryl, wherein the C₆-C₁₀ aryl, 5 to 10 membered heteroaryl is optionally substituted with one or more Q groups;

r⁴ is selected from hydrogen;

R⁵ is selected from hydrogen;

R⁶ is selected from C₅-C₁₂ alkyl; wherein the C₅-C₁₂ alkyl is further substituted with-OR^a;

Q is selected from C₁-C₆ alkyl, 5 to 7 membered heterocyclyl, -NR^aR^b, wherein said C₁-C₆ alkyl is optionally further substituted with one or more groups selected from 5 to 7 membered heterocyclyl;

R^a is selected from hydrogen, or

R^a and R^b together with the nitrogen atom to which they are attached form a 5 to 7 membered nitrogen containing heterocyclic group, said 5 to 7 membered nitrogen containing heterocyclic group optionally further containing one or more heteroatoms selected from N, O, S in addition to N, said 5 to 7 membered nitrogen containing heterocyclic group optionally being further substituted with one or more groups selected from C₁-C₆ alkyl.

2. A compound of formula (IV) according to claim 1, or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

Wherein:

R¹ and R³ are hydrogen;

R² is selected from hydrogen, halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, phenyl, pyridinyl, pyrimidinyl, optionally substituted with one or more Q groups;

Q is as defined in claim 1.

3. A compound of formula (IV) according to claim 1, or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

R¹ and R³ are hydrogen;

r² is selected from halogen;

R⁵ is selected from hydrogen;

R⁶ is selected from C₅-C₁₂ alkyl, said C₅-C₁₂ alkyl optionally further selected from-OR^a;

R^a is selected from hydrogen.

4. A compound selected from the group consisting of stereoisomers, tautomers, meso, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof:

5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4, or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

6. Use of a compound according to any one of claims 1 to 4, or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 5, in the preparation of a TLR8 agonist medicament.