WO2019137201A1

WO2019137201A1 - Heteroarylo tetrahydropyridine compound and preparation method, pharmaceutical composition, and application thereof

Info

Publication number: WO2019137201A1
Application number: PCT/CN2018/123415
Authority: WO
Inventors: 蔡家强; 李桂英; 游泽金; 孙晓阳; 王利春; 王晶翼
Original assignee: 四川科伦博泰生物医药股份有限公司
Priority date: 2018-01-09
Filing date: 2018-12-25
Publication date: 2019-07-18
Also published as: CN111315744B; CN111315744A

Abstract

Disclosed are a heteroarylo tetrahydropyridine compound of formula I as a ‎hepatitis B surface antigen (HBsAg) secretion inhibitor and a preparation method, pharmaceutical composition, and application thereof.

Description

Heteroaryl-tetrahydropyridine compound, preparation method thereof, pharmaceutical composition and application thereof

Technical field

The present invention relates to a heteroaryltetrahydropyridine compound as a hepatitis B surface antigen HBsAg secretion inhibitor, a pharmaceutical composition comprising the same, a process for the preparation thereof, and use thereof.

Background technique

Hepatitis B is a common infectious liver disease caused by Hepatitis B virus (HBV) infection, which can further develop into diseases such as cirrhosis and liver cancer. According to the World Health Organization's (WHO) Global Hepatitis Report 2017, there were 257 million patients with chronic hepatitis B virus infection (HBsAg) in the world in 2015, resulting in 887,000 deaths, mostly from hepatitis B. The disease (including cirrhosis and liver cancer), and the mortality caused by hepatitis has been increasing from 2000 to 2015. Although the incidence of HBV has decreased over the years since the introduction of preventive hepatitis B vaccine, HBsAg-positive patients in the Western Pacific including China still accounted for 6.2% of the total population in 2015 (Global hepatitis report 2017, WHO), and nearly 9000 in China alone. 10,000 patients with chronic hepatitis B need antiviral therapy.

At present, the FDA has approved the approval of eight anti-hepatitis B drugs, which can be divided into two categories: interferon and nucleoside (acid) analogues. Interferons include interferon alpha-2b and polyethylene glycol (PEG) interferon alpha-2a. Interferon inhibits replication of hepatitis B virus by acting with host cell surface receptors to produce antiviral proteins, which have the disadvantage of low effective response rates and severe side effects and require long-term injection. Oral nucleoside (acid) analogs include lamivudine, adefovir dipivoxil, entecavir, telbivudine, tenofovir and tenofovir alafenamide. Nucleoside (acid) analogues work primarily by inhibiting the replication of viral polymerases (reverse transcriptases), which have the disadvantage of long-term use that makes the virus mutate and develops resistance (Jia et al. Future Med. Chem. , 2015, 7, 587-607). And these drugs have little effect on the clearance of HBsAg (a marker of hepatitis B functional healing (Revill et al. Nat. Rev. Gastroenterol. Hepatol., 2016, 13, 239-248)) (Janssen et al. Lancet, 2005, 365, 123-129; Marcellin et al. N. Engl. J. Med., 2004, 351, 1206-1217; Buster et al. Hepatology, 2007, 46, 388-394). Therefore, hepatitis B patients urgently need new drugs that are more effective and safer.

HBsAg is divided into three subtypes: large (L), medium (M), and small (S), which are important components of the membrane of infectious virus particles (Dane particles) and subviral particles (SVPs). It plays an important role in the entry of viruses into cells and the secretion of new viral particles. In the serum of patients with chronic hepatitis B, the number of SVPs assembled into HBsAg can reach 10 ¹³ /mL, which is 100,000 times that of infectious particles, so large and continuous. The expression of SVPs may inhibit the body's specific immune response to HBV by neutralizing hepatitis B surface antibodies (Cornberg et al. J. Hepatol., 2017, 66, 398-411). Therefore, HBsAg secretion inhibitors have a good application prospect in the treatment of HBV.

Recent clinical data published by Replicor show that the combination of HBsAg secretion inhibitors Rep-2139 and Rep-2165 (nucleic acid polymers (NAPs)) with interferon and tenofovir (TDF) can significantly reduce serum HBsAg levels, accompanied by The increase in surface antibody Anti-HBs enables functional control of hepatitis B virus (AASLD: The Liver Meeting. Washington, DC, October 20-24, 2017. Abstract LB-24.). However, because of the need for long-term injection administration, patient compliance will be limited.

Other reported inhibitors of HBsAg secretion include the tetrazoazinopyrimidine small molecule compound HBF-0259 (Dougherty et al. Antimicrob. Agents Ch., 2007, 51, 4427-4437) in vitro at a micromolar level, optimized HBF- The chemically stable triazolopyrimidine derivatives PBHBV-001 and PBHBV-2-15 (Yu et al. J. Med. Chem., 2011, 54, 5660-5670) and benzimidazole derived from 0259 were obtained. BM-601 (Xu et al. Antivir. Res., 2014, 107, 6-15), a compound in the Roche patent with in vitro activity up to the nanomolar level (WO2016107832).

Summary of the invention

The present invention provides novel, highly active inhibitors of HBsAg secretion which can be used alone or in combination with other drugs to treat hepatitis B.

One aspect of the invention provides a compound of Formula I or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite or prodrug thereof:

among them:

R ^{1 is} selected from a C ₆ -C ₁₄ aryl group and a 5-14 membered heteroaryl group, and the C ₆ -C ₁₄ aryl group and the 5-14 membered heteroaryl group may be optionally substituted with a substituent;

R ² and R ³ are each independently selected from hydrogen and unsubstituted C ₁ -C ₆ alkyl, or R ² and R ³ together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl;

R ^{4 is} selected from -C(O)R ⁵ , -CO ₂ R ⁶ , -C(O)NR ⁷ SO ₂ R ⁸ , -C(O)NR ⁹ R ¹⁰ , optionally substituted by a substituent 5 Metaheteroaryl, and

Wherein: R ⁵ and R ⁸ are each independently selected from a C ₁ -C ₆ alkyl group and a C ₃ -C ₇ cycloalkyl group, and the C ₁ -C ₆ alkyl group and the C ₃ -C ₇ cycloalkyl group are optionally selected. The ground is replaced by a substituent;

R ^{6 is} selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, and C ₃ -C ₇ cycloalkyl, and the C ₁ -C ₆ alkyl and C ₃ -C ₇ cycloalkyl may be optionally substituted with a substituent;

R ⁷ , R ⁹ and R ¹⁰ are each independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl and 4- a 7-membered heterocyclic group, or R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic group, said C ₁ -C ₆ alkyl group, C ₃ -C ₇ cycloalkyl group, C ₁ a -C ₆ alkyl-OC ₁ -C ₆ alkyl group and a 4-7 membered heterocyclic group may be optionally substituted with a substituent;

R ¹¹ and R ¹⁶ are each independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl and 4-10 membered heterocyclyl, said C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkyl-OC ₁ -C _{a 6} alkyl group, a C ₆ -C ₁₄ aryl group, a 5-14 membered heteroaryl group, and a 4-10 membered heterocyclic group may be optionally substituted with a substituent;

R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are each independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkane a base-OC ₁ -C ₆ alkyl group and a 4-7 membered heterocyclic group, said C ₁ -C ₆ alkyl group, C ₃ -C ₇ cycloalkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C _{a 6-} alkyl-OC ₁ -C ₆ alkyl group and a 4-7 membered heterocyclic group may be optionally substituted with a substituent;

One of X and Y is N and the other is selected from CH and N;

The "substituted substituent" means optionally substituted by one or more substituents independently selected from the group consisting of hydroxy, halo, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkane , C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OH, halogenated C ₁ -C ₆ alkoxy, C ₃ -C ₇ cycloalkyl, cyano, nitro, -C (O)R ⁵ , -C(O)OR ⁶ , -NR ⁷ SO ₂ R ⁸ , -SO ₂ R ⁸ , -C(O)NR ⁹ R ¹⁰ , -SO ₂ NR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ , -NR ⁹ C(O)R ¹⁰ , -C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, substituted by hydroxy -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, hydroxyalkyl, C ₁ -C ₆ alkyl-NR ⁹ R ¹⁰ , C ₁ -C ₆ alkyl-C(O)NR ⁹ R ¹⁰ , C ₁ -C ₆ alkyl-NR ⁹ C(O)R ¹⁰ , aryl, heteroaryl and heterocyclic;

Provided that when R ⁴ is a 5-membered heteroaryl group optionally substituted with a substituent, X and Y are not simultaneously N.

Another aspect of the invention provides a pharmaceutical composition comprising a compound of the invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate thereof, A metabolite or prodrug, and one or more pharmaceutically acceptable carriers.

Another aspect of the invention provides a compound of the invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite or prodrug thereof Use in the preparation of a medicament for the treatment of a disease associated with excessive secretion of HBsAg.

Another aspect of the invention provides a compound of the invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite, prodrug thereof or A pharmaceutical composition of the invention for use in the treatment of a disease associated with excessive secretion of HBsAg.

Another aspect of the invention provides a method of treating a condition associated with excessive secretion of HBsAg, the method comprising administering to an individual in need thereof an effective amount of a compound of the invention or a stereoisomer, tautomer, pharmaceutically thereof thereof An acceptable salt, polymorph, eutectic, solvate, metabolite, prodrug or pharmaceutical composition of the invention, and optionally including co-administration of other diseases associated with excessive secretion of HBsAg or The agent of the condition.

Another aspect of the invention provides a process for the preparation of a compound of the invention.

Compound and preparation method

A first aspect of the invention provides a compound of formula I or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite or prodrug thereof:

among them:

One of X and Y is N and the other is selected from CH and N;

The "substituted substituent" means optionally substituted by one or more substituents independently selected from the group consisting of hydroxy, halo, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkane , C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OH, halogenated C ₁ -C ₆ alkoxy, C ₃ -C ₇ cycloalkyl, cyano, nitro, -C (O)R ⁵ , -C(O)OR ⁶ , -NR ⁷ SO ₂ R ⁸ , -SO ₂ R ⁸ , -C(O)NR ⁹ R ¹⁰ , -SO ₂ NR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ , -NR ⁹ C(O)R ¹⁰ , -C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, substituted by hydroxy -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, hydroxyalkyl, C ₁ -C ₆ alkyl-NR ⁹ R ¹⁰ , C ₁ -C ₆ alkyl-C(O)NR ⁹ R ¹⁰ C ₁ -C ₆ alkyl-NR ⁹ C(O)R ¹⁰ , aryl, heteroaryl and heterocyclic.

In some embodiments, when R ⁴ is a 5-membered heteroaryl optionally substituted with a substituent, X and Y are not simultaneously N.

In some embodiments, the invention provides a compound of Formula I or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite or pre-form thereof medicine:

among them:

R ^{4 is} selected from -C(O)R ⁵ , -CO ₂ R ⁶ , -C(O)NR ⁷ SO ₂ R ⁸ , -C(O)NR ⁹ R ¹⁰ , 5 yuan optionally substituted by a substituent Heteroaryl, and

One of X and Y is N and the other is selected from CH and N;

The "substituted substituent" means optionally substituted by one or more substituents independently selected from the group consisting of hydroxy, halo, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkane Base, C ₃ -C ₇ cycloalkyl, cyano, nitro, -C(O)R ⁵ , -C(O)OR ⁶ , -NR ⁷ SO ₂ R ⁸ , -SO ₂ R ⁸ , -C( O) NR ⁹ R ¹⁰ , -SO ₂ NR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ , -NR ⁹ C(O)R ¹⁰ , -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, by hydroxyl group Substituted -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, hydroxyalkyl, C ₁ -C ₆ alkyl-NR ⁹ R ¹⁰ , C ₁ -C ₆ alkyl-C(O)NR ⁹ R ¹⁰ , C ₁ -C ₆ alkyl-NR ⁹ C(O)R ¹⁰ , aryl, heteroaryl and heterocyclic.

In some embodiments, the invention provides a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate thereof, as described above , metabolite or prodrug, of which:

R ^{1 is} selected from a C ₆ -C ₁₀ aryl group and a 5-10 membered heteroaryl group, and the C ₆ -C ₁₀ aryl group and the 5-10 membered heteroaryl group may be optionally one or more (for example, 2) Or 3 substituents selected from the group consisting of cyano, halogen, C ₁ -C ₃ alkyl, halogenated C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogenated C ₁ -C ₃ alkoxy, -SO ₂ R ⁸ , -C(O)NR ⁹ R ¹⁰ , -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl-OH , -NR ⁹ R ¹⁰ and a heterocyclic group;

Preferably, R ^{1 is} selected from the group consisting of phenyl and pyridyl, and the phenyl and pyridyl groups may be optionally substituted by one or more (for example 2 or 3) substituents independently selected from the group consisting of cyanogens: Base, halogen, C ₁ -C ₃ alkyl, halogenated C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogenated C ₁ -C ₃ alkoxy, -C(O)NH ₂ , -SO ₂ CH ₃ , -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, -OC ₁ -C ₃ alkyl-OH, -NR ⁹ R ¹⁰ and heterocyclic group;

Preferably, R ^{1 is} selected from the group consisting of phenyl and pyridyl, and the phenyl and pyridyl groups may be optionally substituted by one or more (for example 2 or 3) substituents independently selected from the group consisting of fluorine: , chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl, ethyl, propyl, isopropyl Base, cyano, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, -C(O)NH ₂ , -SO ₂ CH ₃ , -NR ⁹ R ¹⁰ and 5 to 10 membered spiroheterocyclyl;

Preferably, R ^{1 is} selected from the group consisting of phenyl and pyridyl, which may be optionally substituted by one or more substituents independently selected from the group of groups:

Fluorine, chlorine, bromine, methoxy, ethoxy, isopropoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl, cyano, trifluoromethyl, 2-hydroxy Ethoxy, 2-methoxyethoxy, -C(O)NH ₂ and -SO ₂ CH ₃ ;

-NR ⁹ R ¹⁰ , wherein R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group which may be optionally substituted by a substituent, wherein:

Preferably, the 4-6 membered heterocyclic group is selected from the group consisting of substituents which may be optionally substituted by one or more (e.g., 2 or 3) groups independently selected from the group consisting of

Hydroxy, halogen, C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OH, halogenated C ₁ -C ₆ alkane Oxyl, cyano, nitro, -NH ₂ , -C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, substituted by hydroxy -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl and hydroxy C ₁ -C ₁₀ alkyl;

More preferably, the 4-6 membered heterocyclyl is selected from the group consisting of substituents which may be optionally substituted by one or more (e.g., 2 or 3) groups independently selected from the group consisting of

Hydroxy, fluorine, chlorine, bromine, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, -C ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl and hydroxy C ₁ -C ₃ alkyl -;

Hydroxy, fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, hydroxymethyl and hydroxyethyl;

More preferably, the 4-6 membered heterocyclic group is selected from

as well as

9 to 10 yuan nitrogen-containing spiro heterocyclic group, preferably

More preferred

R ^{1 is} selected from C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl, and the C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl may be optionally substituted by one or more of the following groups : cyano, halogen, C ₁ -C ₃ alkyl, halogenated C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, -SO ₂ R ⁸ , -C(O)NR ⁹ R ¹⁰ ,- OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl or -OC ₁ -C ₆ alkyl-OH;

Preferably, R ^{1 is} selected from the group consisting of phenyl and pyridyl, which may be optionally substituted by one or more of the following groups: cyano, halogen, C ₁ -C ₃ alkyl, halogen C _1- C ₃ alkyl, C ₁ -C ₃ alkoxy, -C(O)NH ₂ , -SO ₂ CH ₃ , -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl or -OC ₁ -C ₃ alkyl-OH;

Preferably, R ^{1 is} selected from the group consisting of phenyl and pyridyl, which may be optionally substituted by one or more of the following groups: fluorine, chlorine, bromine, methoxy, ethoxy, isopropyl Oxy, methyl, cyano, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, -C (O) NH ₂ or -SO ₂ CH ₃ ;

Preferably, R ^{1 is} selected from the group consisting of phenyl and pyridyl, which may be optionally substituted by one or more of the following groups: fluorine, methoxy, methyl, cyano, trifluoromethyl , 2-hydroxyethoxy, 2-methoxyethoxy, -C(O)NH ₂ or -SO ₂ CH ₃ .

R ² and R ³ are each independently selected from hydrogen and C ₁ -C ₃ alkyl, or R ² and R ³ together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl;

Preferably, R ² and R ³ are each independently selected from hydrogen, methyl and ethyl, or R ² and R ³ together with the carbon atom to which they are attached form a cyclopropyl group;

More preferably, R ² and R ³ are each independently selected from hydrogen and methyl, or R ² and R ³ together with the carbon atom to which they are attached form a cyclopropyl group;

Particularly preferably, R ² and R ³ are each independently selected from the group consisting of hydrogen and methyl.

R ^{4 is} selected from -C(O)C ₁ -C ₆ alkyl, -C(O)OC ₁ -C ₆ alkyl, -C(O)OH, -C(O)NH ₂ , -C(O) NH(C ₁ -C ₆ alkyl), -C(O)NH-SO ₂ -C ₁ -C ₆ alkyl, -C(O)N(C ₁ -C ₆ alkyl)-SO ₂ -C ₁ a C ₆ alkyl group, optionally substituted by one or more substituents independently selected from C ₁ -C ₆ alkyl (for example, tetrazolyl, thiazolyl, imidazolyl, triazolyl) And oxazolyl), and

In a preferred embodiment, R ^{4 is} selected from the group consisting of -C(O)C ₁ -C ₃ alkyl, -C(O)OC ₁ -C ₃ alkyl, -C(O)OH, -C(O)NH ₂ , -C(O)NH-SO ₂ -C ₁ -C ₃ alkyl,

In a preferred embodiment, R ^{4 is} selected from the group consisting of -C(O)OCH ₃ , -C(O)OEt, -C(O)OH, -C(O)NH ₂ , -C(O)CH ₃ ,- C(O)Et, -C(O)NH-SO ₂ -CH ₃ , -C(O)NH-SO ₂ -Et,

In a preferred embodiment, R ^{4 is} selected from the group consisting of -C(O)OEt, -C(O)OH, -C(O)NH ₂ , -C(O)CH ₃ , -C(O)NH-SO ₂ -CH ₃ ,

In a preferred embodiment, R ^{4 is} selected from the group consisting of -C(O)OEt, -C(O)OH, -C(O)NH ₂ , -C(O)CH ₃ and -C(O)NH-SO ₂ -CH ₃ .

In a preferred embodiment, R ^{4 is} selected from the group consisting of -C(O)OEt and -C(O)OH, and more preferably, R ⁴ is -C(O)OH.

R ⁵ and R ^{8 are} selected from C ₁ -C ₃ alkyl and C ₃ -C ₅ cycloalkyl, and the C ₁ -C ₃ alkyl and C ₃ -C ₅ cycloalkyl may be optionally substituted by a substituent Preferably, R ⁵ and R ⁸ are methyl.

R ^{6 is} selected from the group consisting of hydrogen, C ₁ -C ₃ alkyl, and C ₃ -C ₅ cycloalkyl, and the C ₁ -C ₃ alkyl and C ₃ -C ₅ cycloalkyl may be optionally substituted with a substituent;

Preferably, R ⁶ is hydrogen, methyl or ethyl; more preferably, R ⁶ is hydrogen or ethyl; particularly preferably, R ⁶ is hydrogen.

R ⁷ , R ⁹ and R ¹⁰ are each independently selected from the group consisting of hydrogen, C ₁ -C ₃ alkyl, C ₃ -C ₅ cycloalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl and 4- a 6-membered heterocyclic group, or R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group, said C ₁ -C ₃ alkyl group, C ₃ -C ₅ cycloalkyl group, C ₁ a -C ₃ alkyl-OC ₁ -C ₃ alkyl group or a 4-6 membered heterocyclic group may be optionally substituted with a substituent;

Preferably, R ⁷ , R ⁹ and R ¹⁰ are hydrogen;

Preferably, R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group which may be optionally substituted with a substituent,

Hydroxy, fluorine, chlorine, bromine, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, -C ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl and OH-C ₁ -C ₃ alkane base-;

More preferably, the 4-6 membered heterocyclic group is selected from

In some embodiments, the invention provides a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate thereof, as described above , metabolites, prodrugs, of which:

R ^{1 is} selected from the group consisting of phenyl and pyridyl, and the phenyl and pyridyl groups may be optionally substituted with a substituent selected from the group consisting of:

5 to 10 yuan nitrogen-containing spiroheterocyclyl, preferred

More preferred

R ¹¹ and R ¹⁶ are each independently selected from hydrogen, C ₁ -C ₃ alkyl, C ₃ -C ₅ cycloalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl and 4-6 membered heterocyclyl, said C ₁ -C ₃ alkyl, C ₃ -C ₅ cycloalkyl, C ₁ -C ₃ alkyl-OC ₁ -C _{a 3-} alkyl group, a C ₆ -C ₁₄ aryl group, a 5-14 membered heteroaryl group, and a 4-6 membered heterocyclic group may be optionally substituted with a substituent;

Preferably, R ¹¹ and R ¹⁶ are each independently selected from the group consisting of hydrogen, C ₁ -C ₃ alkyl, 5-10 membered heteroaryl, and 4-6 membered heterocyclyl;

Preferably, R ¹¹ and R ¹⁶ are each independently selected from the group consisting of hydrogen and methyl.

R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are each independently selected from the group consisting of hydrogen, C ₁ -C ₃ alkyl, C ₃ -C ₅ cycloalkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkane a base-OC ₁ -C ₃ alkyl group and a 4-6 membered heterocyclic group, said C ₁ -C ₃ alkyl group, C ₃ -C ₅ cycloalkyl group, C ₁ -C ₃ alkoxy group, C ₁ -C _{The 3-} alkyl-OC ₁ -C ₃ alkyl group and the 4-6 membered heterocyclic group may be optionally substituted with a substituent;

Preferably, R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are all hydrogen.

X is N and Y is CH; or

X is CH and Y is N; or

X is N and Y is N.

The "substituted substituent" means optionally substituted by one or more substituents independently selected from the group consisting of hydroxy, halo, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkane , C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OH, halogenated C ₁ -C ₆ alkoxy, C ₃ -C ₇ cycloalkyl, cyano, nitro, -C (O) C ₁ -C ₆ alkyl, -C(O)OH, -C(O)OC ₁ -C ₆ alkyl, -NHSO ₂ C ₁ -C ₆ alkyl, -N(C ₁ -C ₆ Alkyl)SO ₂ C ₁ -C ₆ alkyl, -SO ₂ C ₁ -C ₆ alkyl, -C(O)NH ₂ , -C(O)NH(C ₁ -C ₆ alkyl), -SO ₂ NH ₂ , -SO ₂ NH(C ₁ -C ₆ alkyl), -NH ₂ , -NH(C ₁ -C ₆ alkyl), as defined above for R ⁹ and R ¹⁰ 4-7 membered heterocyclic group formed by a bonded N atom, -NHC(O)C ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)C(O)C ₁ -C ₆ alkyl , -C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl-OC ₁ substituted by hydroxy -C ₆ alkyl, hydroxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-NH ₂ , C ₁ -C ₆ alkyl-NH(C ₁ -C ₆ alkyl), C ₁ -C ₆ Alkyl-C(O)NH ₂ , C ₁ -C ₆ alkyl-C(O)NH(C ₁ -C ₆ alkyl), C ₁ -C ₆ alkyl-NHC(O)C ₁ -C ₆ alkyl a C ₁ -C ₆ alkyl-N(C ₁ -C ₆ alkyl)C(O)C ₁ -C ₆ alkyl group, an aryl group, a heteroaryl group and a 5-10 membered spiroheterocyclyl group;

Preferably, the "substituted with" means optionally substituted with one or more substituents independently selected from the group consisting of substituted: hydroxy, halo, C ₁ -C ₃ alkyl, halo C ₁ - C ₃ alkyl, C ₁ -C ₃ alkoxy, -OC ₁ -C ₃ alkyl-OH, halogenated C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, cyano, nitro , -C(O)C ₁ -C ₃ alkyl, -C(O)OH, -C(O)OC ₁ -C ₃ alkyl, -NHSO ₂ C ₁ -C ₃ alkyl, -N (C ₁ -C ₃ alkyl)SO ₂ C ₁ -C ₃ alkyl, -SO ₂ C ₁ -C ₃ alkyl, -C(O)NH ₂ , -C(O)NH(C ₁ -C ₃ alkyl) , -SO ₂ NH ₂ , -SO ₂ NH(C ₁ -C ₃ alkyl), -NH ₂ , -NH(C ₁ -C ₃ alkyl), as defined above for R ⁹ and R ¹⁰ 4-6 membered heterocyclic group formed by the N atom to which it is attached, -NHC(O)C ₁ -C ₃ alkyl, -N(C ₁ -C ₃ alkyl)C(O)C ₁ -C ₃ alkyl, -C ₁ -C ₃ alkyl group -OC ₁ -C ₃ alkyl, -OC ₁ -C ₃ alkyl group -OC ₁ -C ₃ alkyl, substituted hydroxyl group -OC ₁ -C ₃ alkyl -OC ₁ -C ₃ alkyl, hydroxy C ₁ -C ₃ alkyl, C ₁ -C ₃ alkyl-NH ₂ , C ₁ -C ₃ alkyl-NH(C ₁ -C ₃ alkyl), C ₁ -C ₃ alkyl-C(O)NH ₂ , C ₁ -C ₃ alkyl-C(O)NH(C ₁ -C ₃ alkyl), C ₁ -C ₃ alkyl-NHC(O) C ₁ -C ₃ alkyl, C ₁ -C ₃ alkyl-N(C ₁ -C ₃ alkyl)C(O)C ₁ -C ₃ alkyl and 9 to 10 membered nitrogen-containing spiroheterocyclyl;

Preferably, the "substituted substituent" means optionally substituted by one or more substituents independently selected from the group consisting of: hydroxy; fluoro, chloro, bromo; methyl, ethyl, isopropyl Fluoromethyl, difluoromethyl, trifluoromethyl; methoxy, ethoxy, isopropoxy; -OCH ₂ OH, -OCH ₂ CH ₃ OH; fluoromethoxy, difluoromethoxy , trifluoromethoxy; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; cyano; nitro; -C(O)CH ₃ , -C(O)CH ₂ CH ₃ ;-C(O ) OH, -C(O)OCH ₃ , -C(O)OCH ₂ CH ₃ ; -NHSO ₂ CH ₃ , -NHSO ₂ CH ₂ CH ₃ , -N(CH ₃ )SO ₂ CH ₃ , -N(CH ₃ ) SO ₂ CH ₂ CH ₃ ; -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ ; -C(O)NH ₂ , -C(O)NHCH ₃ , -C(O)NHCH ₂ CH ₃ ;- SO ₂ NH ₂ , -SO ₂ NHCH ₃ , -SO ₂ NHCH ₂ CH ₃ ; -NH ₂ , -NHCH ₃ , -NHCH ₂ CH ₃ ; as defined above for R ⁹ and R ¹⁰ a 4-6 membered heterocyclic group formed by a combination of N atoms; -NHC(O)CH ₃ , -NHC(O)CH ₂ CH ₃ , -N(CH ₃ )C(O)CH ₃ , -N(CH ₃ C(O)CH ₂ CH ₃ ;-CH ₂ -OCH ₃ , -CH ₂ CH ₂ -OCH ₃ , -CH ₂ -OCH ₂ CH ₃ , -CH ₂ CH ₂ -OCH ₂ CH ₃ ; -OCH ₂ -OCH ₃ , -OCH ₂ -OCH ₂ CH ₃ , -OCH ₂ CH ₂ -OCH ₃ ; -OCH ₂ -OCH ₃ , -OCH ₂ -OCH ₂ CH ₃ or -OCH ₂ substituted by hydroxy group CH ₂ -OCH ₃ ; -CH ₂ OH, -CH ₂ CH ₂ OH; -CH ₂ NH ₂ , -CH ₂ CH ₂ NH ₂ , -CH ₂ -NH(CH ₃ ), -CH ₂ -NH(CH ₂ CH ₃ ), -CH ₂ CH ₂ -NH(CH ₃ ), -CH ₂ CH ₂ -NH(CH ₂ CH ₃ ); -CH ₂ C(O)NH ₂ , -CH ₂ C(O)NH(CH ₃ ), -CH ₂ C(O)NH(CH ₂ CH ₃ ), -CH ₂ CH ₂ C(O)NH(CH ₃ ), -CH ₂ CH ₂ C(O)NH(CH ₂ CH ₃ ); -CH ₂ -NHC(O)CH ₃ , -CH ₂ -N(CH ₃ )C(O)CH ₃ , -CH ₂ -N(CH ₃ )C(O)CH ₂ CH ₃ ; and 9 to 10 a nitrogen-containing spiro heterocyclic group;

Preferably, the "substituted substituent" means optionally substituted by one or more substituents independently selected from the group consisting of fluorine, chlorine, bromine; methyl, ethyl, isopropyl; Methyl, difluoromethyl, trifluoromethyl; methoxy, ethoxy, isopropoxy; -OCH ₂ OH, -OCH ₂ CH ₃ OH; fluoromethoxy, difluoromethoxy, three Fluoromethoxy; cyano; -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ ; -C(O)NH ₂ , -C(O)NHCH ₃ , -C(O)NHCH ₂ CH ₃ ; a 4-6 membered heterocyclic group defined by R ⁹ and R ¹⁰ together with the N atom to which they are attached; -CH ₂ -OCH ₃ , -CH ₂ CH ₂ -OCH ₃ , -CH ₂ -OCH ₂ CH ₃ , -CH ₂ CH ₂ -OCH ₂ CH ₃ ; -OCH ₂ -OCH ₃ , -OCH ₂ -OCH ₂ CH ₃ , -OCH ₂ CH ₂ -OCH ₃ ;-CH ₂ OH, -CH ₂ CH ₂ OH; and

Preferably, the "substituted substituent" means optionally substituted by one or more substituents independently selected from the group consisting of fluorine, chlorine, bromine; methyl; trifluoromethyl; methoxy , ethoxy, isopropoxy; -OCH ₂ CH ₃ OH; fluoromethoxy, difluoromethoxy, trifluoromethoxy; cyano; -SO ₂ CH ₃ ; -C(O)NH ₂ a 4-6 membered heterocyclic group as defined above for R ⁹ and R ¹⁰ together with the N atom to which they are attached; -CH ₂ -OCH ₃ ; -OCH ₂ CH ₂ -OCH ₃ ;-CH ₂ OH; and

The present invention encompasses compounds of formula I which result from the arbitrary combination of the above preferred groups.

In some embodiments, the invention provides a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate thereof, as described above a metabolite or prodrug wherein the compound is a compound of formula II:

Wherein X, Y, R ¹ and R ⁴ are as defined above for formula I.

In some embodiments, the invention provides a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate thereof, as described above a metabolite or prodrug wherein the compound is a compound of formula III:

Wherein R ¹ and R ⁴ are as defined above for formula I;

The condition is that R ^{4 is} not a 5-membered heteroaryl group optionally substituted with a substituent.

In some embodiments, the invention provides a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate thereof, as described above a metabolite or prodrug wherein the compound is a compound of formula IV:

among them:

R ¹ and R ⁴ are as defined above for formula I;

R ² is an unsubstituted C ₁ -C ₆ alkyl group, preferably an unsubstituted C ₁ -C ₃ alkyl group, more preferably a methyl group or an ethyl group, more preferably a methyl group;

R ³ is hydrogen or unsubstituted C ₁ -C ₆ alkyl (preferably unsubstituted C ₁ -C ₃ alkyl, more preferably methyl or ethyl); preferably H or methyl;

or

R ² and R ³ together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl group, preferably a 3-6 membered cycloalkyl group, such as a cyclopropyl group;

In particular, the compound is a compound of formula V or VI:

In some embodiments, the invention provides a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate thereof, as described above a metabolite or prodrug wherein the compound is a compound of formula VII:

among them:

R ^{4 is} as defined above for formula I;

One of W ₁ , W ₂ and W ₃ is N, and the other two are CR ¹⁷ ;

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

R ^{17 is} each independently selected from the group consisting of:

(1) hydrogen, halogen (e.g., fluorine, chlorine, and bromine), C ₁ -C ₆ alkyl, and C ₁ -C ₆ alkoxy;

(2) -NR ⁹ R ¹⁰ , wherein R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl optionally substituted by a substituent, as above for R ⁹ and R of formula I ¹⁰ is defined; and

(3) a 5- to 10-membered spiroheterocyclyl group, preferably a 9- to 10-membered nitrogen-containing spiroheterocyclyl group, more preferably

Particularly preferred

In the preferred embodiment of the compounds of formula VII, R ⁴ is selected from -C (O) OEt, -C ( O) OH, -C (O) NH 2, -C (O) CH 3 and -C (O NH-SO ₂ -CH ₃ ;

R ^{17 is} each independently selected from the group consisting of:

(1) hydrogen, halogen (such as fluorine, chlorine and bromine), C ₁ -C ₃ alkyl (such as methyl, ethyl and propyl) and C ₁ -C ₃ alkoxy (such as methoxy and ethoxy) base);

(3)

Optimal

In a preferred embodiment of the compound of Formula VII, R ⁴ is -C(O)OH;

R ^{17 is} each independently selected from the group consisting of hydrogen, methyl, methoxy, and fluorine.

In some embodiments, the invention provides a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate thereof, as described above a metabolite or prodrug wherein the compound is a compound of formula VIII:

among them:

R ^{4 is} as defined above for formula I;

R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ are each independently selected from H, halogen, cyano, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl-OH, halogenated C ₁ -C ₆ alkoxy, -C(O)R ⁵ , -C( O) OR ⁶ , -NR ⁷ SO ₂ R ⁸ , -SO ₂ R ⁸ , -C(O)NR ⁹ R ¹⁰ , -SO ₂ NR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ and -NR ⁹ C(O) R ¹⁰ ; and

R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each as defined above for formula I.

In the preferred embodiment of the compounds of formula VIII, R ⁴ is selected from -C (O) OEt, -C ( O) OH, -C (O) NH 2, -C (O) CH 3 and -C (O NH-SO ₂ -CH ₃ ; Preferably, R ^{4 is} selected from the group consisting of -C(O)OEt and -C(O)OH.

In a preferred embodiment of the compound of Formula VIII, R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ are each independently selected from H, halo, cyano, halo C ₁ -C ₃ alkyl, C ₁ -C ₃ Alkyl, -OC ₁ -C ₃ alkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, -OC ₁ -C ₃ alkyl-OH, halogenated C ₁ -C ₃ alkoxy And -S(O) ₂ -C ₁ -C ₃ alkyl.

In a preferred embodiment of the compound of Formula VIII, R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ are each independently selected from the group consisting of H, fluorine, chlorine, bromine, cyano, trifluoromethyl, methyl, methoxy. , ethoxy, isopropoxy, -O-CH ₂ -CH ₂ -OMe, -O-CH ₂ CH ₂ -OH, trifluoromethoxy, fluoromethoxy, difluoromethoxy and -S (O) ₂ CH ₃ .

In a preferred embodiment of the compound of Formula VIII, R ^{4 is} selected from the group consisting of -C(O)OEt and -C(O)OH;

R ^{18 is} selected from the group consisting of H, fluorine, chlorine, methyl, cyano and trifluoromethyl;

R ^{19 is} selected from the group consisting of H, fluorine, chlorine, methoxy and methyl;

R ^{20 is} selected from the group consisting of H, fluorine, chlorine, trifluoromethyl, methyl, cyano and -S(O) ₂ CH ₃ ;

R ^{21 is} selected from the group consisting of H, fluorine, chlorine, bromine, methoxy, ethoxy, -O-CH ₂ -CH ₂ -OMe, trifluoromethyl, -O-CH ₂ -CH ₂ -OH, cyano, -C(O)NH ₂ , trifluoromethoxy, isopropoxy, difluoromethoxy, fluoromethoxy and methyl.

In some embodiments, the invention provides a compound, or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite thereof, as described above a prodrug wherein the compound is selected from the group consisting of:

A second aspect of the invention provides a process for the preparation of a compound of the invention.

In some embodiments, the invention provides a method of preparing a compound of Formula II:

among them:

R ^{4 is} selected from the group consisting of -C(O)R ⁵ , -CO ₂ R ⁶ , -C(O)NR ⁷ SO ₂ R ⁸ and -C(O)NR ⁹ R ¹⁰ ;

X, Y, R ¹ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are as defined above for formula I;

The method includes the following steps:

The first step: the compound II-1 is reduced to give the compound II-2, wherein R ^a is a C ₁ -C ₄ alkyl group, such as a methyl group, an ethyl group or an isopropyl group, preferably an ethyl group;

For example, the compound II-1 is in the presence of a reducing agent (for example, hydrogen, sodium borohydride or lithium borohydride) and a catalyst (for example, Pd/C, etc.) in a polar protic solvent (for example, methanol or ethanol, etc.) at room temperature. The compound II-2 is produced by a reduction reaction at 90 °C.

Step 2: Compound II-2 and R ¹ -L are coupled or nucleophilic substituted to form compound II-3, wherein L is a leaving group such as halogen (eg F, Cl, Br or I) or Trifluoromethanesulfonyloxy (OTf), etc.;

For example, the compound II-2 is in the presence of a base (for example, sodium carbonate, potassium carbonate, cesium carbonate or potassium acetate, etc.) and a ligand (for example, RuPhos, BINAP or SPhos, etc.) in a palladium catalyst (for example, Pd(PPh ₃ ) ₄ , Pd(dppf)Cl ₂ , Pd(OAc) ₂ or Pd ₂ (dba) ₃ ) catalyzed by an inert gas (eg N ₂ ) and at room temperature to 100 ° C in a non-polar solvent (eg toluene or two In toluene, etc., is coupled with R ¹ -L to form compound II-3; or, compound II-2 is in a base (for example, potassium carbonate, N,N-diisopropylethylamine (DIPEA) or t-butanol In the presence of potassium or the like, in a high boiling solvent such as N,N-dimethylformamide (DMF) or N-methylpyrrolidone (NMP), etc., at 100 ° C to 160 ° C, with R ¹ - L is subjected to a nucleophilic substitution reaction to give compound II-3.

The third step: the compound II-3 is converted into the target compound of the formula II by a suitable reaction.

among them:

R ^{4 is} selected from a 5-membered heteroaryl group optionally substituted with a substituent

X, Y, R ¹ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ are as defined above for formula I;

The method includes the following steps:

Step 1: Compound II-4 is reduced to give compound II-5, wherein PG ¹ is a suitable hydroxy protecting group (for example C ₁ -C ₃ alkyl, such as methyl, ethyl or isopropyl, preferably methyl );

For example, compound II-4 is present in a polar protic solvent (eg, methanol or ethanol, etc.) in the presence of a reducing agent (eg, hydrogen, sodium borohydride or lithium borohydride) and a catalyst (eg, Pd/C, etc.) at room temperature. The compound II-5 is produced by a reduction reaction at 90 °C.

The second step: compound II-5 and R ¹ -L are coupled or nucleophilic substitution reaction to form compound II-6, wherein L is a leaving group, such as halogen (such as F, Cl, Br or I) or OTf;

Compound II-5 is present in a catalyst (for example, Pd(PPh ₃ ) ₄ , Pd (in the presence of a base such as sodium carbonate, potassium carbonate, cesium carbonate or potassium acetate, etc.) and a ligand (for example, RuPhos, BINAP or SPhos, etc.). Dppf)Cl _{2 ,} Pd(OAc) ₂ or Pd ₂ (dba) ₃ ) catalyzed by an inert gas (eg N ₂ ) and at room temperature to 100 ° C in a non-polar solvent (eg toluene or xylene, etc.) In the reaction with R ¹ -L to form compound II-6; or, compound II-5 in the presence of a base (such as potassium carbonate, DIPEA or potassium t-butoxide) in a high boiling solvent (such as DMF or In NMP or the like, the compound II-6 is produced by nucleophilic substitution reaction with R ¹ -L at 100 ° C to 160 ° C.

The third step: compound II-6 is deprotected to form compound II-7;

For example, the compound II-6 is deprotected in the presence of a protic acid (for example, hydrochloric acid, hydrobromic acid, etc.) or a Lewis acid (for example, a boron tribromide diethyl ether solution or aluminum trichloride, etc.) at 0 ° C to 90 ° C. (e.g., demethylation) produces compound II-7.

Step 4: Conversion of compound II-7 to compound II-8, wherein PG ² is a suitable hydroxy protecting group (eg, trifluoromethanesulfonyl (Tf));

For example, compound II-7 is reacted with Tf ₂ O at room temperature to form compound II-8 wherein PG ² is Tf.

Step 5: Compound II-8 is coupled with R ⁴ -boric acid or R ⁴ -borate to form a compound of formula II;

For example, compound II-8 is present in a palladium catalyst (eg, Pd(PPh ₃ ) ₄ , Pd(dppf)Cl ₂ or Pd ₂ (dba) in the presence of a base such as sodium carbonate, potassium carbonate, cesium carbonate or potassium acetate. _3, etc. catalyzed by an inert gas (such as N ₂ ) and at room temperature to 120 ° C in an aprotic solvent (such as 1,4 dioxane, toluene or xylene, etc.) with R ⁴ -boric acid or R ^{The 4} -borate coupling reaction produces a compound of formula II.

In some embodiments, the invention provides a method of preparing a compound of Formula V:

among them:

R ¹ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are as defined above for formula I;

The method includes the following steps:

First step: Compound V-1 is coupled with a suitable organotin compound (such as tributylvinyltin) to form compound V-2, wherein each occurrence of R ^a is independently selected from C ₁ -C ₄ An alkyl group, such as methyl, ethyl or isopropyl, preferably ethyl; R ^b is a leaving group such as halogen (eg Cl, Br or I) or OTf;

For example, compound V-1 is in the presence of a ligand (eg, RuPhos, BINAP, or SPHos, etc.) in a palladium catalyst (eg, Pd(PPh ₃ ) ₄ , Pd(dppf)Cl ₂ , Pd(OAc) ₂ or Pd ₂ ( Dba) ₃ ) catalyzed by inert gas (eg N ₂ ) and at room temperature to 100 ° C in a polar aprotic solvent (eg DMF, etc.), coupled with tributylvinyltin to form compound V -2.

The second step: the compound V-2 is cyclized to form the compound V-3;

For example, compound V-2 is reacted with ammonium chloride (NH ₄ Cl) in acetic acid under reflux to form compound V-3.

The third step: conversion of compound V-3 to compound V-4, wherein PG ³ is a suitable amino protecting group, such as benzyl, p-toluenesulfonyl (Ts), benzoyl, benzyloxycarbonyl (Cbz), alkene Propoxycarbonyl (Alloc), methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl (Boc), etc.;

For example, the NH group in compound V-3 is protected with a protecting group PG ³ (eg, benzyl, Boc, etc.) to yield compound V-4.

The fourth step: Compound V-4 is reacted by Kulinkovich to form compound V-5;

For example, the alkoxypeptide catalyst used in the reaction may be Ti(OiPr) ₄ and the format reagent used may be EtMgBr.

Step 5: Compound V-5 is deprotected to form compound V-6;

Step 6: Compound V-6 and R ¹ -L are reacted or nucleophilically substituted to form compound V-7, wherein L is a leaving group such as halogen (for example, F, Cl, Br or I) or OTf, etc. ;

For example, the compound V-6 is in the presence of a base (for example, sodium carbonate, potassium carbonate, cesium carbonate or potassium acetate, etc.) and a ligand (for example, RuPhos, BINAP or SPHos, etc.) in a palladium catalyst (for example, Pd(PPh ₃ ) ₄ , Pd(dppf)Cl ₂ , Pd(OAc) ₂ or Pd ₂ (dba) ₃ ) catalyzed by an inert gas (eg N ₂ ) and at room temperature to 100 ° C in a non-polar solvent (eg toluene or two In toluene or the like, a reaction with R ¹ -L is carried out to form a compound V-7; or, a compound V-6 is present in a high-boiling solvent in the presence of a base (for example, potassium carbonate, DIPEA or potassium t-butoxide). For example, in DMF or NMP, etc., a compound V-7 is formed by nucleophilic substitution reaction with R ¹ -L at 100 ° C to 160 ° C.

Step 7: Compound V-7 is converted to the target compound of formula V by a suitable reaction.

In some embodiments, the invention provides a method of preparing a compound of Formula VI:

among them:

The method includes the following steps:

The first step: compound VI-1 and NC-C(O)OR ^a undergo a [2+2+2] cycloaddition reaction to form compound VI-2, wherein PG ³ is an amino protecting group, such as Ts, benzoyl, Cbz, Alloc, methoxycarbonyl, ethoxycarbonyl or Boc, especially Ts; R ^a is C ₁ -C ₄ alkyl, such as methyl, ethyl or isopropyl, preferably methyl or ethyl;

For example, compound VI-1 and ethyl cyanoformate are present in a suitable solvent (eg, two in the presence of a suitable rhodium catalyst (eg, Rh(COD) ₂ BF _{4 ,} etc.) and a ligand (eg, RuPhos, BINAP, SPHos, etc.) In the case of methyl chloride (DCM), 1,2-dichloroethane, or a compound of DCM and water, etc., a [2+2+2] cycloaddition reaction occurs at room temperature to 80 ° C to form compound VI-2.

The second step: compound VI-2 is deprotected to form compound VI-3;

For example, compound VI-2 is deprotected in the presence of a suitable acid (e.g., hydrobromic acid) at 80 ° C to 120 ° C to yield compound VI-3.

Step 3: Compound VI-3 undergoes a coupling reaction or nucleophilic substitution reaction with R ¹ -L to form compound VI-4, wherein L is a leaving group such as a halogen (for example, F, Cl, Br or I) or OTf ;

For example, compound VI-3 is in the presence of a suitable base (eg, sodium carbonate, potassium carbonate, cesium carbonate or potassium acetate, etc.) and a ligand (eg, RuPhos, BINAP, or SPHos, etc.) in a suitable palladium catalyst (eg, Pd ( PPh ₃ ) ₄ , Pd ₂ (dba) ₃ , Pd (dppf) Cl ₂ or Pd (OAc) _{2 ,} etc. catalyzed by inert gas (eg N ₂ ) protection and room temperature to 100 ° C, suitable for non-polar In a solvent such as toluene or xylene, coupling reaction with R ¹ -L to form compound VI-4; or compound VI-3 in a suitable base (for example, potassium carbonate, DIPEA or potassium t-butoxide) In the presence of a suitable high-boiling organic solvent (for example, DMF or NMP, etc.), a nucleophilic substitution reaction with R ¹ -L is carried out at 100 ° C to 160 ° C to form compound VI-4.

Fourth step: Compound VI-4 is converted to the target compound of formula VI by a suitable reaction.

In the third step of the method for the preparation of the compound of formula II, the seventh step of the method for preparing the compound of formula V, and the fourth step of the method for preparing the compound of formula VI, the suitable reaction is selected from the group consisting of :

(1) by hydrolysis to form a target compound wherein R ⁴ is -CO ₂ H;

(2) transesterification with an alcohol R ⁶ OH to form a target compound wherein R ⁴ is -CO ₂ R ⁶ and R ^{6 is} not H;

(3) reacting with HN(OMe)Me to form Weinreb amide, and then reacting the obtained Weinreb amide with Grignard reagent R ⁵ MgBr to form a target compound wherein R ⁴ is -C(O)R ⁵ ;

(4) was hydrolyzed to the acid, and the resulting acid with HNR ⁷ SO ₂ R ⁸ wherein R ⁴ is generated -C (O) NR title compound ⁷ SO ₂ R ⁸ is a condensation reaction; and

(5) an amine hydrolysis reaction with HNR ⁹ R ¹⁰ to form a target compound in which R ⁴ is -C(O)NR ⁹ R ¹⁰ , or a hydrolysis reaction occurs to form an acid, and then the resulting acid is condensed with an amine HNR ⁹ R ¹⁰ to form R ⁴ is a target compound of -C(O)NR ⁹ R ¹⁰ .

Pharmaceutical composition, preparation method and treatment method

A third aspect of the invention provides a pharmaceutical composition comprising a compound of the invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate thereof, A metabolite or prodrug, and one or more pharmaceutically acceptable carriers.

A fourth aspect of the invention provides a process for the preparation of a pharmaceutical composition of the invention, which comprises the compound of the invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph thereof a eutectic, solvate, metabolite or prodrug, and one or more pharmaceutically acceptable carrier combinations.

A fifth aspect of the invention provides a pharmaceutical preparation comprising a compound of the invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolism thereof , prodrug or pharmaceutical composition of the invention.

A sixth aspect of the invention provides a compound of the invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite, prodrug thereof, Use of the pharmaceutical composition of the present invention or the pharmaceutical preparation of the present invention for the preparation of a medicament for treating a disease associated with excessive secretion of HBsAg. Preferably, the disease is hepatitis B.

A seventh aspect of the invention provides a compound of the invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite, prodrug thereof, The pharmaceutical composition of the present invention or the pharmaceutical preparation of the present invention for use in the treatment of a disease associated with excessive secretion of HBsAg. Preferably, the disease is hepatitis B.

An eighth aspect of the invention provides a method of treating a disease associated with excessive secretion of HBsAg, the method comprising administering to an individual in need thereof an effective amount of a compound of the invention or a stereoisomer, tautomer, pharmaceutically thereof thereof An acceptable salt, polymorph, eutectic, solvate, metabolite or prodrug, a pharmaceutical composition of the invention or a pharmaceutical formulation of the invention, and optionally including co-administration and other treatments An agent that secretes an excessively associated disease or condition by HBsAg. Preferably, the disease is hepatitis B.

definition

Unless otherwise defined below, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques that are generally understood in the art, including those that are obvious to those skilled in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the invention.

The terms "including", "comprising", "having", "containing", or "comprising", as used herein, and other variants thereof, are inclusive or open, and not Exclude other unlisted elements or method steps.

As used herein, the term "alkyl" is defined as a straight or branched saturated aliphatic hydrocarbon group. In some embodiments, an alkyl group has from 1 to 10 carbon atoms, such as from 1 to 8 carbon atoms (C ₁ -C ₈ alkyl), from 1 to 6 carbon atoms (C ₁ -C ₆ alkyl), 1 Up to 4 carbon atoms (C ₁ -C ₄ alkyl), 1 to 3 carbon atoms (C ₁ -C ₃ alkyl), 2 to 6 carbon atoms (C ₂ -C ₆ alkyl), 2 to 4 One carbon atom (C ₂ -C ₄ alkyl) or 3 to 4 carbon atoms (C ₃ -C ₄ alkyl). For example, as used herein, the term "C ₁ -C ₆ alkyl" refers to a straight or branched chain group having from 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl) , n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl). In some embodiments, the alkyl is optionally substituted with one or more (such as 1 to 3) suitable substituents such as halo-substituted (in this case the group is referred to as "haloalkyl", e.g. -CF ₃ , -C ₂ F ₅ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CH ₂ Cl or -CH ₂ CH ₂ CF _{3 ,} etc.).

As used herein, the term "cycloalkyl" refers to a saturated or unsaturated, non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg, a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, or bicyclic, including spiro, fused or bridging systems (such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, etc.), It is optionally substituted by one or more (such as 1 to 3) suitable substituents. The cycloalkyl group has 3 to 15, for example 3 to 10 carbon atoms, 3 to 7 carbon atoms, 3 to 6 carbon atoms, 3 to 5 carbon atoms, 5 to 7 carbon atoms, 4 to 6 carbon atoms or 5 to 6 carbon atoms, etc. For example, as used herein, the term "C ₃ -C ₇ ring "Alkyl" means a saturated or unsaturated, non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring having from 3 to 7 ring-forming carbon atoms (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cycloheptyl), which is optionally substituted by one or more (such as 1 to 3) suitable substituents, such as methyl substituted cyclopropyl. The term "3-7 membered cycloalkyl" refers to having 3 to 7 saturated or unsaturated non-aromatic atoms a monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), optionally one or more (such as 1 to 3) Substituted for a suitable substituent, such as a methyl substituted cyclopropyl group.

As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system. For example, as used herein, the term "C ₆ -C ₁₄ aryl" means an aromatic group containing from 6 to 14 carbon atoms, and the term "C ₆ -C ₁₀ aryl" means 6 to 10 An aromatic group of a carbon atom such as a phenyl group or a naphthyl group. The aryl group is optionally substituted with one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO ₂ , C ₁ -C ₆ alkyl, etc.).

The term "heteroaryl" as used herein refers to a monocyclic, bicyclic or tricyclic aromatic ring system having from 5 to 14 ring atoms, especially having 5, 6, 7, 8, 9, 10, 11 , 12, 13 or 14 ring atoms, in particular 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, and which comprise at least one hetero atom which may be the same or different (for example oxygen , nitrogen or sulfur), and, in each case, may be benzo-fused. For example, as used herein, the term "5-14 membered heteroaryl" means a heteroaryl group containing from 5 to 14 ring atoms. Specific examples of heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, Oxadiazolyl, thiadiazolyl, etc., or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., or azaindole, and their benzo derivatives such as hydrazine, benzo Imidazole, quinoline, isoquinoline and the like.

The term "halo" or "halogen" group, as used herein, is defined to include F, Cl, Br or I.

As used herein, the term "alkoxy" refers to an alkyl group, as defined above, appended to the parent molecular moiety through an oxygen atom. Representative examples of C ₁ -C ₆ alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyl Oxyl, hexyloxy, and the like.

The term "hydroxyalkyl" as used herein means a hydrogen atom in an alkyl group as defined above (eg, a straight or branched alkyl group having from 1 to about 10 carbon atoms). Any one or more are substituted by one or more hydroxyl groups. For example, as used herein, the term "hydroxy C ₁ -C ₁₀ alkyl" means that any one or more of the hydrogen atoms of the C ₁ -C ₁₀ alkyl group is substituted with one or more hydroxyl groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl.

The term "heterocyclyl," as used herein, refers to a monocyclic or polycyclic group having 2, 3, 4, 5, 6, 7, 8, 9 carbon atoms and one or more (in the ring) For example, 1, 2, 3 or 4) are selected from C(=O), O, S, S(=O), S(=O) ₂ and NR (R represents a hydrogen atom or a substituent, for example but It is not limited to a group of an alkyl group or a cycloalkyl group. Particularly, the 3-10 membered heterocyclic group is a group having 3 to 10 carbon atoms and a hetero atom in the ring, for example, it has 4 to 10, 4 to 7, 4 to 6, 5 to 6, and 5 To 7, 5 to 9 and 5 to 10 carbon atoms and heteroatoms (referred to as 4 to 10 yuan, 4 to 7 yuan, 4 to 6 yuan, 5 to 6 yuan, 5 to 7 yuan, 5 to 9 yuan, and 5, respectively) To a 10-membered heterocyclic group, such as, but not limited to, oxiranyl, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyridyl An oxazolidinyl group, a tetrahydropyranyl group, a piperidinyl group, a morpholinyl group, a dithianyl group, a thiomorpholinyl group, a piperazinyl group, a trithianyl group, etc.; And, for example, but not limited to, pyrrolidino-cyclopropyl, cyclopentyl-azacyclopropyl, pyrrolidinocyclobutyl, pyrrolidinopyrrolidinyl, pyrrolidinopiperidinyl, pyrrolidine a oxapiperazinyl group, a pyrrolidino-morpholinyl group, a piperidinyl-morpholinyl group; or a spiro ring derivative; or a benzo derivative or a heteroaryl derivative, such as but not limited to

Wait.

The term "substituted" means that one or more (eg, 1, 2, 3 or 4) hydrogens on the designated atom are replaced by the selection of the indicated group, provided that the specified atom is not exceeded. The normal valence of the current case and the substitution form a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.

If a group is described as "optionally substituted with a substituent", the group may be unsubstituted (1) or (2) substituted with one or more substituents. If the carbon in the group is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the carbon (to the extent of any hydrogen present) may be isolated separately and/or together The optional substituents are selected instead. If the nitrogen in the group is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected Substituted substituents are substituted.

If a substituent is described as being "independently selected from" a group, each substituent is selected independently of the other. Thus, each substituent may be the same or different from another (other) substituent.

If the variable or substituent can be selected from a different variation and the variable or substituent occurs more than once, then the variations can be the same or different.

As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10 under reasonable conditions.

Unless otherwise indicated, a point of attachment of a substituent, as used herein, may come from any suitable position of the substituent.

The invention also includes all pharmaceutically acceptable isotopic compounds which are identical to the compounds of the invention, except that one or more atoms are of the same atomic number but the atomic mass or mass number differs from the atomic mass or mass which is dominant in nature. A number of atomic substitutions. Examples of isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., ² H, ³ H); isotopes of carbon (e.g., ¹¹ C, ¹³ C, and ¹⁴ C); isotopes of chlorine (e.g. ³⁶ Cl); isotope of fluorine (eg ¹⁸ F); isotopes of iodine (eg ¹²³ I and ¹²⁵ I); isotopes of nitrogen (eg ¹³ N and ¹⁵ N); isotopes of oxygen (eg ¹⁵ O, ¹⁷ O and ¹⁸ O) ); an isotope of phosphorus (eg, ³² P); and an isotope of sulfur (eg, ³⁵ S).

The term "stereoisomer" denotes an isomer formed by at least one asymmetric center. In a compound having one or more (eg, 1, 2, 3, or 4) asymmetric centers, which can produce a racemic mixture, a single enantiomer, a mixture of diastereomers, and Separate diastereomers. Specific individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the invention may exist as mixtures (often referred to as tautomers) of two or more different forms in a rapidly balanced structure. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. For example, a dihydropyrimidinyl group, a 2(1H)-pyridinone group or the like may exist in equilibrium in the following tautomeric forms in solution. It is to be understood that the scope of the present application covers all such ratios in any ratio (eg, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99). %) isomer or a mixture thereof.

Unless otherwise indicated, the compounds of the invention are intended to be stereoisomers (including cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformers, atropisomers, and mixtures thereof exist. The compounds of the invention may exhibit more than one type of isomerism and consist of a mixture thereof (e.g., a racemic mixture and a diastereomeric pair).

For example, in the present invention, a compound of the formula I or a salt thereof, in stereoisomeric form (for example, which contains one or more asymmetric carbon atoms), is a single stereoisomer (enantiomer and non-pair) The enantiomers) and mixtures thereof are included within the scope of the invention. The invention also includes individual isomers of the compound or salt represented by Formula I, as well as mixtures with isomers in which one or more of the center of the hand is inverted. The scope of the invention includes: mixtures of stereoisomers, as well as purified enantiomers or enantiomerically/diastereomerically enriched mixtures. The invention includes mixtures of stereoisomers of all possible different combinations of all enantiomers and diastereomers. The invention includes all combinations and subsets of stereoisomers of all the specific groups defined above. The invention also includes geometric isomers of a compound of formula I or a salt thereof, including cis-isomers.

Herein, the bond in the structure diagram represented by the wavy line "~~" is intended to mean a cis or trans isomer, or a mixture of cis and trans isomers in any ratio.

The invention encompasses all possible crystalline forms or polymorphs of the compounds of the invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio. It will also be understood that certain compounds of the invention may exist in free form for treatment or, where appropriate, in the form of their pharmaceutically acceptable derivatives. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, solvates, metabolites or prodrugs which, after administration to a patient in need thereof, can be directly or indirectly A compound of the invention or a metabolite or residue thereof is provided. Thus, when reference is made herein to a "compound of the invention," it is also intended to encompass the various derivative forms described above for the compound.

The pharmaceutically acceptable salts of the compounds of the present invention include the acid addition salts and base addition salts thereof. For example, hexafluorophosphate, meglumine salt, and the like. For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

The compound of the present invention may exist in the form of a solvate (preferably a hydrate) wherein the compound of the present invention contains a polar solvent as a structural element of the crystal lattice of the compound, particularly such as water, methanol or ethanol. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios.

Also included within the scope of the invention are metabolites of the compounds of the invention, i.e., substances formed in vivo upon administration of a compound of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidization, enzymatic hydrolysis, and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds prepared by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolic product thereof.

The invention further includes within its scope prodrugs of the compounds of the invention which are certain derivatives of the compounds of the invention which may themselves have less or no pharmacological activity, when administered to or into the body It can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional group derivatives of the compounds which are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 ( Edited by EBRoche, American Pharmaceutical Association). Prodrugs of the invention may, for example, be known by those skilled in the art as "pro-moiety" (e.g., "Design of Prodrugs", H. Bundgaard (Elsevier, 1985))" It is prepared in place of the appropriate functional groups present in the compounds of the invention.

The invention also encompasses compounds of the invention containing a protecting group. In any process for preparing a compound of the invention, it may be necessary and/or desirable to protect a sensitive group or reactive group on any of the molecules of interest, thereby forming a chemically protected form of the compound of the invention. This can be achieved by conventional protecting groups such as those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P. GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. Protecting groups, which are incorporated herein by reference. The protecting group can be removed at a suitable subsequent stage using methods known in the art.

"Pharmaceutically acceptable carrier" in the context of the present invention means a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting humans and/or within the scope of sound medical judgment. Tissues of other animals without excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit/risk ratio.

Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, minerals. Oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. It is also possible to use physiological saline and an aqueous solution of glucose and glycerin as a liquid carrier, particularly for injection. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol and the like. The composition may also contain minor amounts of wetting agents, emulsifying agents or pH buffering agents as needed. Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are as described in Remington's Pharmaceutical Sciences (1990).

The compositions of the invention may act systemically and/or locally. For this purpose, they may be administered in a suitable route, for example by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, It is administered in the form of an ophthalmic preparation or by inhalation.

For these routes of administration, the compositions of the invention may be administered in a suitable dosage form.

The dosage forms include, but are not limited to, tablets, capsules, troches, hard candy, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions. Injectable solutions, elixirs, syrups.

The term "effective amount" as used herein refers to an amount of a compound that, to a certain extent, relieves one or more symptoms of the condition being treated after administration.

The dosing regimen can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the urgent need for treatment. It is noted that the dose value can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering the composition or the composition of the supervised composition.

The amount of the compound of the invention administered will depend on the severity of the individual, condition or condition being treated, the rate of administration, the handling of the compound, and the judgment of the prescribing physician. Generally, an effective dose will be from about 0.0001 to about 50 mg per kg body weight per day, for example from about 0.01 to about 10 mg/kg/day (single or divided doses). For a 70 kg person, this would add up to about 0.007 mg/day to about 3500 mg/day, such as from about 0.7 mg/day to about 700 mg/day. In some cases, a dose level that is not higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose may still be employed without causing any harmful side effects, provided that the larger The dose is divided into several smaller doses to be administered throughout the day.

The amount of the compound of the present invention in the pharmaceutical composition may be from about 0.01 mg to about 1000 mg.

The term "treating" as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progression of a condition or condition to which such a term applies or one or more symptoms of such a condition or condition, or Prevention of such a condition or condition or one or more symptoms of such condition or condition.

"Individual" as used herein includes human or non-human animals. Exemplary human individuals include a human individual (referred to as a patient) or a normal individual having a disease, such as the disease described herein. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (eg, birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals, and/or domesticated animals (eg, sheep, dogs). , cats, cows, pigs, etc.).

Advantageous effects of the invention

The compounds of the present invention have potent inhibitory activity against HBsAg secretion, have good physicochemical properties (such as solubility, physical and/or chemical stability), good pharmacokinetic properties (eg good bioavailability, suitable Excellent plasma properties, half-life), good safety (lower toxicity (eg lower heart, liver toxicity) and / or fewer side effects, wider treatment window) and other excellent properties.

Detailed ways

Example

The invention is further described in the following examples, but the examples are not intended to limit the scope of the invention.

The abbreviations in the present invention have the following meanings:

The structure of the compounds of the invention is confirmed by nuclear magnetic resonance spectroscopy ( ¹ H NMR) and/or mass spectrometry (MS).

The monitoring of the reaction was carried out by thin layer chromatography (TLC) or LC-MS.

¹ H NMR spectrometer: Bruker superconducting nuclear magnetic resonance spectrometer (model AVACE III HD 400 MHz).

LC/MS mass spectrometer: Aglient 1260 Infinity/Aglient 6120 Quadrupole.

Thin layer chromatography was performed using silica gel GF 254 as the stationary phase.

The compound of the present invention can be separated and purified by preparative silica gel plate, silica gel column chromatography, preparative high performance liquid chromatography (Prep-HPLC), and flash column chromatography (Flash column chromatography).

Column chromatography generally uses 200-300 mesh silica gel (Qingdao Ocean) as the stationary phase.

Flash column chromatography was performed using a Biotage flash column chromatograph.

Prep-HPLC was performed on an Agilent 1260 chromatograph.

The microwave reaction was carried out using a Biotage Initiator microwave reactor.

The system of the eluent includes: A: dichloromethane and methanol; B: petroleum ether and ethyl acetate, and the volume ratio of the solvent is adjusted depending on the polarity of the compound.

In the following examples, the temperature of the reaction was room temperature (20 ° C to 30 ° C) unless otherwise specified.

The reagents used in the present application were purchased from companies such as Acros Organics, Aldrich Chemical Company or Tiber Chemical.

Example 1: Ethyl 7-(3,4-difluoro-5-methoxyphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (1)

First step: 5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylic acid ethyl ester (1b)

Compound 1a (2.02 g, 10 mmol, prepared by reference to "Heterocycl. Commun., 2000, 6, 25") was dissolved in 40 mL of ethanol, 100 mg of 10% Pd/C was added under N ₂ protection, and replaced with H ₂ After N ₂ , the reaction was carried out at room temperature for 24 h. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 207.2 [M+H] ⁺ .

Second step: ethyl 7-(3,4-difluoro-5-methoxyphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (1)

Compound 1b (220 mg, 1.07 mmol), 5-bromo-1,2-difluoro-3-methoxybenzene (357 mg, 1.60 mmol), Pd(OAc) ₂ (20 mg, 0.085 mmol), BINAP (106 mg, 0.17 mmol) and Cs ₂ CO ₃ (869 mg, 2.67 mmol) were dissolved in 20 mL of toluene and heated to 90 ° C under N ₂ for overnight. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 349.1 [M+H] ⁺ .

^{_{1 H NMR (CDCl 3, 400MHz}} ) δ8.53 (s, 1H), 7.94 (s, 1H), 6.36-6.31 (m, 2H), 4.45 (q, J = 7.2Hz, 2H), 4.36 (s, 2H), 3.88 (s, 3H), 3.48 (t, J = 5.6 Hz, 2H), 3.03 (t, J = 5.6 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H).

Example 2: 7-(3,4-Difluoro-5-methoxyphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (2)

Compound 1 (35 mg, 0.1 mmol) was dissolved in 1 mL of tetrahydrofuran and 0.5 mL water, and then LiOH·H ₂ O (21 mg, 0.5 mmol) was added and allowed to react at room temperature for 1 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, extracted with ethyl acetate, dried over anhydrous sodium sulfate and dried, and then purified to afford compound 2 (20 mg).

Prep-HPLC conditions:

Instrument model: Agilent 1260, column: Waters SunFire Prep C ₁₈ OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 ° C; flow rate: 20.0 mL / min; detection wavelength: 214 nm; elution gradient: (0 min: 10% A, 90% B; 16.0 min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous formic acid.

MS (ESI, m/z): 321.2 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.54 (s, 1H), 7.91 (s, 1H), 6.64-6.60 (m, 2H), 4.50 (s, 2H), 3.88 (s, 3H), 3.56 (t, J = 5.6 Hz, 2H), 3.00 (t, J = 5.6 Hz, 2H).

Example 3: 7-(3,4-Difluoro-5-methoxyphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxamide (3)

Compound 1 (28 mg, 0.08 mmol) was dissolved in 5 mL of 7N MeOH MeOH.

MS (ESI, m/z): 320.2 [M+H] ⁺ .

¹ H NMR (CDCl ₃ , 400 MHz) δ 8.37 (s, 1H), 8.03 (s, 1H), 7.81 (br, 1H), 6.39-6.34 (m, 2H), 5.57 (br, 1H), 4.38 ( s, 2H), 3.92 (s, 3H), 3.50 (t, J = 5.6 Hz, 2H), 3.06 (t, J = 5.6 Hz, 2H).

Example 4: 1-(7-(3,4-Difluoro-5-methoxyphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)ethanone (4)

First step: 7-(3,4-difluoro-5-methoxyphenyl)-N-methoxy-N-methyl-5,6,7,8-tetrahydro-2,7-naphthalene Pyridine-3-carboxamide (4a)

Compound 2 (161 mg, 0.5 mmol), methoxymethylamine hydrochloride (74 mg, 0.75 mmol), HATU (229 mg, 0.6 mmol) and DIPEA (226 mg, 1.75 mmol) in 3 mL DMF at room temperature Stir for 2 h. After completion of the reaction, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated.

MS (ESI, m/z): 364.2 [M+H] ⁺ .

Second step: 1-(7-(3,4-difluoro-5-methoxyphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)ethanone (4)

The next compound 4a (81mg, 0.22mmol) was dissolved in 2mL of anhydrous tetrahydrofuran, N ₂ protection, tetrahydrofuran was added dropwise under ice-bath and 3N methyl magnesium bromide (0.144mL, 0.433mmol), in an ice bath under reaction 2h. After completion of the reaction, the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate.

MS (ESI, m/z): 319.1 [M+H] ⁺ .

¹ H NMR (CDCl ₃ , 400 MHz) δ 6.49 (s, 1H), 7.87 (s, 1H), 6.39-6.35 (m, 2H), 4.40 (s, 2H), 3.92 (s, 3H), 3.50 ( t, J = 5.6 Hz, 2H), 3.06 (t, J = 5.6 Hz, 2H), 2.72 (s, 3H).

Example 5: 7-(3,4-Difluoro-5-methoxyphenyl)-N-(methylsulfonyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-3 -formamide (5)

Compound 2 (56 mg, 0.174 mmol), methanesulfonamide (34 mg, 0.348 mmol), DCC (72 mg, 0.348 mmol), DMAP (5 mg, 0.04 mmol) was dissolved in 5 mL of dichloromethane and allowed to react at room temperature for 2 h. Then, the mixture was filtered through Celite, and the filtrate was evaporated to dryness, and the compound 5 (3 mg) was obtained by Prep-HPLC (Prep-HPLC conditions with reference to Example 2).

MS (ESI, m/z): 398.1 [M+H] ⁺ .

¹ H NMR (CDCl ₃ , 400 MHz) δ 8.39 (s, 1H), 8.02 (s, 1H), 6.38-6.30 (m, 3H), 4.39 (s, 2H), 3.92 (s, 3H), 3.50 ( t, J = 5.2 Hz, 2H), 3.40 (s, 3H), 3.08 (t, J = 5.2 Hz, 2H).

Example 6: 7-(3,4-Difluoro-5-(2-methoxyethoxy)phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-3- Carboxylic acid (6)

First step: 7-(3,4-difluoro-5-(2-methoxyethoxy)phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3- Ethyl carboxylate (6a)

Compound 1b (63 mg, 0.305 mmol), 5-bromo-1,2-difluoro-3-(2-methoxyethoxy)benzene (122 mg, 0.458 mmol), Pd(OAc) ₂ (3 mg, 0.015) Methyl), BINAP (19 mg, 0.03 mmol) and Cs ₂ CO ₃ (253 mg, 0.610 mmol) were dissolved in 5 mL of toluene and heated to 90 ° C under N ₂ for overnight. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 393.2 [M+H] ⁺

Second step: 7-(3,4-difluoro-5-(2-methoxyethoxy)phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-3- Carboxylic acid (6)

Compound 6a (30 mg, 0.076 mmol) was dissolved in 5 mL of tetrahydrofuran and 1 mL of water, and then LiOH·H ₂ O (10 mg, 0.229 mmol) was added and allowed to react at room temperature for 1 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 6 (5 mg) was obtained by Prep-HPLC (Prep-HPLC conditions are referred to Example 2).

MS (ESI, m/z): 365.2 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.54 (s, 1H), 7.90 (s, 1H), 6.71-6.56 (m, 2H), 4.49 (s, 2H), 4.28 - 4.18 (m, 2H) ), 3.71-3.66 (m, 2H), 3.55 (t, J = 5.7 Hz, 2H), 3.32 (s, 3H), 2.99 (t, J = 5.5 Hz, 2H).

Example 7: 7-(3-Fluoro-4-methylphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (7)

First step: ethyl 7-(3-fluoro-4-methylphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (7a)

Compound 1b (50 mg, 0.242 mmol), 4-bromo-2-fluoro-1-methylbenzene (69 mg, 0.364 mmol), Pd(OAc) ₂ (4 mg, 0.017 mmol), BINAP (22 mg, 0.034 mmol) and Cs ₂ CO ₃ (198 mg, 0.606 mmol) was dissolved in 5 mL of toluene and heated to 90 ° C under N ₂ for overnight. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 393.2 [M+H] ⁺

Second step: 7-(3-Fluoro-4-methylphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (7)

Compound 7a (20 mg, 0.063 mmol) was dissolved in 5 mL of tetrahydrofuran and 1 mL of water, and then LiOH·H ₂ O (10 mg, 0.229 mmol) was added and allowed to react at room temperature for 1 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 7 (2 mg) was obtained by Prep-HPLC (Prep-HPLC conditions are referred to Example 2).

MS (ESI, m/z):287.2 [M+H] ⁺ .

¹ H NMR (CD ₃ OD, 400 MHz) δ 8.49 (s, 1H), 8.01 (s, 1H), 6.95-6.89 (m, 3H), 4.40 (s, 2H), 3.51 (t, J = 5.6 Hz) , 2H), 3.10 (t, J = 5.6 Hz, 2H), 2.24 (s, 3H).

Example 8: 7-(6-Methylpyridin-3-yl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (8)

First step: ethyl 7-(6-methylpyridin-3-yl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (8a)

Compound 1b (50 mg, 0.242 mmol), 5-bromo-2-methylpyridine (83 mg, 0.484 mmol), Pd(OAc) ₂ (4 mg, 0.018 mmol), BINAP (23 mg, 0.036 mmol) and Cs ₂ CO ₃ (236 mg, 0.726 mmol) was dissolved in 10 mL of toluene and heated to 90 ° C under N ₂ for overnight. After completion of the reaction, the mixture was filtered through Celite, and then filtered and evaporated.

MS (ESI, m/z): 298.2 [M+H] ⁺ .

Second step: 7-(6-methylpyridin-3-yl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (8)

Compound 8a (40mg, 0.134mmol) was dissolved in 2mL of tetrahydrofuran and 1mL of water was added _{LiOH · H 2 O (28mg,} 0.67mmol), the reaction at room temperature for 2h. After the reaction, the pH of the system was adjusted to about 3 with 1 N HCl. After the Prep-HPLC separation (Prep-HPLC conditions, refer to Example 2), 1 N HCl was added and stirred for 5 min, and lyophilized to obtain the hydrochloride salt of Compound 8 ( 10mg).

MS (ESI, m/z): 270.1 [M+H] ⁺ .

¹ H NMR (D ₂ O, 400 MHz) δ 8.53 (s, 1H), 8.15 (d, J = 2.4 Hz, 1H), 8.1 (m, 2H), 7.62 (d, J = 9.2 Hz, 1H), 4.69(s, 2H), 3.88 (t, J = 5.6 Hz, 2H), 3.20 (m, 2H), 2.58 (s, 3H).

Example 9: 7-(3,4-Difluoro-5-(2-hydroxyethoxy)phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (10)

First step: 7-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4,5-difluorophenyl)-5,6,7,8- Ethyl tetrahydro-2,7-naphthyridine-3-carboxylate (10a)

Compound 1b (73 mg, 0.354 mmol), (2-(5-bromo-2,3-difluorophenoxy)ethoxy)(tert-butyl)dimethylsilane (195 mg, 0.531 mmol), Pd ( OAc) ₂ (4.0 mg, 0.018 mmol), BINAP (22 mg, 0.035 mmol) and Cs ₂ CO ₃ (231 mg, 0.708 mmol) were dissolved in 5 mL of toluene and heated to 90 ° C under N ₂ for 4 h. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m / z) : 493.3 [M + H] +.

Second step: 7-(3,4-difluoro-5-(2-hydroxyethoxy)phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylic acid (10)

Compound 10a (123 mg, 0.250 mmol) was dissolved in 4 mL of tetrahydrofuran and 1 mL water, and then LiOH·H ₂ O (31 mg, 0.750 mmol) was added and allowed to react at room temperature for 1 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 10 (18 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

Instrument model: Agilent 1260, column: Waters XBridge Prep C ₁₈ OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 ° C; flow rate: 24.0 mL / min; detection wavelength: 214 nm; elution gradient: (0 min: 10% A, 90% B; 16.0 min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous formic acid.

MS (ESI, m/z): 351.1 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.54 (s, 1H), 7.90 (s, 1H), 6.71-6.57 (m, 2H), 4.95 (s, 1H), 4.49 (s, 2H), 4.12 (t, J = 4.9 Hz, 2H), 3.74 (s, 2H), 3.55 (t, J = 5.7 Hz, 2H), 2.99 (t, J = 5.5 Hz, 2H).

Example 10: 7-(3-Fluoro-5-methylphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (14)

First step: ethyl 7-(3-fluoro-5-methylphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylate (14a)

Compound 1b (50 mg, 242.43 μmol), 1-bromo-3-fluoro-5-methylbenzene (68.74 mg, 363.65 μmol), Pd(OAc) ₂ (3.81 mg, 16.97 μmol), BINAP (21.13 mg, 33.94) Μmol) and Cs ₂ CO ₃ (197.47 mg, 606.07 μmol) were dissolved in 5 mL of toluene and heated to 90 ° C for 5 h under N ₂ protection. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 315.3 [M+H] ⁺ .

Second step: 7-(3-Fluoro-5-methylphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (14)

Compound 14a (36 mg, 114.52 μmol) was dissolved in 3 mL of tetrahydrofuran and 1 mL of water, and then LiOH·H ₂ O (24.05 mg, 572.60 μmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 14 (25 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

Instrument model: Agilent 1260, column: Waters SunFire Prep C ₁₈ OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 ° C; flow rate: 20.0 mL / min; detection wavelength: 214 nm; elution gradient: (0 min: 10% A, 90% B; 16 min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous formic acid.

MS (ESI, m/z): 287.3 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.56 (s, 1H), 7.90 (s, 1H), 6.70 (s, 1H), 6.68-6.63 (m, 1H), 6.39 (d, J = 9.6 Hz, 1H), 4.52 (s, 2H), 3.58 (t, J = 6.0 Hz, 2H), 2.99 (t, J = 5.7 Hz, 2H), 2.27 (s, 3H).

Example 11: 7-(3-Fluoro-5-methoxyphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (15)

First step: ethyl 7-(3-fluoro-5-methoxyphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (15a)

Compound 1b (50 mg, 242.44 μmol), 1-bromo-3-fluoro-5-methoxybenzene (75 mg, 363.65 μmol), Pd(OAc) ₂ (3.81 mg, 16.97 μmol), BINAP (21.13 mg, 33.94) Molmol) and Cs ₂ CO ₃ (197.48 mg, 606.09 μmol) were dissolved in 5 mL of toluene and heated to 90 ° C for 5 h under N ₂ protection. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 331.3 [M+H] ⁺ .

Second step: 7-(3-Fluoro-5-methoxyphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (15)

Compound 15a (35 mg, 105.95 μmol) was dissolved in 3 mL of tetrahydrofuran and 1 mL of water, and then LiOH·H ₂ O (22.25 mg, 529.74 μmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 15 (24 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

Instrument model: Agilent 1260, column: Waters SunFire Prep C ₁₈ OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 ° C; flow rate: 20.0 mL / min; detection wavelength: 214 nm; elution gradient: (0 min: 30% A, 70% B; 5.0 min: 70% A, 30% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous formic acid.

MS (ESI, m/z): 303.3 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.56 (s, 1H), 7.89 (s, 1H), 6.48 (dt, J = 12.6, 2.0 Hz, 1H), 6.38 (s, 1H), 6.21. Dt, J = 10.8, 2.0 Hz, 1H), 4.52 (s, 2H), 3.74 (s, 3H), 3.58 (t, J = 5.8 Hz, 2H), 2.98 (t, J = 5.8 Hz, 2H).

Example 12: 7-(4-Fluoro-3-methoxyphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (16)

First step: ethyl 7-(4-fluoro-3-methoxyphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (16a)

Compound 1b (50.0 mg, 0.242 mmol), 4-bromo-1-fluoro-2-methoxybenzene (89.0 mg, 0.434 mmol), Pd(OAc) ₂ (1.6 mg, 0.007 mmol), BINAP (9 mg, 0.015 mmol) and Cs ₂ CO ₃ (95 mg, 0.292 mmol) were dissolved in 5 mL of toluene and heated to 90 ° C under N ₂ for overnight. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness and then purified (yield system B) to afford 16a (40 mg).

MS (ESI, m/z): 331.1 [M+H] ⁺ .

Second step: 7-(4-Fluoro-3-methoxyphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (16)

Compound 16a (40 mg, 0.121 mmol) was dissolved in 5 mL of tetrahydrofuran and 1 mL water, and then LiOH·H ₂ O (12.8 mg, 0.305 mmol) was added and allowed to react at room temperature for 1 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 16 (2 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

Instrument model: Agilent 1260, column: Waters SunFire Prep C ₁₈ OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 ° C; flow rate: 20.0 mL / min; detection wavelength: 214 nm; elution gradient: (0 min: 40% A, 60% B; 16.0 min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous trifluoroacetic acid.

MS (ESI, m / z) : 303.1 [M + H] +.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.56 (s, 1H), 7.91 (s, 1H), 7.79 (dd, J = 12.0, 8.0 Hz, 1H), 6.83 (s, 1H), 6.54 ( d, J = 8.0 Hz, 1H), 4.46 (s, 2H), 3.85 (s, 3H), 3.53 (t, J = 4.0 Hz, 2H), 3.02 (t, J = 4.0 Hz, 2H).

Example 13: 7-(3-Cyano-5-fluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (17)

First step: ethyl 7-(3-cyano-5-fluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (17a)

Compound 1b (50 mg, 0.24 mmol), 3-bromo-5-fluorobenzonitrile (63.04 mg, 0.32 mmol), Pd(OAc) ₂ (5.43 mg, 24.24 μmol), BINAP (30.19 mg, 48.49 μmol) and Cs ₂ CO ₃ (197.58 mg, 0.61 mmol) was dissolved in 5 mL of toluene and heated to 90 ° C under N ₂ for 5 h. After completion of the reaction, the mixture was filtered through Celite, and then filtered and evaporated.

MS (ESI, m/z): 226.1 [M+H] ⁺ .

Second step: 7-(3-cyano-5-fluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (17)

Compound 17a (40 mg, 0.12 mmol) was dissolved in 1 mL of methanol and 2 mL of water, and then LiOH·H ₂ O (25.82 mg, 0.61 mmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl and concentrated to dryness. Compound 17 (6 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

Instrument model: Agilent 1260, column: Waters SunFire Prep C ₁₈ OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 ° C; flow rate: 20.0 mL / min; detection wavelength: 214 nm; elution gradient: (0 min: 10% A, 90% B; 16.0 min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous ammonium bicarbonate solution.

MS (ESI, m/z): 298.1 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.55 (s, 1H), 7.91 (s, 1H), 7.33 (s, 1H), 7.24 - 7.21 (m, 1H), 7.08 - 7.06 (m, 1H) ), 4.63s, 2H), 3.69–3.66 (m, 2H), 3.01–2.99 (m, 2H).

Example 14: 7-(4-Cyano-3-fluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (35)

First step: ethyl 7-(4-cyano-3-fluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (35a)

Compound 1b (50 mg, 242.43 μmol), 4-bromo-2-fluoro-benzonitrile (72.73 mg, 363.65 μmol), Pd(OAc) ₂ (3.81 mg, 16.97 μmol), BINAP (21.13 mg, 33.94 μmol) and Cs ₂ CO ₃ (197.47 mg, 606.07 μmol) was dissolved in 5 mL of toluene and heated to 90 ° C for 5 h under N ₂ protection. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 326.3 [M+H] ⁺ .

Second step: 7-(4-cyano-3-fluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (35)

Compound 35a (35 mg, 107.58 μmol) was dissolved in 3 mL of tetrahydrofuran and 1 mL of water, and then LiOH·H ₂ O (22.59 mg, 537.90 μmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and the compound 35 (22 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

MS (ESI, m/z): 298.2 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.56 (s, 1H), 7.94 (s, 1H), 7.66 (t, J = 8.8Hz, 1H), 7.05 (dd, J = 14.0,2.4Hz, 1H), 6.95 (dd, J = 8.8, 2.4 Hz, 1H), 4.71 (s, 2H), 3.73 (t, J = 6.0 Hz, 2H), 3.02 (t, J = 6.0 Hz, 2H).

Example 15: 7-(4-Chloro-3-fluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (36)

First step: ethyl 7-(4-chloro-3-fluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylate (36a)

Compound 1b (40 mg, 0.194 mmol), 4-bromo-1-chloro-2-fluorobenzene (61 mg, 0.291 mmol), Pd(OAc) ₂ (2.2 mg, 0.010 mmol), BINAP (12 mg, 0.019 mmol) and Cs ₂ CO ₃ (126 mg, 0.388 mmol) was dissolved in 5 mL of toluene and heated to 90 ° C under N ₂ for 4 h. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 335.1 [M+H] ⁺ .

Second step: 7-(4-chloro-3-fluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylic acid (36)

Compound 36a (65mg, 0.194mmol) was dissolved in 1mL water and 4mL of tetrahydrofuran, was added _{LiOH · H 2 O (24mg,} 0.582mmol), the reaction at room temperature for 1h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 36 (15 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

Instrument model: Agilent 1260, column: Waters XBridge Prep C ₁₈ OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 ° C; flow rate: 24.0 mL / min; detection wavelength: 214 nm; elution gradient: (0 min: 0% A, 100% B; 25.0 min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous trifluoroacetic acid.

MS (ESI, m/z): 307.1 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.55 (s, 1H), 7.90 (s, 1H), 7.37 (t, J = 8.9Hz, 1H), 7.08 (dd, J = 13.2,2.8Hz, 1H), 6.89 (dd, J = 9.0, 2.5 Hz, 1H), 4.55 (s, 2H), 3.61 (t, J = 5.8 Hz, 2H), 2.99 (t, J = 5.7 Hz, 2H).

Example 16: 7-(3,5-Difluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (37)

First step: ethyl 7-(3,5-difluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (37a)

Compound 1b (40 mg, 0.194 mmol), 1-bromo-3,5-difluorobenzene (56 mg, 0.291 mmol), Pd(OAc) ₂ (2.2 mg, 0.010 mmol), BINAP (12 mg, 0.019 mmol) and Cs ₂ CO ₃ (126 mg, 0.388 mmol) was dissolved in 5 mL of toluene and heated to 90 ° C under N ₂ for 4 h. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 319.2 [M+H] ⁺ .

Second step: 7-(3,5-difluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (37)

Compound 37a (62mg, 0.194mmol) was dissolved in 1mL water and 4mL of tetrahydrofuran, was added _{LiOH · H 2 O (24mg,} 0.582mmol), the reaction at room temperature for 1h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 37 (8 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

Instrument model: Agilent 1260, column: Waters XBridge Prep C ₁₈ OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 ° C; flow rate: 24.0 mL / min; detection wavelength: 214 nm; elution gradient: (0 min: 10% A, 90% B; 25.0 min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous trifluoroacetic acid.

MS (ESI, m/z): 29.21. [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.55 (s, 1H), 7.91 (s, 1H), 6.73 (d, J = 9.4Hz, 2H), 6.48 (t, J = 9.2Hz, 1H) , 4.57 (s, 2H), 3.62 (t, J = 5.8 Hz, 2H), 2.99 (t, J = 5.7 Hz, 2H).

Example 17: 7-(3-Fluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (38)

First step: ethyl 7-(3-fluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (38a)

Compound 1b (50 mg, 0.24 mmol), 1-bromo-3-fluorobenzene (55.68 mg, 0.32 mmol), Pd(OAc) ₂ (5.43 mg, 24.24 μmol), BINAP (30.19 mg, 48.49 μmol) and Cs ₂ CO ₃ (197.58 mg, 0.61 mmol) was dissolved in 5 mL of toluene and heated to 90 ° C under N ₂ for 4 h. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 301.1 [M+H] ⁺ .

Second step: 7-(3-Fluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (38)

Compound 38a (40 mg, 0.13 mmol) was dissolved in 1 mL of methanol and 2 mL of water, and then LiOH·H ₂ O (27.98 mg, 0.67 mmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 38 (6 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

MS (ESI, m/z): 298.1 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.63-8.10 (m, 1H), 7.86-8.45 (m, 1H), 7.22 - 7.23 (m, 1H), 6.89 - 6.87 (m, 2H), 6. –6.51 (m, 1H) 4.51–4.45 (m, 2H), 3.58–3.57 (m, 2H), 2.99–2.98 (m, 2H).

Example 18: 7-(5-Chloro-2-cyanophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (39)

First step: ethyl 7-(5-chloro-2-cyanophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (39a)

Compound 1b (50.0 mg, 0.242 mmol), 2-bromo-4-chlorobenzonitrile (105.0 mg, 0.484 mmol), Pd(OAc) ₂ (1.6 mg, 0.007 mmol), BINAP (9 mg, 0.015 mmol) and Cs ₂ CO ₃ (95 mg, 0.292 mmol) was dissolved in 5 mL of toluene and heated to 90 ° C under N ₂ for overnight. After completion of the reaction, the mixture was filtered through Celite, and then filtered and evaporated.

MS (ESI, m/z): 3421. [M+H] ⁺ .

Second step: 7-(5-chloro-2-cyanophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (39)

Compound 39a (70 mg, 0.204 mmol) was dissolved in 5 mL of tetrahydrofuran and 1 mL of water, and then LiOH·H ₂ O (12.8 mg, 0.305 mmol) was added and allowed to react at room temperature for 1 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 39 (9 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

MS (ESI, m/z): 314.1 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.53 (s, 1H), 7.95 (s, 1H), 7.79 (d, J = 8.0Hz, 1H), 7.33 (s, 1H), 7.18 (d, J = 8.0 Hz, 1H), 4.54 (s, 2H), 3.62 (t, J = 4.0 Hz, 2H), 3.10 (t, J = 4.0 Hz, 2H).

Example 19: 7-(4-Chloro-3-methoxyphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (40)

First step: ethyl 7-(4-chloro-3-methoxyphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (40a)

Compound 1b (50 mg, 242.43 μmol), 4-bromo-1-chloro-2-methoxybenzene (80.54 mg, 363.65 μmol), Pd(OAc) ₂ (3.81 mg, 16.97 μmol), BINAP (21.13 mg, 33.94 μmol) and Cs ₂ CO ₃ (197.47 mg, 606.07 μmol) were dissolved in 5 mL of toluene and heated to 90 ° C for 5 h under N ₂ protection. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 347.8 [M+H] ⁺ .

Second step: 7-(4-chloro-3-methoxyphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (40)

Compound 40a (26 mg, 74.97 μmol) was dissolved in 3 mL of tetrahydrofuran and 1 mL of water, then LiOH·H ₂ O (15.74 mg, 374.85 μmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 40 (8 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

MS (ESI, m/z): 319.7 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.58 (s, 1H), 7.92 (s, 1H), 7.23 (d, J = 8.8Hz, 1H), 6.78 (s, 1H), 6.62 (d, J = 8.8 Hz, 1H), 4.54 (s, 2H), 3.88 (s, 3H), 3.63 - 3.58 (m, 2H), 3.03 (d, J = 5.3 Hz, 2H).

Example 20: 7-(3-Chloro-4-fluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (41)

First step: ethyl 7-(3-chloro-4-fluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (41a)

Compound 1b (50 mg, 242.43 μmol), 4-bromo-2-chloro-1-fluorobenzene (76.16 mg, 363.65 μmol), Pd(OAc) ₂ (3.81 mg, 16.97 μmol), BINAP (21.13 mg, 33.94 μmol) And Cs ₂ CO ₃ (197.47 mg, 606.07 μmol) was dissolved in 5 mL of toluene, and heated to 90 ° C for 5 h under N ₂ protection. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 335.7 [M+H] ⁺ .

Second step: 7-(3-chloro-4-fluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (41)

Compound 41a (36 mg, 107.54 μmol) was dissolved in 3 mL of tetrahydrofuran and 1 mL of water, and then LiOH·H ₂ O (22.58 mg, 537.68 μmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 41 (23 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions: instrument model: Agilent 1260, column: Waters SunFire Prep C ₁₈ OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 ° C; flow rate: 20.0 mL / min; detection wavelength: 214 nm; elution Gradient: (0 min: 10% A, 90% B; 16 min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous formic acid.

MS (ESI, m/z): 307.7 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.55 (s, 1H), 7.89 (s, 1H), 7.29 (t, J = 9.2 Hz, 1H), 7.21. (dd, J = 6.4, 3.0 Hz, 1H), 7.09–7.01 (m, 1H), 4.49 (s, 2H), 3.55 (t, J = 5.6 Hz, 2H), 2.99 (t, J = 5.6 Hz, 2H).

Example 21: 7-(3-Chloro-5-fluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (42)

First step: ethyl 7-(3-chloro-5-fluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (42a)

Compound 1b (50 mg, 242.43 μmol), 1-bromo-3-chloro-5-fluorobenzene (76.16 mg, 363.65 μmol), Pd(OAc) ₂ (3.81 mg, 16.97 μmol), BINAP (21.13 mg, 33.94 μmol) And Cs ₂ CO ₃ (197.47 mg, 606.07 μmol) was dissolved in 5 mL of toluene, and heated to 90 ° C for 5 h under N ₂ protection. After completion of the reaction, the mixture was filtered through celite, and then filtered and evaporated.

MS (ESI, m/z): 335.7 [M+H] ⁺ .

Second step: 7-(3-chloro-5-fluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (42)

Compound 42a (46 mg, 137.41 μmol) was dissolved in 3 mL of tetrahydrofuran and 1 mL of water, and then LiOH·H ₂ O (28.86 mg, 687.03 μmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and the compound 42 (32 mg) was obtained by Prep-HPLC.

MS (ESI, m/z): 307.7 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.56 (s, 1H), 7.90 (s, 1H), 6.92 (s, 1H), 6.87 (dd, J = 12.8, 2.0 Hz, 1H), 6.69 ( Dd, J = 8.4, 1.6 Hz, 1H), 4.58 (s, 2H), 3.62 (t, J = 5.8 Hz, 2H), 2.99 (t, J = 5.7 Hz, 2H).

Example 22: 7-(4-Chloro-3,5-difluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (43)

First step: 7-(4-Chloro-3,5-difluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylic acid ethyl ester (43a)

Compound 1b (50 mg, 0.24 mmol), 5-bromo-2-chloro-1,3-difluorobenzene (71.68 mg, 0.32 mmol), Pd(OAc) ₂ (5.43 mg, 24.24 μmol), BINAP (30.19 mg) 48.49 μmol) and Cs ₂ CO ₃ (197.58 mg, 0.61 mmol) were dissolved in 5 mL of toluene and heated to 90 ° C for 6 h under N ₂ protection. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 3521. [M+H] ⁺ .

Second step: 7-(4-chloro-3,5-difluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (43)

Compound 43a (40mg, 0.11mmol) was dissolved in 1mL methanol and 2mL of water was added _{LiOH · H 2 O (23.81mg,} 0.57mmol), the reaction at room temperature for 2h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and a yellow solid was precipitated, filtered, and dried to give compound 43 (15 mg).

MS (ESI, m/z): 325.1 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.54 (s, 1H), 7.91 (s, 1H), 6.99 - 6.96 (m, 2H), 4.59 (s, 2H), 3.65 - 3.62 (m, 2H) ), 2.97–2.98 (m, 2H).

Example 23: 7-(3-(Trifluoromethoxy)phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (44)

First step: ethyl 7-(3-(trifluoromethoxy)phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (44a)

Compound 1b (50 mg, 0.242 mmol), 1-bromo-3-(trifluoromethoxy)benzene (88 mg, 0.364 mmol), Pd(OAc) ₂ (2.7 mg, 0.012 mmol), BINAP (15 mg, 0.024 mmol) And Cs ₂ CO ₃ (158 mg, 0.485 mmol) was dissolved in 5 mL of toluene and heated to 90 ° C for 4 h under N ₂ protection. After completion of the reaction, the mixture was filtered through Celite, and then filtered and evaporated.

MS (ESI, m/z): 367.2 [M+H] ⁺ .

Second step: 7-(3-(Trifluoromethoxy)phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (44)

Compound 44a (73mg, 0.194mmol) was dissolved in 1mL water and 4mL of tetrahydrofuran, was added _{LiOH · H 2 O (25mg,} 0.600mmol), the reaction at room temperature for 1h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 44 (25 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

Instrument model: Agilent 1260, column: Waters XBridge Prep C ₁₈ OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 ° C; flow rate: 20.0 mL / min; detection wavelength: 214 nm; elution gradient: (0 min: 30% A, 70% B; 25.0 min: 45% A, 55% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous formic acid.

MS (ESI, m/z): 339.2 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.58 (s, 1H), 7.90 (s, 1H), 7.34 (t, J = 8.2Hz, 1H), 7.06 (d, J = 8.4Hz, 1H) , 6.97 (s, 1H), 6.71 (d, J = 7.7 Hz, 1H), 4.56 (s, 2H), 3.62 (t, J = 5.6 Hz, 2H), 3.01 (t, J = 5.2 Hz, 2H) .

Example 24: 7-(2-Fluoro-3-methylphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (45)

First step: ethyl 7-(2-fluoro-3-methylphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (45a)

Compound 1b (54 mg, 0.262 mmol), 1-bromo-2-fluoro-3-methylbenzene (74 mg, 0.393 mmol), Pd(OAc) ₂ (2.9 mg, 0.013 mmol), BINAP (16 mg, 0.026 mmol) And Cs ₂ CO ₃ (171 mg, 0.524 mmol) was dissolved in 5 mL of toluene and heated to 90 ° C for 4 h under N ₂ protection. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 315.2 [M+H] ⁺ .

Second step: 7-(2-Fluoro-3-methylphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (45)

Compound 45a (63 mg, 0.200 mmol) was dissolved in 4 mL of tetrahydrofuran and 1 mL water, and then LiOH·H ₂ O (25 mg, 0.600 mmol) was added and allowed to react at room temperature for 1 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and the compound 45 (17 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

Instrument model: Agilent 1260, column: Waters XBridge Prep C ₁₈ OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 ° C; flow rate: 20.0 mL / min; detection wavelength: 214 nm; elution gradient: (0 min: 20% A, 80% B; 20.0 min: 45% A, 55% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous formic acid.

MS (ESI, m/z):287.2 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.52 (s, 1H), 7.89 (s, 1H), 7.06 - 6.86 (m, 3H), 4.32 (s, 2H), 3.50 - 3.25 (m, 2H) ), 3.01 (t, J = 5.4 Hz, 2H), 2.23 (d, J = 1.6 Hz, 3H).

Example 25: 7-(3-Fluoro-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (46)

First step: ethyl 7-(3-fluoro-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (46a)

Compound 1b (50 mg, 242.43 μmol), 4-bromo-2-fluoro-1-(trifluoromethyl)benzene (88.37 mg, 363.65 μmol), Pd(OAc) ₂ (3.81 mg, 16.97 μmol), BINAP ( 21.13 mg, 33.94 μmol) and Cs ₂ CO ₃ (197.47 mg, 606.07 μmol) were dissolved in 5 mL of toluene and heated to 90 ° C for 5 h under N ₂ protection. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 369.3 [M+H] ⁺ .

Second step: 7-(3-Fluoro-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (46)

Compound 46a (25 mg, 137.41 μmol) was dissolved in 3 mL of tetrahydrofuran and 1 mL of water, and then LiOH·H ₂ O (14.25 mg, 339.37 μmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 46 (7 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

Instrument model: Agilent 1260, column: Waters SunFire Prep C ₁₈ OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 ° C; flow rate: 20.0 mL / min; detection wavelength: 214 nm; elution gradient: (0 min: 30% A, 70% B; 16 min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous formic acid.

MS (ESI, m/z): 341.2 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.59 (s, 1H), 7.93 (s, 1H), 7.54 (t, J = 8.8Hz, 1H), 7.06 (d, J = 15.2Hz, 1H) , 6.95 (d, J = 8.6 Hz, 1H), 4.68 (s, 2H), 3.71 (t, J = 5.6 Hz, 2H), 3.03 (t, J = 5.2 Hz, 2H).

Example 26: 7-(3-Bromo-5-fluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (47)

First step: ethyl 7-(3-bromo-5-fluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (47a)

Compound 1b (52 mg, 0.252 mmol), 1,3-dibromo-5-fluorobenzene (96 mg, 0.378 mmol), Pd(OAc) ₂ (2.8 mg, 0.013 mmol), BINAP (16 mg, 0.025 mmol) and Cs ₂ CO ₃ (164 mg, 0.504 mmol) was dissolved in 5 mL of toluene and heated to 90 ° C under N ₂ for 4 h. After completion of the reaction, the mixture was filtered through Celite, and then filtered and evaporated.

MS (ESI, m/z): 382.2 [M+H] ⁺ .

Second step: 7-(3-Bromo-5-fluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (47)

Compound 47a (57mg, 0.150mmol) was dissolved in 1mL water and 4mL of tetrahydrofuran, was added _{LiOH · H 2 O (19mg,} 0.450mmol), the reaction at room temperature for 1h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl. Compound 47 (45 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

Instrument model: Agilent 1260, column: Waters XBridge Prep C ₁₈ OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 ° C; flow rate: 24.0 mL / min; detection wavelength: 214 nm; elution gradient: (0 min: 30% A, 70% B; 20.0 min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous formic acid.

MS (ESI, m/z): 352.0 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.56 (s, 1H), 7.91 (s, 1H), 7.04 (s, 1H), 6.90 (d, J = 12.9Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 4.57 (s, 2H), 3.62 (t, J = 5.8 Hz, 2H), 2.99 (t, J = 5.6 Hz, 2H).

Example 27: 7-(4-Chlorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (48)

First step: ethyl 7-(4-chlorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (48a)

Compound 1b (50 mg, 242.43 μmol), 1-bromo-4-chlorobenzene (69.62 mg, 363.65 μmol), Pd(OAc) ₂ (3.81 mg, 16.97 μmol), BINAP (21.13 mg, 33.94 μmol) and Cs ₂ CO ₃ (197.47 mg, 606.07 μmol) was dissolved in 5 mL of toluene and heated to 90 ° C for 5 h under N ₂ protection. After completion of the reaction, the mixture was filtered through Celite, and then filtered and evaporated.

MS (ESI, m/z): 317.7 [M+H] ⁺ .

Second step: 7-(4-chlorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (48)

Compound 48a (39 mg, 123.11 μmol) was dissolved in 3 mL of tetrahydrofuran and 1 mL of water, and then LiOH·H ₂ O (25.85 mg, 615.57 μmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 48 (23 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

Instrument model: Agilent 1260, column: Waters SunFire Prep C ₁₈ OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 ° C; flow rate: 20.0 mL / min; detection wavelength: 214 nm; elution gradient: (0 min: 30% A, 70% B; 5 min: 30% A, 70% B; 16 min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous formic acid.

MS (ESI, m/z): 289.7 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.56 (s, 1H), 7.89 (s, 1H), 7.27 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H) , 4.50 (s, 2H), 3.57 (t, J = 6.0 Hz, 2H), 2.99 (t, J = 5.6 Hz, 2H).

Example 28: 7-(4-Fluoro-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (49)

First step: ethyl 7-(4-fluoro-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (49a)

Compound 1b (50 mg, 242.43 μmol), 1-bromo-4-fluoro-2-(trifluoromethyl)benzene (88.37 mg, 363.65 μmol), Pd(OAc) ₂ (3.81 mg, 16.97 μmol), BINAP ( 21.13 mg, 33.94 μmol) and Cs ₂ CO ₃ (197.47 mg, 606.07 μmol) were dissolved in 5 mL of toluene and heated to 90 ° C for 5 h under N ₂ protection. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 369.3 [M+H] ⁺ .

Second step: 7-(4-fluoro-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (49)

Compound 49a (55 mg, 149.32 μmol) was dissolved in 3 mL of tetrahydrofuran and 1 mL of water, and then LiOH.H ₂ O (31.36 mg, 746.62 μmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 49 (36 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

MS (ESI, m/z): 341.2 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.57 (s, 1H), 7.91 (s, 1H), 7.43-7.36 (m, 2H), 7.29 (d, J = 6.4Hz, 1H), 4.54 ( s, 2H), 3.60 (t, J = 5.8 Hz, 2H), 3.02 (t, J = 5.6 Hz, 2H).

Example 29: 7-(3-Chloro-4,5-difluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (50)

First step: ethyl 7-(3-chloro-4,5-difluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (50a)

Compound 1b (42 mg, 0.202 mmol), 5-bromo-1-chloro-2,3-difluorobenzene (55 mg, 0.242 mmol), Pd(OAc) ₂ (2.3 mg, 0.010 mmol), BINAP (13 mg, 0.020) Methyl) and Cs ₂ CO ₃ (131 mg, 0.403 mmol) were dissolved in 5 mL of toluene and heated to 90 ° C for 4 h under N ₂ protection. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 353.2 [M+H] ⁺ .

Second step: 7-(3-chloro-4,5-difluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxy (50)

Compound 50a (25mg, 0.071mmol) was dissolved in 1mL water and 4mL of tetrahydrofuran, was added _{LiOH · H 2 O (9mg,} 0.213mmol), the reaction at room temperature for 1h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 50 (10 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

MS (ESI, m/z): 324.9 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.54 (s, 1H), 7.90 (s, 1H), 7.15 (ddd, J = 14.0, 6.3, 3.0 Hz, 1H), 7.03 (dd, J = 5.2 , 2.2 Hz, 1H), 4.53 (s, 2H), 3.59 (t, J = 5.9 Hz, 2H), 2.99 (t, J = 5.7 Hz, 2H).

Example 30: 7-(3,4,5-Trifluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (51)

First step: ethyl 7-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylate (51a)

Compound 1b (50 mg, 0.24 mmol), 5-bromo-1,2,3-trifluorobenzene (76.72 mg, 0.36 mmol), Pd(OAc) ₂ (5.43 mg, 24.24 μmol), BINAP (30.19 mg, 48.49) Molmol) and Cs ₂ CO ₃ (197.58 mg, 0.61 mmol) were dissolved in 5 mL of toluene and heated to 90 ° C for 5 h under N ₂ protection. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 337.1 [M+H] ⁺ .

Second step: 7-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (51)

Compound 51a (20 mg, 59.47 μmol) was dissolved in 1 mL of methanol and 2 mL of water, and then LiOH·H ₂ O (12.6 mg, 0.30 mmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and a yellow solid precipitated, which was filtered and dried to give compound 51 (10 mg).

MS (ESI, m/z): 308.2 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.53 (s, 1H), 7.90 (s, 1H), 6.98 - 6.94 (m, 2H), 4.53 (s, 2H), 3.59 - 3.57 (m, 2H) ), 3.00–2.97 (m, 2H).

Example 31: 7-(3,4-Difluoro-5-isopropoxyphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (52)

First step: ethyl 7-(3,4-difluoro-5-isopropoxyphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylate (52a )

Compound 1b (250 mg, 1.21 mmol), 5-bromo-1,2-difluoro-3-isopropoxybenzene (456.51 mg, 1.82 mmol), Pd(OAc) ₂ (19.05 mg, 84.85 μmol), BINAP (105.67 mg, 169.70 μmol) and Cs ₂ CO ₃ (987.38 mg, 3.03 mmol) were dissolved in 30 mL of toluene and heated to 90 ° C for 5 h under N ₂ protection. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 377.4 [M+H] ⁺

Second step: 7-(3,4-difluoro-5-isopropoxyphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (52)

Compound 52a (320 mg, 850.17 μmol) was dissolved in 6 mL of tetrahydrofuran and 2 mL of water, and then LiOH·H ₂ O (357.07 mg, 78.50 mmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 52 (55 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

Instrument model: Agilent 1260, column: Waters SunFire Prep C ₁₈ OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 ° C; flow rate: 20.0 mL / min; detection wavelength: 214 nm; elution gradient: (0 min: 30% A, 70% B; 16 min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous formic acid. Compound retention time R _t = 6.2 min.

MS (ESI, m/z): 349.3 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.54 (s, 1H), 7.90 (s, 1H), 6.69 - 6.59 (m, 2H), 4.77 - 4.70 (m, 1H), 4.48 (s, 2H) ), 3.54 (t, J = 5.8 Hz, 2H), 2.99 (t, J = 6.0 Hz, 2H), 1.29 (d, J = 6.0 Hz, 6H).

Example 32: 7-(3,4-Difluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (53)

First step: ethyl 7-(3,4-difluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (53a)

Compound 1b (50 mg, 242.43 μmol), 4-bromo-1,2-difluorobenzene (94 mg, 484.87 μmol), Pd ₂ (dba) ₃ (22.20 mg, 24.24 μmol), Ru-phos (22.63 mg, 48.49) Molmol) and Cs ₂ CO ₃ (197.48 mg, 606.09 μmol) were dissolved in 5 mL of toluene and heated to 90 ° C for 5 h under N ₂ protection. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 319.1 [M+H] ⁺ .

Second step: 7-(3,4-difluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (53)

Compound 53a (27 mg, 84.82 μmol) was dissolved in 5 mL of THF and 2 mL of water, and then LiOH·H ₂ O (35.62 mg, 848.2 μmol) was added and allowed to react at room temperature for 1 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 53 (7 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

Instrument model: Agilent 1260, column: Waters XBridge Prep C ₁₈ OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 ° C; flow rate: 20.0 mL / min; detection wavelength: 214 nm; elution gradient: (0 min: 10% A, 90% B; 16.0 min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous ammonium bicarbonate solution.

MS (ESI, m/z): 29.21. [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.45 (s, 1H), 7.90 (s, 1H), 7.13 (dd, J = 19.5, 9.2 Hz, 1H), 6.97 (m, 1H), 6.85 - 6.78 (m, 1H), 4.42 (s, 2H), 3.55 (t, J = 5.8 Hz, 2H), 3.06 (t, J = 5.7 Hz, 2H).

Example 33: 7-(3,4-Dichloro-5-fluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (54)

First step: ethyl 7-(3,4-dichloro-5-fluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (54a)

Compound 1b (0.1 g, 0.48 mmol), 5-bromo-1,2-dichloro-3-fluorobenzene (0.18 g, 0.73 mmol), Pd(OAc) ₂ (10.86 mg, 48.49 μmol), BINAP (60.38) Mg, 96.97 μmol) and Cs ₂ CO ₃ (0.39 mg, 1.21 mmol) were dissolved in 5 mL of toluene and heated to 90 ° C for 4 h under N ₂ protection. After completion of the reaction, the mixture was filtered through Celite, and then filtered and evaporated.

MS (ESI, m/z): 369.1 [M+H] ⁺ .

Second step: 7-(3,4-Dichloro-5-fluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (54)

Compound 54a (40mg, 0.11mmol) was dissolved in 1mL methanol and 2mL of water was added _{LiOH · H 2 O (22.76mg,} 0.55mmol), the reaction at room temperature for 2h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and a yellow solid precipitated, which was filtered and dried to give compound 54 (30 mg).

MS (ESI, m/z): 340.1 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.56 (s, 1H), 7.90 (s, 1H), 6.98 - 6.94 (m, 2H), 4.53 (s, 2H), 3.59 - 3.57 (m, 2H) ), 3.00–2.97 (m, 2H).

Example 34: 7-(3,5-Difluoro-4-methylphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (55)

First step: ethyl 7-(3,5-difluoro-4-methylphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (55a)

Compound 1b (0.1 g, 0.48 mmol), 5-bromo-1,3-difluoro-2-methylbenzene (150.56 mg, 0.73 mmol), Pd(OAc) ₂ (10.86 mg, 48.49 μmol), BINAP ( 60.38 mg, 96.97 μmol) and Cs ₂ CO ₃ (0.39 mg, 1.21 mmol) were dissolved in 5 mL of toluene and heated to 90 ° C for 4 h under N ₂ protection. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 333.1 [M+H] ⁺ .

Second step: 7-(3,5-Difluoro-4-methylphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (55)

Compound 55a (30 mg, 90.27 μmol) was dissolved in 1 mL of methanol and 2 mL of water, and then LiOH·H ₂ O (18.9 mg, 0.45 mmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and a yellow solid precipitated, which was filtered and dried to yield compound 55 (18 mg).

MS (ESI, m/z): 305.1 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.54 (s, 1H), 7.89 (s, 1H), 6.77 - 6.70 (m, 2H), 4.52 (s, 2H), 3.59 - 3.56 (m, 2H) ), 2.97–2.96 (m, 2H), 2.02 (s, 3H).

Example 35: 7-(3-(Difluoromethoxy)-4-5-difluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid ( 56)

First step: 7-(3-(Difluoromethoxy)-4-5-difluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid B Ester (56a)

Compound 1b (60 mg, 0.29 mmol), 5-bromo-1-(difluoromethoxy)-2,3-difluorobenzene (90.42 mg, 0.35 mmol), Pd(OAc) ₂ (6.52 mg, 29.09 μmol) BINAP (36.23 mg, 58.18 μmol) and Cs ₂ CO ₃ (235.65 mg, 0.73 mmol) were dissolved in 5 mL of toluene and heated to 90 ° C for 4 h under N ₂ protection. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 385.1 [M+H] ⁺ .

Second step: 7-(3-(Difluoromethoxy)-4-5-difluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid ( 56)

Compound 56a (10 mg, 26.02 μmol) was dissolved in 1 mL of methanol and 2 mL of water, and then LiOH·H ₂ O (5.5 mg, 0.13 mmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and a yellow solid precipitated, which was filtered and dried to give compound 56 (4mg).

MS (ESI, m/z): 357.1 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.54 (s, 1H), 7.90 (s, 1H), 7.31 - 7.04 (m, 1H), 7.07 - 7.02 (m, 1H), 6.82 - 6.83 (m) , 1H), 4.52 (s, 2H), 3.59–3.56 (m, 2H), 3.01–2.98 (m, 2H).

Example 36: 7-(3-Ethoxy-4,5-difluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (57)

First step: ethyl 7-(3-ethoxy-4,5-difluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (57a)

Compound 1b (60 mg, 290.92 μmol), 5-bromo-1-ethoxy-2,3-difluorobenzene (124.13 mg, 523.66 μmol), Pd(OAc) ₂ (13.03 mg, 58.18 μmol), BINAP ( 36.23 mg, 58.18 μmol) and Cs ₂ CO ₃ (236.97 mg, 727.31 μmol) were dissolved in 5 mL of toluene and heated to 90 ° C for 4 h under N ₂ protection. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 363.1 [M+H] ⁺ .

Second step: 7-(3-ethoxy-4,5-difluorophenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (57)

Compound 57a (45 mg, 124.18 μmol) was dissolved in 5 mL of THF and 2 mL of water, and then LiOH·H ₂ O (52.16 mg, 1214.8 μmol) was added and allowed to react at room temperature for 1 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 57 (15 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

MS (ESI, m/z): 335.1 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.38 (s, 1H), 7.74 (s, 1H), 6.64-6.55 (m, 2H), 4.42 (s, 2H), 4.16 (m, 2H), 3.51 (d, J = 5.8 Hz, 2H), 2.92 (s, 2H), 1.35 (t, J = 7.0 Hz, 3H).

Example 37: 7-(3,4-Difluoro-5-(fluoromethoxy)phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (58 )

First step: ethyl 7-(3,4-difluoro-5-(fluoromethoxy)phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylate (58a)

Compound 1b (89 mg, 0.432 mmol), 5-bromo-1,2-difluoro-3-(fluoromethoxy)benzene (125 mg, 0.519 mmol), Pd(OAc) ₂ (4.9 mg, 0.022 mmol), BINAP (27 mg, 0.043 mmol) and Cs ₂ CO ₃ (282 mg, 0.864 mmol) were dissolved in 5 mL of toluene and heated to 90 ° C under N ₂ for 4 h. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 367.1 [M+H] ⁺ .

Second step: 7-(3,4-difluoro-5-(fluoromethoxy)phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (58 )

Compound 58a (80mg, 0.218mmol) was dissolved in 1mL water and 4mL of tetrahydrofuran, was added _{LiOH · H 2 O (27mg,} 0.655mmol), the reaction at room temperature for 1h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 58 (20 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

Instrument model: Agilent 1260, column: Waters XBridge Prep C ₁₈ OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 ° C; flow rate: 24.0 mL / min; detection wavelength: 214 nm; elution gradient: (0 min: 30% A, 70% B; 16.0 min: 50% A, 50% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous formic acid.

MS (ESI, m/z): 339.0 [M+H] ⁺

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.55 (s, 1H), 7.90 (s, 1H), 6.93 - 6.82 (m, 1H), 6.81 - 6.71 (m, 1H), 6.00 (d, J) = 7.6 Hz, 1H), 5.88 (s, 1H), 4.51 (s, 2H), 3.57 (t, J = 5.8 Hz, 2H), 3.00 (t, J = 5.5 Hz, 2H).

Example 38: 7-(6-Fluoro-4-methoxypyridin-2-yl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (59)

First step: 7-(6-Fluoro-4-methoxypyridin-2-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylic acid ethyl ester 59a)

Compound 1b (60 mg, 290.92 μmol), 2,6-difluoro-4-methoxypyridine (84.43 mmol, 581.84 μmol), DIPEA (112.80 mg, 872.77 μmol) were reacted in NMP at 150 ° C in a microwave. After 2 h, after completion of the reaction, it was extracted with ethyl acetate, dried, and then purified and purified by chromatography (eluent system B) to afford compound 59a (96.39mg).

MS (ESI, m/z): 332.3 [M+H] ⁺

Second step: 7-(6-fluoro-4-methoxypyridin-2-yl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (59)

Compound 59a (85 mg, 256.53 μmol) was dissolved in 3 mL of tetrahydrofuran and 1 mL of water, and then LiOH·H ₂ O (107.74 mg, 2.57 mmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 59 (46 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

MS (ESI, m/z): 304.3 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.59 (s, 1H), 7.90 (s, 1H), 6.29 (s, 1H), 6.00 (d, J = 1.2Hz, 1H), 4.76 (s, 2H), 3.84 (s, 3H), 3.80 (t, J = 5.8 Hz, 2H), 2.96 (t, J = 5.6 Hz, 2H).

Example 39: 7-(2-Fluoro-6-(3-methoxypyrrolidin-1-yl)pyridin-4-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine 3-carboxylic acid (60)

First step: ethyl 7-(2,6-difluoropyridin-4-yl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (60a) and 7- Ethyl (4,6-difluoropyridin-2-yl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (60b)

Compound 1b (4.5 g, 21.8 mmol) and 2,4,6-trifluoropyridine (3.48 g, 26.18 mmol), DIPEA (8.46 g, 65.43 mmol) were dissolved in 30 mL of NMP and then reacted in a microwave at 150 ° C After 1 h, after completion of the reaction, the mixture was extracted with ethyl acetate. EtOAc was evaporated.

MS (ESI, m/z): 320.3 [M+H] ⁺ .

Second step: 7-(2-Fluoro-6-(3-methoxypyrrolidin-1-yl)pyridin-4-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine Ethyl-3-carboxylate (60c)

Compound 60a (60 mg, 187.91 μmol), 3-methoxypyrrolidine hydrochloride (77.57 mg, 563.72 μmol), K ₂ CO ₃ (77.79 mg, 563.72 μmol) was dissolved in 1 mL of NMP and then heated to 150 in a microwave. After reacting at ° C for 3 h, after completion of the reaction, the mixture was extracted with ethyl acetate, and the organic phase was dried and then purified and purified (eluent system B) to afford compound 60c (62 mg).

MS (ESI, m/z): 401.4 [M+H] ⁺ .

Third step: 7-(2-Fluoro-6-(3-methoxypyrrolidin-1-yl)pyridin-4-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine 3-carboxylic acid (60)

Compound 60c (60 mg, 149.83 μmol) was dissolved in 3 mL of tetrahydrofuran and 1 mL of water, and then LiOH·H ₂ O (62.93 mg, 1.5 mmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 60 (26 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

MS (ESI, m/z): 373.3 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.56 (s, 1H), 7.91 (s, 1H), 5.91 (s, 1H), 5.67 (s, 1H), 4.63 (s, 2H), 4.07– 4.00 (m, 1H), 3.65 (t, J = 5.6 Hz, 2H), 3.47 - 3.39 (m, 2H), 3.38 - 3.27 (m, 2H), 3.26 (s, 3H), 2.98 (t, J = 5.6 Hz, 2H), 2.06–1.98 (m, 2H).

Example 40: 7-(6-Fluoro-4-(3-methoxypyrrolidin-1-yl)pyridin-2-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine -3-carboxylic acid (61)

First step: 7-(6-fluoro-4-(3-methoxypyrrolidin-1-yl)pyridin-2-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine Ethyl-3-carboxylate (61a) and 7-(4-fluoro-6-(3-methoxypyrrolidin-1-yl)pyridin-2-yl)-5,6,7,8-tetrahydro -2,7-naphthyridine-3-carboxylic acid ethyl ester (61b)

Compound 60b (400 mg, 1.25 mmol), 3-methoxypyrrolidine hydrochloride (517.15 mg, 3.76 mmol) and DIPEA (809.51 mg, 6.26 mmol) were dissolved in 5 mL of NMP and heated to 150 ° C for 2 h. After the completion of the reaction, 50 mL of water was added to the system, and the mixture was extracted with EA. The organic phase was dried over anhydrous sodium sulfate and filtered, and the organic phase was dried and then purified by preparative silica gel plate (eluent system B) to give compound 61a (370 mg) And 61b (150 mg).

MS (ESI, m/z): 4021. [M+H] ⁺ .

Second step: 7-(6-fluoro-4-(3-methoxypyrrolidin-1-yl)pyridin-2-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine -3-carboxylic acid (61)

Compound 61a (370 mg, 923.97 μmol) was dissolved in 10 mL of THF and 4 mL of water, and then LiOH·H ₂ O (387.70 mg, 9.24 mmol) was added and allowed to react at room temperature for 1 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 61 (105 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

MS (ESI, m/z): 373.2 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.58 (s, 1H), 7.89 (s, 1H), 5.72 (s, 1H), 5.55 (d, J = 1.1Hz, 1H), 4.71 (s, 2H), 4.07 (d, J = 2.7 Hz, 1H), 3.77 (dd, J = 8.7, 6.2 Hz, 2H), 3.44 (m, 2H), 3.32 (m, 2H), 3.27 (s, 3H), 2.95 (t, J = 5.7 Hz, 2H), 2.05 (m, 2H).

Example 41: 7-(4-Fluoro-6-(3-methoxypyrrolidin-1-yl)pyridin-2-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine -3-carboxylic acid (62)

Compound 61b (150 mg, 374.58 μmol) was dissolved in 10 mL of THF and 4 mL of water, and then LiOH·H ₂ O (157.17 mg, 3.75 mmol) was added and allowed to react at room temperature for 1 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 62 (50 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

MS (ESI, m/z): 373.2 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.43 (s, 1H), 7.77 (s, 1H), 5.94 (dd, J = 12.5, 1.5 Hz, 1H), 5.56 (dd, J = 11.6, 1.5 Hz, 1H), 4.71 (s, 2H), 4.06 - 4.00 (m, 1H), 3.79 (t, J = 5.9 Hz, 2H), 3.45 (m, 2H), 3.43 (m, 1H), 3.32 (d) , J = 9.2 Hz, 1H), 3.25 (s, 3H), 2.89 (t, J = 5.6 Hz, 2H), 2.02 (m, 2H).

Example 42: 7-(2-Fluoro-6-(2-methylmorpholino)pyridin-4-yl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate Acid (63)

First step: 7-(2-Fluoro-6-(2-methylmorpholino)pyridin-4-yl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate Ethyl acetate (63a)

Compound 60a (60 mg, 187.91 μmol), 2-methylmorpholine (57.02 mg, 563.72 μmol), K ₂ CO ₃ (77.79 mg, 563.72 μmol) was dissolved in 1 mL of NMP, and then heated to 150 ° C for 2 h. After completion of the reaction, the mixture was extracted with EtOAc. EtOAc (EtOAc)

MS (ESI, m/z): 401.4 [M+H] ⁺ .

Second step: 7-(2-Fluoro-6-(2-methylmorpholino)pyridin-4-yl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate Acid (63)

Compound 63a (53 mg, 132.35 μmol) was dissolved in 3 mL of tetrahydrofuran and 1 mL of water, and then LiOH·H ₂ O (55.59 mg, 1.32 mmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 63 (10 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

MS (ESI, m/z): 373.3 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.55 (s, 1H), 7.91 (s, 1H), 6.05 (s, 1H), 6.00 (s, 1H), 4.65 (s, 2H), 4.06– 3.86 (m, 3H), 3.67 (t, J = 6.0 Hz, 2H), 3.57 - 3.48 (m, 2H), 2.98 (t, J = 5.4 Hz, 2H), 2.77 - 2.70 (m, 1H), 2.42 (t, J = 12.4 Hz, 1H), 1.16 (d, J = 6.4 Hz, 3H).

Example 43: 7-(6-Fluoro-4-(2-methylmorpholino)pyridin-2-yl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate Acid (64)

First step: 7-(6-fluoro-4-(2-methylmorpholino)pyridin-2-yl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate Ethyl ester (64a) and 7-(4-fluoro-6-(2-methylmorpholino)pyridin-2-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine- 3-carboxylic acid ethyl ester (64b)

Compound 60b (100 mg, 313.18 μmol), 2-methylmorpholine (95.03 mg, 939.54 μmol), DIPEA (121.43 mg, 939.54 μmol) was dissolved in 2 mL of NMP, and then heated to 150 ° C for 2 h. After completion of the reaction, the mixture was extracted with EtOAc. EtOAc (EtOAc)

MS (ESI, m/z): 401.4 [M+H] ⁺ .

Second step: 7-(6-fluoro-4-(2-methylmorpholino)pyridin-2-yl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate Acid (64)

Compound 64a (66 mg, 164.82 μmol) was dissolved in 3 mL of tetrahydrofuran and 1 mL of water, and then LiOH·H ₂ O (69.22 mg, 1.65 mmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 64 (50 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

MS (ESI, m/z): 373.3 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.57 (s, 1H), 7.89 (s, 1H), 6.09 (s, 1H), 5.92 (s, 1H), 4.72 (s, 2H), 3.91– 3.72 (m, 5H), 3.58–3.52 (m, 2H), 2.95 (t, J = 5.6 Hz, 2H), 2.83–2.73 (m, 1H), 2.46 (d, J = 12.4 Hz, 1H), 1.16 (d, J = 6.2 Hz, 3H).

Example 44: 7-(4-Fluoro-6-(2-methylmorpholino)pyridin-2-yl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate Acid (65)

Compound 64b (43 mg, 107.38 μmol) was dissolved in 3 mL of tetrahydrofuran and 1 mL of water, and then LiOH·H ₂ O (45.10 mg, 1.07 mmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 65 (20 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

MS (ESI, m/z): 373.3 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) 8.56 (s, 1 H), 7.88 (s, 1H), 6.07 (d, J = 12.0 Hz, 1H), 5.96 (d, J = 12.2 Hz, 1H), 4.74 (s, 2H), 4.03 (d, J = 12.8 Hz, 2H), 3.88 (dd, J = 11.4, 2.4 Hz, 1H), 3.79 (t, J = 5.6 Hz, 2H), 3.57 - 3.49 (m, 2H), 2.93 (t, J = 5.2 Hz, 2H), 2.79 - 2.72 (m, 1H), 2.45 (dd, J = 12.6 Hz, 1H), 1.15 (d, J = 6.2 Hz, 3H).

Example 45: 7-(4-(3,3-Difluoropyrrolidin-1-yl)-6-fluoropyridin-2-yl)-5,6,7,8-tetrahydro-2,7-naphthalene Pyridine-3-carboxylic acid (66)

First step: 7-(4-(3,3-difluoropyrrolidin-1-yl)-6-fluoropyridin-2-yl)-5,6,7,8-tetrahydro-2,7-naphthalene Ethyl pyridine-3-carboxylate (66a) and 7-(6-(3,3-difluoropyrrolidin-1-yl)-4-fluoropyridin-2-yl)-5,6,7,8- Ethyl tetrahydro-2,7-naphthyridine-3-carboxylate (66b)

Compound 60b (100 mg, 0.313 mmol), 3,3-difluoropyrrolidine hydrochloride (135 mg, 0.940 mmol) and DIPEA (121 mg, 0.940 mmol) were dissolved in 2 mL of NMP and heated to 150 ° C under N ₂ protection. 4h. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 407.1 [M+H] ⁺ .

Second step: 7-(4-(3,3-difluoropyrrolidin-1-yl)-6-fluoropyridin-2-yl)-5,6,7,8-tetrahydro-2,7-naphthalene Pyridine-3-carboxylic acid (66)

Compound 66a (70mg, 0.172mmol) was dissolved in 1mL water and 4mL of tetrahydrofuran, was added _{LiOH · H 2 O (22mg,} 0.517mmol), the reaction at room temperature for 1h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 66 (25 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

Instrument model: Agilent 1260, column: Waters XBridge Prep C ₁₈ OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 ° C; flow rate: 28.0 mL / min; detection wavelength: 214 nm; elution gradient: (0 min: 10% A, 90% B; 16.0 min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous formic acid.

MS (ESI, m/z): 379.1 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.57 (s, 1H), 7.89 (s, 1H), 5.79 (s, 1H), 5.64 (d, J = 1.2Hz, 1H), 4.73 (s, 2H), 3.85–3.74 (m, 4H), 3.55 (t, J = 7.3 Hz, 2H), 2.95 (t, J = 5.7 Hz, 2H), 2.62–2.52 (m, 2H).

Example 46: 7-(6-(3,3-Difluoropyrrolidin-1-yl)-4-fluoropyridin-2-yl)-5,6,7,8-tetrahydro-2,7-naphthalene Pyridine-3-carboxylic acid (67)

Compound 66b (25 mg, 0.062 mmol) was dissolved in 4 mL of tetrahydrofuran and 1 mL water, and then LiOH·H ₂ O (8 mg, 0.185 mmol) was added and allowed to react at room temperature for 1 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 67 (12 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

Instrument model: Agilent 1260, column: Waters XBridge Prep C ₁₈ OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 ° C; flow rate: 24.0 mL / min; detection wavelength: 214 nm; elution gradient: (0 min: 30% A, 70% B; 16.0 min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous formic acid.

MS (ESI, m/z): 379.1 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.56 (s, 1H), 7.88 (s, 1H), 6.08 (dd, J = 12.4, 1.3 Hz, 1H), 5.69 (dd, J = 11.3, 1.3 Hz, 1H), 4.78 (s, 2H), 3.89 - 3.77 (m, 4H), 3.58 (t, J = 7.3 Hz, 2H), 2.94 (t, J = 5.7 Hz, 2H), 2.60 - 2.51 (m) , 2H).

Example 47: 7-(2-(3,3-Difluoropyrrolidin-1-yl)-6-fluoropyridin-4-yl)-5,6,7,8-tetrahydro-2,7-naphthalene Pyridine-3-carboxylic acid (68)

First step: 7-(2-(3,3-difluoropyrrolidin-1-yl)-6-fluoropyridin-4-yl)-5,6,7,8-tetrahydro-2,7-naphthalene Ethyl pyridine-3-carboxylate (68a)

Compound 60a (100 mg, 0.313 mmol), 3,3-difluoropyrrolidine hydrochloride (135 mg, 0.940 mmol) and DIPEA (130 mg, 0.940 mmol) were dissolved in 2 mL of NMP and heated to 150 ° C under N ₂ protection. 4h. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 407.1 [M+H] ⁺ .

Second step: 7-(2-(3,3-difluoropyrrolidin-1-yl)-6-fluoropyridin-4-yl)-5,6,7,8-tetrahydro-2,7-naphthalene Pyridine-3-carboxylic acid (68)

Compound 68a (60mg, 0.148mmol) was dissolved in 1mL water and 4mL of tetrahydrofuran, was added _{LiOH · H 2 O (19mg,} 0.443mmol), the reaction at room temperature for 1h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 68 (25 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

Instrument model: Agilent 1260, column: Waters XBridge Prep C ₁₈ OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 ° C; flow rate: 24.0 mL / min; detection wavelength: 214 nm; elution gradient: (0 min: 20% A, 80% B; 6.0 min: 42.5% A, 57.5% B); Mobile phase A: 100% acetonitrile; Mobile phase B: 0.05% aqueous formic acid.

MS (ESI, m/z): 379.1 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.55 (s, 1H), 7.92 (s, 1H), 6.01 (s, 1H), 5.77 (s, 1H), 4.66 (s, 2H), 3.78 ( t, J = 13.3 Hz, 2H), 3.67 (t, J = 5.8 Hz, 2H), 3.58 (t, J = 7.3 Hz, 2H), 2.99 (t, J = 5.7 Hz, 2H), 2.58 - 2.45 ( m, 2H).

Example 48: 7-(6-Fluoro-4-(3-methylpyrrolidin-1-yl)pyridin-2-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine- 3-carboxylic acid (69)

First step: 7-(6-fluoro-4-(3-methylpyrrolidin-1-yl)pyridin-2-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine- Ethyl 3-carboxylate (69a) and 7-(4-fluoro-6-(3-methylpyrrolidin-1-yl)pyridin-2-yl)-5,6,7,8-tetrahydro-2 , 7-naphthyridine-3-carboxylic acid ethyl ester (69b)

The compound was heated to 150 deg.] C under 60b (97mg, 0.304mmol), 3- methyl-pyrrolidine hydrochloride (110mg, 0.911mmol) and DIPEA (118mg, 0.911mmol) was dissolved in 2mL NMP, N ₂ protection reaction 4h. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 385.2 [M+H] ⁺ .

Second step: 7-(6-fluoro-4-(3-methylpyrrolidin-1-yl)pyridin-2-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine- 3-carboxylic acid (69)

Compound 69a (60mg, 0.156mmol) was dissolved in 1mL water and 4mL of tetrahydrofuran, was added _{LiOH · H 2 O (20mg,} 0.468mmol), the reaction at room temperature for 1h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 69 (25 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

Instrument model: Agilent 1260, column: Waters XBridge Prep C ₁₈ OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 ° C; flow rate: 24.0 mL / min; detection wavelength: 214 nm; elution gradient: (0 min: 30% A, 70% B; 16.0 min: 70% A, 30% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous formic acid.

MS (ESI, m/z): 357.2 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.58 (s, 1H), 7.89 (s, 1H), 5.68 (s, 1H), 5.51 (s, 1H), 4.70 (s, 2H), 3.76 ( s, 2H), 3.56–3.20 (m, 3H), 2.95 (s, 2H), 2.90–2.77 (m, 1H), 2.33 (td, J = 14.5, 7.3 Hz, 1H), 2.08 (dt, J= 11.6, 6.9 Hz, 1H), 1.57 (td, J = 17.2, 8.4 Hz, 1H), 1.07 (d, J = 6.5 Hz, 3H).

Example 49: 7-(4-Fluoro-6-(3-methylpyrrolidin-1-yl)pyridin-2-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine- 3-carboxylic acid (70)

Compound 69b (20mg, 0.052mmol) was dissolved in 1mL water and 4mL of tetrahydrofuran, was added _{LiOH · H 2 O (7mg,} 0.156mmol), the reaction at room temperature for 1h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 70 (13 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

MS (ESI, m/z): 357.2 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.55 (s, 1H), 7.78 (s, 1H), 5.94 (d, J = 12.5 Hz, 1H), 5.53 (d, J = 11.7 Hz, 1H) , 4.75 (s, 2H), 3.81 (t, J = 5.8 Hz, 2H), 3.56 - 3.20 (m, 3H), 2.99 - 2.78 (m, 3H), 2.37 - 2.23 (m, 1H), 2.05 (dd , J = 10.9, 4.4 Hz, 1H), 1.54 (td, J = 16.8, 8.3 Hz, 1H), 1.07 (d, J = 6.6 Hz, 3H).

Example 50: 7-(2-Fluoro-6-(3-methylpyrrolidin-1-yl)pyridin-4-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine- 3-carboxylic acid (71)

First step: 7-(2-Fluoro-6-(3-methylpyrrolidin-1-yl)pyridin-4-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine- 3-carboxylic acid ethyl ester (71a)

Compound 60a (75mg, 0.235mmol), 3- methyl-pyrrolidine hydrochloride (86mg, 0.705mmol) and DIPEA (130mg, 0.940mmol) was dissolved in 2mL NMP, under N ₂ was heated to 150 deg.] C reaction 4h. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 385.2 [M+H] ⁺ .

Second step: 7-(2-Fluoro-6-(3-methylpyrrolidin-1-yl)pyridin-4-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine- 3-carboxylic acid (71)

Compound 71a (70 mg, 0.148 mmol) was dissolved in 4 mL of tetrahydrofuran and 1 mL water, and then LiOH·H ₂ O (23 mg, 0.546 mmol) was added and allowed to react at room temperature for 1 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 71 (25 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

Instrument model: Agilent 1260, column: Waters SunFire Prep C ₁₈ OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 ° C; flow rate: 24.0 mL / min; detection wavelength: 214 nm; elution gradient: (0 min: 30% A, 70% B; 6.0 min: 70% A, 30% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous formic acid.

MS (ESI, m/z): 357.2 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.57 (s, 1H), 7.91 (s, 1H), 5.88 (s, 1H), 5.64 (s, 1H), 4.63 (s, 2H), 3.64 ( t, J = 5.8 Hz, 2H), 3.57 - 3.50 (m, 2H), 2.98 (t, J = 5.7 Hz, 2H), 2.91 - 2.84 (m, 1H), 2.30 (dd, J = 14.7, 6.7 Hz , 2H), 2.12–1.99 (m, 1H), 1.53 (dt, J=20.6, 8.3 Hz, 1H), 1.07 (d, J=6.6 Hz, 3H).

Example 51: 7-(4-(2,2-Dimethylmorpholino)-6-fluoropyridin-2-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine- 3-carboxylic acid (72)

First step: 7-(4-(2,2-dimethylmorpholino)-6-fluoropyridin-2-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine- 3-carboxylic acid ethyl ester (72a)

Compound 60b (100 mg, 0.31 mmol), 2,2-dimethylmorpholine (107.53 mg, 0.93 mmol) and DIPEA (120.66 mg, 0.93 mmol) were dissolved in 5 mL of NMP and heated to 150 ° C for 2 h. After completion of the reaction, ethyl acetate was extracted, and the organic phase was concentrated to dryness and then purified by flash column chromatography (eluent system B) to afford compound 72a (30 mg).

MS (ESI, m/z): 415.2 [M+H] ⁺

Second step: 7-(4-(2,2-dimethylmorpholino)-6-fluoropyridin-2-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine- 3-carboxylic acid (72)

Compound 72a (30 mg, 72.38 μmol) was dissolved in 1 mL of methanol and 2 mL of water, and then LiOH·H ₂ O (15.2 mg, 0.36 mmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and a yellow solid was precipitated, filtered, and dried to give compound 72 (27 mg).

MS (ESI, m/z): 387.2 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.63 (s, 1H), 7.95 (s, 1H), 6.06 (s, 1H), 5.91 (s, 1H), 4.74 (s, 2H), 3.80– 3.77 (m, 2H), 3.71 - 3.68 (m, 2H), 3.33-3.30 (m, 2H), 3.21 (s, 2H), 2.98 - 2.96 (m, 2H), 1.18 (s, 6H).

Example 52: 7-(2-(2,2-Dimethylmorpholino)-6-fluoropyridin-4-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine- 3-carboxylic acid (73)

First step: 7-(2-(2,2-dimethylmorpholino)-6-fluoropyridin-4-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine- 3-carboxylic acid ethyl ester (73a)

Compound 60a (100 mg, 0.31 mmol), 2,2-dimethylmorpholine (107.53 mg, 0.93 mmol) and DIPEA (120.66 mg, 0.93 mmol) were dissolved in 2 mL of NMP and heated to 150 ° C for 2 h. After completion of the reaction, ethyl acetate was extracted, and the organic layer was concentrated to dryness.

MS (ESI, m/z): 415.2 [M+H] ⁺

Second step: 7-(2-(2,2-dimethylmorpholino)-6-fluoropyridin-4-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine- 3-carboxylic acid (73)

Compound 73a (50 mg, 0.12 mmol) was dissolved in 1 mL of methanol and 2 mL of water, and then LiOH·H ₂ O (25.2 mg, 0.60 mmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and a yellow solid precipitated, which was filtered and dried to give compound 73 (27 mg).

MS (ESI, m/z): 387.2 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.57 (s, 1H), 7.94 (s, 1H), 6.04 (s, 1H), 5.97 (s, 1H), 4.65 (s, 2H), 3.68– 3.65 (m, 4H), 3.40–3.39 (m, 2H), 3.28 (s, 2H), 3.00–2.99 (m, 2H), 1.18 (s, 6H).

Example 53: 7-(6-Fluoro-4-(3-methoxyazetidin-1-yl)pyridin-2-yl)-5,6,7,8-tetrahydro-2,7 -naphthyridine-3-carboxylic acid (74)

First step: 7-(6-fluoro-4-(3-methoxyazetidin-1-yl)pyridin-2-yl)-5,6,7,8-tetrahydro-2,7 - naphthyridine-3-carboxylic acid ethyl ester (74a)

Compound 60b (100 mg, 0.31 mmol), 3-methoxyazetidine hydrochloride (116.11 mg, 0.93 mmol) and DIPEA (120.66 mg, 0.93 mmol) were dissolved in 2 mL of NMP and heated to 150 ° C. Reaction for 3 h. After completion of the reaction, ethyl acetate was extracted, and the organic phase was concentrated to dryness and then purified by flash column chromatography (eluent system B) to afford compound 74a (35 mg).

MS (ESI, m/z): 387.2 [M+H] ⁺ .

Second step: 7-(6-fluoro-4-(3-methoxyazetidin-1-yl)pyridin-2-yl)-5,6,7,8-tetrahydro-2,7 -naphthyridine-3-carboxylic acid (74)

Compound 74a (30 mg, 77.64 μmol) was dissolved in 1 mL of methanol and 2 mL of water, and then LiOH·H ₂ O (16.4 mg, 0.39 mmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 74 (9 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

MS (ESI, m/z): 359.1 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.46 (s, 1H), 7.79 (s, 1H), 5.61 (s, 1H), 5.41-5.40 (m, 1H), 4.65 (s, 2H), 4.33–4.30 (m, 1H), 4.13–4.09 (m, 2H), 3.75–3.70 (m, 4H), 3.24 (s, 3H), 2.91–2.88 (m, 2H).

Example 54: 7-(6-Fluoro-4-(2-(hydroxymethyl)pyrrolidin-1-yl)pyridin-2-yl)-5,6,7,8-tetrahydro-2,7- Naphthyridine-3-carboxylic acid (75)

First step: 7-(6-fluoro-4-(2-(hydroxymethyl)pyrrolidin-1-yl)pyridin-2-yl)-5,6,7,8-tetrahydro-2,7- Ethyl naphthyridine-3-carboxylate (75a) and 7-(4-fluoro-6-(2-(hydroxymethyl)pyrrolidin-1-yl)pyridin-2-yl)-5,6,7, 8-tetrahydro-2,7-naphthyridine-3-carboxylic acid ethyl ester (75b)

Compound 60b (100 mg, 313.18 μmol), 2-(hydroxymethyl)pyrrolidine hydrochloride (95.03 mg, 939.54 μmol) and DIPEA (202.38 mg, 1570 μmol) were dissolved in 2 mL of NMP and heated to 150 ° C for 2 h. . After the completion of the reaction, 30 ml of water was added to the system, and the mixture was extracted with EA. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (eluent system B) to give compound 75a (45mg) and 75b (23mg) ).

MS (ESI, m/z): 4021. [M+H] ⁺ .

Second step: 7-(6-fluoro-4-(2-(hydroxymethyl)pyrrolidin-1-yl)pyridin-2-yl)-5,6,7,8-tetrahydro-2,7- Naphthyridine-3-carboxylic acid (75)

Compound 75a (45 mg, 112.37 μmol) was dissolved in 5 mL of THF and 2 mL of water, and then LiOH·H ₂ O (47.15 mg, 1.12 mmol) was added and allowed to react at room temperature for 1 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 75 (7 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

MS (ESI, m/z): 373.2 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.47 (s, 1H), 7.92 (s, 1H), 5.77 (s, 1H), 5.62 (s, 1H), 4.69 (s, 2H), 3.81 ( t, J = 5.8 Hz, 3H), 3.62 (dd, J = 11.2, 3.5 Hz, 1H), 3.50 - 3.39 (m, 2H), 3.22 (dd, J = 12.4, 6.0 Hz, 1H), 3.01 (s) , 2H), 2.21–2.06 (m, 2H), 2.05–1.96 (m, 2H).

Example 55: 7-(2-Fluoro-6-(2-(hydroxymethyl)pyrrolidin-1-yl)pyridin-4-yl)-5,6,7,8-tetrahydro-2,7- Naphthyridine-3-carboxylic acid (76)

First step: 7-(2-fluoro-6-(2-(hydroxymethyl)pyrrolidin-1-yl)pyridin-4-yl)-5,6,7,8-tetrahydro-2,7- Naphthyridine-3-carboxylic acid ethyl ester (76a)

Compound 60a (60 mg, 187.91 μmol), 2-(hydroxymethyl)pyrrolidine hydrochloride (77.57 mg, 563.72 μmol) and DIPEA (121.43 mg, 939.54 μmol) were dissolved in 2 mL of NMP and heated to 150 ° C in a microwave. 2h. After completion of the reaction, 30 mL of water was added to the system, and the mixture was extracted with ethyl acetate. The organic phase was evaporated to dryness.

MS (ESI, m/z): 4021. [M+H] ⁺ .

Second step: 7-(2-Fluoro-6-(2-(hydroxymethyl)pyrrolidin-1-yl)pyridin-4-yl)-5,6,7,8-tetrahydro-2,7- Naphthyridine-3-carboxylic acid (76)

Compound 76a (40 mg, 99.89 μmol) was dissolved in 5 mL of THF and 2 mL of water, and then LiOH·H ₂ O (41.95 mg, 999.8 μmol) was added and allowed to react at room temperature for 1 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 76 (15 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

MS (ESI, m/z): 373.2 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.55 (s, 1H), 7.90 (s, 1H), 5.91 (s, 1H), 5.69 (s, 1H), 4.62 (s, 2H), 3.95 ( Dd, J = 11.3, 7.7 Hz, 1H), 3.64 (t, J = 5.8 Hz, 2H), 3.59 - 3.55 (m, 1H), 3.40 (s, 2H), 3.22 - 3.16 (m, 2H), 2.98 (t, J = 5.7 Hz, 2H), 2.02 - 1.94 (m, 2H), 1.91 - 1.79 (m, 2H).

Example 56: 7-(6-Fluoro-4-(3-hydroxypyrrolidin-1-yl)pyridin-2-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine-3 -carboxylic acid (77)

First step: 7-(6-fluoro-4-(3-hydroxypyrrolidin-1-yl)pyridin-2-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine-3 -Carboxylic acid ethyl ester (77a)

Compound 60b (100 mg, 0.31 mmol), 3-hydroxypyrrolidine hydrochloride (116.11 mg, 0.94 mmol) and DIPEA (120.66 mg, 0.93 mmol) were dissolved in 2 mL of NMP and heated to 150 ° C for 3 h. After completion of the reaction, the mixture was extracted with ethyl acetate. EtOAc (EtOAc)

MS (ESI, m/z): 387.2 [M+H] ⁺ .

Second step: 7-(6-fluoro-4-(3-hydroxypyrrolidin-1-yl)pyridin-2-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine-3 -carboxylic acid (77)

Compound 77a (30 mg, 77.64 μmol) was dissolved in 1 mL of methanol and 2 mL of water, and then LiOH·H ₂ O (16.4 mg, 0.39 mmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 77 (20 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

MS (ESI, m/z): 359.1 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.58 (s, 1H), 7.88 (s, 1H), 5.69 (s, 1H), 5.23 (m, 1H), 4.70 (s, 2H), 4.38 - 4.37 (m, 1H), 3.78–3.75 (m, 2H), 3.44–3.35 (m, 2H), 3.17–3.14 (m, 2H), 2.96–2.93 (m, 2H), 2.02–1.96 (m, 1H) ), 1.91–1.86 (m, 1H).

Example 57: 7-(4-Fluoro-6-(2-(hydroxymethyl)morpholino)pyridin-2-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine- 3-carboxylic acid (78)

First step: 7-(4-fluoro-6-(2-(hydroxymethyl)morpholino)pyridin-2-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine- 3-carboxylic acid ethyl ester (78a)

Compound 60b (100 mg, 0.31 mmol), morpholin-2-ylmethanol (110.06 mg, 0.94 mmol) and DIPEA (120.66 mg, 0.93 mmol) were dissolved in 2 mL of NMP and heated to 150 ° C for 3 h. After completion of the reaction, the reaction mixture was poured into water (20 mL), EtOAc (EtOAc)

MS (ESI, m/z): 417.2 [M+H] ⁺

Second step: 7-(4-fluoro-6-(2-(hydroxymethyl)morpholino)pyridin-2-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine- 3-carboxylic acid (78)

Compound 78a (20 mg, 48.03 μmol) was dissolved in 1 mL of methanol and 2 mL of water, and then LiOH·H ₂ O (10.10 mg, 0.24 mmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl.

Prep-HPLC conditions:

MS (ESI, m/z): 389.1 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.55 (s, 1H), 7.88 (s, 1H), 6.09 - 6.07 (m, 1H), 5.94 - 5.92 (m, 1H), 4.70 (s, 2H) ), 4.11–4.00 (m, 2H), 3.92–3.90 (m, 1H), 3.82–3.79 (m, 2H), 3.54–3.50 (m, 4H), 2.95–2.93 (m, 2H), 2.85–2.77 (m, 1H), 2.58–2.53 (m, 1H).

Example 58: 7-(2-(2-Ethylmorpholino)-6-fluoropyridin-4-yl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate Acid (79)

First step: 7-(2-(2-ethylmorpholino)-6-fluoropyridin-4-yl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate Ethyl acetate (79a)

Compound 60a (100 mg, 313.18 μmol), 2-ethylmorpholine (108.21 mg, 939.54 μmol) and DIPEA (121.43 mg, 939.54 μmol) were dissolved in 1.5 mL of NMP, then heated to 150 ° C for 2 h in a microwave, and the reaction was completed. After that, it was extracted with ethyl acetate, and the organic phase was dried and then purified (yield from eluent system B) to afford 79a (105 mg).

MS (ESI, m/z): 415.4 [M+H] ⁺ .

Second step: 7-(2-(2-ethylmorpholino)-6-fluoropyridin-4-yl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate Acid (79)

Compound 79a (100 mg, 241.27 μmol) was dissolved in 8 mL of tetrahydrofuran and 2 mL of water, and then LiOH·H ₂ O (101.24 mg, 2.41 mmol) was added and allowed to react at room temperature for 2 h. After the end of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 79 (80 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

MS (ESI, m/z): 387.2 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.68 (s, 1H), 8.05 (s, 1H), 6.17 (s, 1H), 6.12 (s, 1H), 4.77 (s, 2H), 4.16 ( d, J = 12.3 Hz, 1H), 4.12 - 4.00 (m, 2H), 3.79 (t, J = 5.8 Hz, 2H), 3.62 (d, J = 2.7 Hz, 1H), 3.45 - 3.41 (m, 1H) ), 3.11 (t, J = 5.7 Hz, 2H), 2.97 - 2.82 (m, 1H), 2.56 (dd, J = 12.6, 10.5 Hz, 1H), 1.67 - 1.54 (m, 2H), 1.06 (t, J=7.5Hz, 3H).

Example 59: 7-(2-Fluoro-6-(2-oxa-7-azaspiro[4.4]decane-7-yl)pyridin-4-yl)-5,6,7,8-tetra Hydrogen-2,7-naphthyridine-3-carboxylic acid (80)

First step: 7-(2-fluoro-6-(2-oxa-7-azaspiro[4.4]decane-7-yl)pyridin-4-yl)-5,6,7,8-tetra Hydrogen-2,7-naphthyridine-3-carboxylic acid ethyl ester (80a)

Compound 60a (100 mg, 313.18 μmol), 2-oxa-7-azaspiro[4.4]decane (119.49 mg, 939.54 μmol) and DIPEA (121.43 mg, 939.54 μmol) were dissolved in 1.5 mL of NMP, then microwave The mixture was heated to 150 ° C for 2 h, and after completion of the reaction, the mixture was extracted with ethyl acetate. The organic phase was dried and then purified and purified (eluent system B) to afford 80a (65 mg).

MS (ESI, m/z): 427.1 [M+H] ⁺ .

The second step: 7-(2-fluoro-6-(2-oxa-7-azaspiro[4.4]decane-7-yl)pyridin-4-yl)-5,6,7,8-tetra Hydrogen-2,7-naphthyridine-3-carboxylic acid (80)

Compound 80a (60 mg, 140.69 μmol) was dissolved in 4 mL of tetrahydrofuran and 1 mL of water, and then LiOH·H ₂ O (59.03 mg, 1.41 mmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 80 (30 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

Instrument model: Agilent 1260, column: Waters SunFire Prep C ₁₈ OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 ° C; flow rate: 26.0 mL / min; detection wavelength: 254 nm; elution gradient: (0 min: 10% A, 90% B; 16 min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous formic acid.

MS (ESI, m/z): 399.2 [M+H] ⁺

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.56 (s, 1H), 7.91 (s, 1H), 5.90 (s, 1H), 5.67 (s, 1H), 4.63 (s, 2H), 3.81 ( t, J = 7.0 Hz, 2H), 3.64 (t, J = 5.8 Hz, 2H), 3.57 (s, 2H), 3.43 (s, 4H), 2.98 (t, J = 5.7 Hz, 2H), 1.97 - 1.84 (m, 4H).

Example 60: 7-(2-Fluoro-6-(2-(methoxymethyl)pyrrolidin-1-yl)pyridin-4-yl)-5,6,7,8-tetrahydro-2, 7-naphthyridine-3-carboxylic acid (81)

First step: 7-(2-fluoro-6-(2-(methoxymethyl)pyrrolidin-1-yl)pyridin-4-yl)-5,6,7,8-tetrahydro-2, 7-naphthyridine-3-carboxylic acid ethyl ester (81a)

Compound 60a (100 mg, 313.18 μmol), 2-(methoxymethyl)pyrrolidine hydrochloride (142.47 mg, 939.54 μmol) and DIPEA (202.38 mg, 1.57 mmol) were dissolved in 2 mL NMP and heated to 150. °C reaction for 2h. After the completion of the reaction, 30 mL of water was added to the mixture, and the mixture was evaporated.

MS (ESI, m/z): 415.2 [M+H] ⁺

Second step: 7-(2-Fluoro-6-(2-(methoxymethyl)pyrrolidin-1-yl)pyridin-4-yl)-5,6,7,8-tetrahydro-2, 7-naphthyridine-3-carboxylic acid (81)

The crude compound 81a (130 mg, 324.64 μmol) was dissolved in 5 mL of THF and 2 mL of water, and then LiOH·H ₂ O (68.11 mg, 1.62 mmol) was added and allowed to react at room temperature for 1 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and concentrated under reduced pressure to afford compound 81 (25 mg).

Prep-HPLC conditions:

MS (ESI, m/z): 387.2 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.56 (s, 1H), 7.91 (s, 1H), 5.92 (s, 1H), 5.70 (s, 1H), 4.63 (s, 2H), 4.10 ( s, 1H), 3.64 (t, J = 5.8 Hz, 2H), 3.48 - 3.45 (m, 1H), 3.40 (s, 1H), 3.26 (s, 3H), 3.24 - 3.16 (m, 2H), 2.98 (t, J = 5.7 Hz, 2H), 2.04 - 1.82 (m, 4H).

Example 61: 7-(4-(3,3-Dimethylazetidin-1-yl)-6-fluoropyridin-2-yl)-5,6,7,8-tetrahydro-2 ,7-naphthyridine-3-carboxylic acid (82)

First step: 7-(4-(3,3-dimethylazetidin-1-yl)-6-fluoropyridin-2-yl)-5,6,7,8-tetrahydro-2 , 7-naphthyridine-3-carboxylic acid ethyl ester (82a)

Compound 60b (100 mg, 313.18 μmol), 3,3-dimethylazetidine (76.17 mg, 626.36 μmol) and DIPEA (161.91 mg, 1.25 mmol) were dissolved in 1 mL of NMP and then in a microwave at 110 °C reaction for 3h. After completion of the reaction, the mixture was extracted with EtOAc. EtOAc (EtOAc)

MS (ESI, m/z): 385.4 [M+H] ⁺ .

Second step: 7-(4-(3,3-dimethylazetidin-1-yl)-6-fluoropyridin-2-yl)-5,6,7,8-tetrahydro-2 ,7-naphthyridine-3-carboxylic acid (82)

Compound 82a (65 mg, 169.07 μmol) was dissolved in 3 mL of tetrahydrofuran and 1 mL of water, and then LiOH·H ₂ O (71.01 mg, 1.65 mmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 82 (38 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

MS (ESI, m/z): 357.3 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.57 (s, 1H), 7.88 (s, 1H), 5.58 (s, 1H), 5.38 (d, J = 0.9Hz, 1H), 4.69 (s, 2H), 3.74 (t, J = 5.8 Hz, 2H), 3.61 (s, 4H), 2.94 (t, J = 5.7 Hz, 2H), 1.28 (s, 6H).

Example 62: 7-(2-(3,3-Dimethylazetidin-1-yl)-6-fluoropyridin-4-yl)-5,6,7,8-tetrahydro-2 ,7-naphthyridine-3-carboxylic acid (83)

First step: 7-(2-(3,3-dimethylazetidin-1-yl)-6-fluoropyridin-4-yl)-5,6,7,8-tetrahydro-2 , 7-naphthyridine-3-carboxylic acid ethyl ester (83a)

Compound 60a (100 mg, 313.18 μmol), 3,3-dimethylazetidine (76.17 mg, 626.36 μmol) and DIPEA (161.91 mg, 1.25 mmol) were dissolved in 1 mL of NMP and then in a microwave at 110 °C reaction for 2h. After completion of the reaction, the mixture was extracted with EtOAc. EtOAc (EtOAc)

MS (ESI, m/z): 385.4 [M+H] ⁺ .

Second step: 7-(2-(3,3-dimethylazetidin-1-yl)-6-fluoropyridin-4-yl)-5,6,7,8-tetrahydro-2 ,7-naphthyridine-3-carboxylic acid (83)

Compound 83a (65 mg, 169.07 μmol) was dissolved in 3 mL of tetrahydrofuran and 1 mL of water, and then LiOH·H ₂ O (71.01 mg, 1.65 mmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and the compound 83 (35 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

Instrument model: Agilent 1260, column: Waters SunFire Prep C ₁₈ OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 ° C; flow rate: 20.0 mL / min; detection wavelength: 214 nm; elution gradient: (0 min: 20% A, 80% B; 16 min: 80% A, 20% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous formic acid.

MS (ESI, m/z): 357.3 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.55 (s, 1H), 7.91 (s, 1H), 5.93 (s, 1H), 5.59 (s, 1H), 4.61 (s, 2H), 3.62 ( t, J = 5.8 Hz, 2H), 3.58 (s, 4H), 2.97 (t, J = 5.7 Hz, 2H), 1.26 (s, 6H).

Example 63: (S)-7-(2-Fluoro-6-(3-fluoropyrrolidin-1-yl)pyridin-4-yl)-5,6,7,8-tetrahydro-2,7- Naphthyridine-3-carboxylic acid (84)

First step: (S)-7-(2-fluoro-6-(3-fluoropyrrolidin-1-yl)pyridin-4-yl)-5,6,7,8-tetrahydro-2,7- Naphthyridine-3-carboxylic acid ethyl ester (84a)

Compound 60a (100 mg, 313.18 μmol), (S)-3-fluoropyrrolidine hydrochloride (78.65 mg, 626.36 μmol) and DIPEA (121.43 mg, 939.54 μmol) were dissolved in 1.5 mL of NMP and then under microwave The reaction was carried out at 150 ° C for 2 h. After completion of the reaction, the mixture was extracted with EtOAc. EtOAc (EtOAc)

MS (ESI, m/z): 389.2 [M+H] ⁺ .

The second step: (S)-7-(2-fluoro-6-(3-fluoropyrrolidin-1-yl)pyridin-4-yl)-5,6,7,8-tetrahydro-2,7- Naphthyridine-3-carboxylic acid (84)

Compound 84a (90 mg, 231.71 μmol) was dissolved in 6 mL of tetrahydrofuran and 1.5 mL of water, and then LiOH·H ₂ O (97.23 mg, 2.32 mmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 84 (30 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

Instrument model: Agilent 1260, column: Waters SunFire Prep C ₁₈ OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 ° C; flow rate: 28.0 mL / min; detection wavelength: 254 nm; elution gradient: (0 min: 10% A, 90% B; 16 min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous formic acid.

MS (ESI, m/z): 361.1 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.56 (s, 1H), 7.91 (s, 1H), 5.94 (s, 1H), 5.72 (s, 1H), 5.48-5.35 (m, 1H), 4.65(s, 2H), 3.68–3.63 (m, 3H), 3.59 (dd, J = 14.5, 5.5 Hz, 3H), 2.99 (t, J = 5.7 Hz, 2H), 2.27–2.17 (m, 2H) .

Example 64: (R)-7-(2-Fluoro-6-(3-fluoropyrrolidin-1-yl)pyridin-4-yl)-5,6,7,8-tetrahydro-2,7- Naphthyridine-3-carboxylic acid (85)

First step: (R)-7-(2-fluoro-6-(3-fluoropyrrolidin-1-yl)pyridin-4-yl)-5,6,7,8-tetrahydro-2,7- Naphthyridine-3-carboxylic acid ethyl ester (85a)

Compound 60a (100 mg, 0.31 mmol), (R)-3-fluoropyrrolidine hydrochloride (47 mg, 0.38 mmol) and DIPEA (120.66 mg, 0.93 mmol) were dissolved in 2 mL of NMP and reacted at 150 ° C under microwave. 3h. After completion of the reaction, the reaction mixture was poured into water (20 mL), EtOAc (EtOAc)

MS (ESI, m/z): 388.2 [M+H] ⁺ .

The second step: (R)-7-(2-fluoro-6-(3-fluoropyrrolidin-1-yl)pyridin-4-yl)-5,6,7,8-tetrahydro-2,7- Naphthyridine-3-carboxylic acid (85)

Compound 85a (25 mg, 64.36 μmol) was dissolved in 1 mL of methanol and 2 mL of water, and then LiOH·H ₂ O (13.52 mg, 0.32 mmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 85 (14 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

MS (ESI, m/z): 361.1 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.46 (s, 1H), 8.71 (s, 1H), 5.93 (s, 1H), 5.71 (s, 1H), 5.48 - 5.35 (m, 1H), 4.64–4.56 (m, 2H), 3.67–3.46 (m, 4H), 3.41–3.34 (m 2H), 2.93–2.95 (m, 2H), 2.24–2.08 (m, 2H).

Example 65: (R)-7-(6-Fluoro-4-(3-fluoropyrrolidin-1-yl)pyridin-2-yl)-5,6,7,8-tetrahydro-2,7- Naphthyridine-3-carboxylic acid (86)

First step: (R)-7-(6-fluoro-4-(3-fluoropyrrolidin-1-yl)pyridin-2-yl)-5,6,7,8-tetrahydro-2,7- Ethyl naphthyridine-3-carboxylate (86a)

Compound 60b (100 mg, 0.31 mmol), (R)-3-fluoropyrrolidine hydrochloride (47 mg, 0.38 mmol) and DIPEA (120.66 mg, 0.93 mmol) were dissolved in 2 mL of NMP and reacted at 150 ° C under microwave 3h. After completion of the reaction, the reaction mixture was poured into water (20 mL), EtOAc (EtOAc)

MS (ESI, m/z): 388.2 [M+H] ⁺ .

The second step: (R)-7-(6-fluoro-4-(3-fluoropyrrolidin-1-yl)pyridin-2-yl)-5,6,7,8-tetrahydro-2,7- Naphthyridine-3-carboxylic acid (86)

Compound 86a (15 mg, 38.62 μmol) was dissolved in 1 mL of methanol and 2 mL of water, and then LiOH·H ₂ O (8.11 mg, 0.19 mmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 1 (9 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

MS (ESI, m/z): 361.1 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.50 (s, 1H), 7.82 (s, 1H), 5.74 (s, 1H), 5.59 (s, 1H), 5.52 - 5.38 (m, 1H), 4.74–4.64 (m, 2H), 3.78–3.34 (m, 2H), 3.61–3.34 (m 4H), 2.93–2.92 (m, 2H), 2.26–2.11 (m, 2H).

Example 66: 7-(3,5-Difluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (87)

First step: tert-butyl 3-butyno-2-yl(toluenesulfonyl)carbamate (87b)

87a (50g, 184.28mmol), but-3-yne-2-ol (19.37g, 276.41mmol) and PPh ₃ (72.42g, 276.41mmol) were dissolved in 500mL of THF, and DIAD (55.84g) was added to the ice bath. , 276.41 mmol), after completion of the dropwise addition, the reaction was carried out at 25 ° C for 3 h. After completion of the reaction, the reaction mixture was poured into 1000 mL of water, extracted with ethyl acetate, and the organic phase was concentrated to dryness, and then purified by column chromatography (eluent system B) to give compound 87b (56 g).

MS (ESI, m/z): 324.1 [M+H] ⁺ .

Second step: N-(but-3-yn-2-yl)-4-methylbenzenesulfonamide (87c)

87b (56g, 173.16mmol) was dissolved in 300mL DCM, 200mL TFA was added under ice bath, and reacted at 25 ° C for 2h. After the completion of the reaction, the reaction solution was directly concentrated under reduced pressure to remove DCM and most of the TFA. To the residue after concentration under reduced pressure, 300 mL of EA and 200 mL of water were added, and the pH was adjusted to about 7-8 with sodium hydrogen carbonate solution. After extracting with ethyl acetate, the organic layer was concentrated to dryness to afford compound 87c (40.5 g).

MS (ESI, m/z):224.1 [M+H] ⁺ .

The third step: N-(but-3-yn-1-yl)-N-(but-3-yn-2-yl)-4-methylbenzenesulfonamide (87d)

87c (40g, 179.14mmol, FR), but-3-yn-1-ol (18.83g, 268.66mmol) and PPh ₃ (70.40g, 268.71mmol) were dissolved in 400mL of THF and added to DIAD under ice bath ( 54.28 g, 268.71 mmol), after completion of the dropwise addition, the reaction was carried out at 25 ° C for 3 h. After completion of the reaction, the reaction mixture was poured into 1000 mL of water, extracted with ethyl acetate, and the organic phase was concentrated to dryness, and then purified by flash column chromatography (eluent system B) to give compound 87d (30 g).

MS (ESI, m/z):276.1 [M+H] ⁺ .

Fourth step: 8-methyl-7-toluenesulfonyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid ethyl ester (87e)

87d (30g, 108.95mmol), Rh(COD) ₂ BF ₄ (2.21g, 5.45mmol), BINAP (3.39g, 5.45mmol) were dissolved in a mixture of 300mL DCM and 30mL water, N ₂ replacement and stirring at room temperature After 10 min, ethyl cyanoformate (16.19 g, 163.42 mmol) was added dropwise and the mixture was reacted at 25 ° C for 16 h. After completion of the reaction, the reaction mixture was poured into 100 mL of water, extracted with DCM, and the organic phase was concentrated to dryness.

MS (ESI, m/z): 375.1 [M+H]+.

Step 5: 8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylic acid ethyl ester (87f)

87e (13 g, 34.72 mmol), phenol (8.17 g, 86.79 mmol) was dissolved in 130 mL of 33% HBr in AcOH and reacted at 90 ° C for 2 h. After the reaction, the reaction solution was directly concentrated to dryness, and then 100 mL of EA was added to the system, stirred for 30 min, filtered, and the solid was washed with EA, then dissolved in 100 mL of water, extracted twice with EA, and the aqueous phase was adjusted with sodium bicarbonate solution. It is about 7-8 and is extracted 4 times (100 ml*4) with isopropyl alcohol/DCM (1/3). The organic phases were combined and dried with EtOAcqqqq

MS (ESI, m/z): 221 [M+H] ⁺ .

Step 6: 7-(3,5-Difluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylic acid ethyl ester (87 g)

87f (3.78g, 17.16mmol), 1-bromo-3,5-difluorobenzene (6.62g, 34.32mmol), Pd(OAc) ₂ (384.41mg, 1.72mmol), Cs ₂ CO ₃ (13.98g, 42.90 mmol) and BINAP (2.14 g, 3.43 mmol) were dissolved in 50 mL of toluene and heated to 90 ° C for 16 h under N ₂ protection. After completion of the reaction, the mixture was filtered through celite, and then filtered and evaporated.

MS (ESI, m/z): 333.1 [M+H] ⁺ .

Step 7: 7-(3,5-Difluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (87)

87 g (2 g, 6.02 mmol) was dissolved in 25 mL of tetrahydrofuran and 10 mL of water, and then LiOH·H ₂ O (1.26 g, 30.09 mmol) was added and allowed to react at room temperature for 3 h. After the completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and then the solvent was evaporated to remove the solvent. The solid was precipitated and filtered, and the filter cake was washed with a small amount of water and dried under reduced pressure to give compound 87 (955 mg).

MS (ESI, m/z): 305.1 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.56 (s, 1H), 7.90 (s, 1H), 6.75-6.63 (m, 2H), 6.42 (tt, J = 9.2,2.1Hz, 1H), 5.28 (q, J = 6.5 Hz, 1H), 3.83 (dt, J = 13.2, 4.6 Hz, 1H), 3.37 (dd, J = 9.1, 4.6 Hz, 1H), 2.98 (dd, J = 9.4, 5.5 Hz) , 2H), 1.41 (d, J = 6.7 Hz, 3H).

Examples 67 and 68: (S)-7-(3,5-Difluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylic acid And (R)-7-(3,5-difluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid

First step: ethyl 7-(3,5-difluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (87 g) Chiral separation

87 g (1.175 g, 3.54 mmol) was isolated on a chiral column to afford a peak 1 - 87 g-1 (500 mg, 1.5 mmol) and a peak 2 - 87 g-2 (550 mg, 1.65 mmol).

Chiral separation method: Instrument: YMC-K preparation system, column: CHIRALPAK IC 2.5 cm ID × 25 cm L × 5 μm; column temperature: 35 ° C; flow rate: 30.0 mL / min; detection wavelength: 214 nm; mobile phase: MeOH =100%. Peak 1: 7.5-8.5 min; peak 2: 11.0-12.5 min.

Second step: (S)-7-(3,5-difluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid and R)-7-(3,5-Difluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylic acid

87 g-1 (500 mg, 1.5 mmol) was dissolved in 15 mL of tetrahydrofuran and 3 mL of water, and NaOH (180 mg, 4.5 mmol) was added and the mixture was reacted at room temperature for 2 h. After the end of the reaction, the pH of the system was adjusted to about 5-6 with 1 N HCl. After most of the solvent was removed by rotary evaporation, the solid was precipitated, filtered, filtered, washed with a little water and dried under reduced pressure to give 88 (420 mg).

MS (ESI, m/z): 305.1 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.56 (s, 1H), 7.89 (s, 1H), 6.70 - 6.67 (m, 2H), 6.42 - 6.39 (m, 1H), 5.30 - 5.26 (m) , 1H), 3.85–3.80 (m, 1H), 3.37–3.33 (m, 1H), 2.99–2.96 (m, 2H), 1.41–1.39 (m, 3H).

87 g-2 (550 mg, 1.65 mmol) was dissolved in 12 mL of tetrahydrofuran and 3 mL of water, and then LiOH·H ₂ O (347.20 mg, 8.27 mmol) was added and allowed to react at room temperature for 2 h. After the completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and then the solvent was evaporated to remove the solvent. The solid was precipitated and filtered, and the filter cake was washed with a small amount of water and dried under reduced pressure to give 89 (420 mg).

MS (ESI, m/z): 305.1 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.56 (s, 1H), 7.90 (s, 1H), 6.69 (d, J = 10.1Hz, 2H), 6.42 (t, J = 9.1Hz, 1H) , 5.29 (d, J = 6.3 Hz, 1H), 3.83 (dd, J = 8.8, 4.4 Hz, 1H), 3.00 - 2.95 (m, 3H), 1.41 (d, J = 6.6 Hz, 3H).

Example 69: 7-(3-Chloro-5-fluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (90)

First step: ethyl 7-(3-chloro-5-fluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (90a)

Compound 87f (60 mg, 272.40 μmol), 1-bromo-3-chloro-5-fluorobenzene (85.60 mg, 408.60 μmol), Pd(OAc) ₂ (6.11 mg, 27.24 μmol), BINAP (33.90 mg, 54.48 μmol) And Cs ₂ CO ₃ (221.88 mg, 680.99 μmol) was dissolved in 5 mL of toluene and heated to 90 ° C for 5 h under N ₂ protection. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 349.8 [M+H] ⁺ .

Second step: 7-(3-chloro-5-fluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (90)

Compound 90a (40 mg, 114.68 μmol) was dissolved in 3 mL of tetrahydrofuran and 1 mL of water, and then LiOH·H ₂ O (48.10 mg, 1.15 mmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 90 (4 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

Instrument model: Agilent 1260, column: Waters SunFire Prep C ₁₈ OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 ° C; flow rate: 28.0 mL / min; detection wavelength: 214 nm; elution gradient: (0 min: 30% A, 70% B; 16 min: 70% A, 30% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous formic acid.

MS (ESI, m/z): 321.7 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.56 (s, 1H), 7.89 (s, 1H), 6.88 (s, 1H), 6.82 (dd, J = 13.1,2.1Hz, 1H), 6.63 ( Dt, J = 8.4, 1.8 Hz, 1H), 5.30 (q, J = 6.6 Hz, 1H), 3.84 (dt, J = 13.3, 4.7 Hz, 1H), 3.04 - 2.91 (m, 3H), 1.40 (d , J = 6.6Hz, 3H).

Examples 70 and 71: (S)-7-(3-chloro-5-fluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate Acid and (R)-7-(3-chloro-5-fluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylic acid

First step: ethyl 7-(3-chloro-5-fluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (90a) Chiral separation

90a (1.241 g, 3.56 mmol) was isolated by chiral to afford peaks 1 - 90a-1 (530 mg, 1.52 mmol) and peaks 2 - 90a-2 (280 mg, 0.80 mmol).

Chiral separation method: Instrument: YMC-K preparation system, column: CHIRALPAK AY 5.0 cm ID × 25 cm L × 10 μm; column temperature: 35 ° C; flow rate: 60.0 mL / min; detection wavelength: 254 nm; mobile phase: EtOH =100%. Peak 1: 8.5-10.0 min; peak 2: 11.2-13.2 min.

Second step: (S)-7-(3-chloro-5-fluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid and (R)-7-(3-chloro-5-fluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylic acid

90a-1 (530 mg, 1.52 mmol) was dissolved in 10 mL of tetrahydrofuran and 3 mL of water, and then LiOH·H ₂ O (318.79 mg, 7.60 mmol) was added and allowed to react at room temperature for 2 h. After the completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl. After the solvent was removed, the solid was separated and filtered, filtered, washed with a small amount of water and dried under reduced pressure to give compound 91 (355 mg).

MS (ESI, m/z): 321.7 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.60 (s, 1H), 7.96 (s, 1H), 6.88 (s, 1H), 6.83 (d, J = 13.0Hz, 1H), 6.63 (d, J = 8.2 Hz, 1H), 5.34 (d, J = 6.5 Hz, 1H), 3.90 - 3.80 (m, 1H), 3.43 - 3.33 (m, 1H), 3.00 - 2.95 (m, 2H), 1.41 (d , J = 6.5 Hz, 3H).

90a-2 (280 mg, 0.80 mmol) was dissolved in 6 mL of tetrahydrofuran and 2 mL of water, and then LiOH·H ₂ O (168.58 mg, 4.01 mmol) was added and allowed to react at room temperature for 2 h. After the completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl. After the solvent was removed, the solid was separated, filtered, and filtered, washed with a small amount of water and dried under reduced pressure to give compound 92 (190 mg).

MS (ESI, m/z): 321.7 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.57 (s, 1H), 7.90 (s, 1H), 6.88 (s, 1H), 6.82 (dt, J = 13.1,2.1Hz, 1H), 6.63 ( Dt, J = 8.4, 1.8 Hz, 1H), 5.31 (q, J = 6.5 Hz, 1H), 3.84 (dt, J = 13.2, 4.6 Hz, 1H), 3.42 - 3.35 (m, 1H), 2.97 (d) , J = 4.0 Hz, 2H), 1.40 (d, J = 6.6 Hz, 3H).

Example 72: 7-(4-Chloro-3,5-difluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (93 )

First step: ethyl 7-(4-chloro-3,5-difluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (93a)

Compound 87f (70 mg, 317.80 μmol), 5-bromo-2-chloro-1,3-difluorobenzene (108.42 mg, 476.69 μmol), Pd(OAc) ₂ (7.10 mg, 31.78 μmol), BINAP (39.61 mg) 63.56 μmol) and Cs ₂ CO ₃ (258.90 mg, 794.49 μmol) were dissolved in 5 mL of toluene and heated to 90 ° C for 15 h under N ₂ protection. After completion of the reaction, the mixture was filtered through celite, and then filtered and evaporated.

MS (ESI, m/z): 367.1 [M+H] ⁺ .

Second step: 7-(4-chloro-3,5-difluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (93 )

Compound 93a (50 mg, 136.32 μmol) was dissolved in 4 mL of tetrahydrofuran and 1 mL water, and then LiOH·H ₂ O (57.20 mg, 1.36 mmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and the compound 93 (35 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

MS (ESI, m/z): 339.1 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.56 (s, 1H), 7.91 (s, 1H), 6.95 (d, J = 11.4Hz, 2H), 5.31 (q, J = 6.5Hz, 1H) , 4.04 (dd, J = 14.2, 7.1 Hz, 1H), 3.86 (dt, J = 13.2, 4.6 Hz, 1H), 2.99 (dd, J = 9.0, 5.2 Hz, 2H), 1.42 (d, J = 6.6) Hz, 3H).

Examples 73 and 74: (S)-7-(4-chloro-3,5-difluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine- 3-carboxylic acid and (R)-7-(4-chloro-3,5-difluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3 -carboxylic acid

First step: ethyl 7-(4-chloro-3,5-difluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate Chiral separation of (93a)

Separation of 93a (0.843 g, 2.30 mmol) by chirality gave peaks 1 - 93a-1 (380 mg, 1.04 mmol) and peaks 2 - 93a-2 (400 mg, 1.09 mmol).

Chiral separation method: Instrument: YMC-K preparation system, column: CHIRALPAK IC 5.0 cm ID × 25 cm L × 10 μm; column temperature: 35 ° C; flow rate: 30.0 mL / min; detection wavelength: 214 nm; mobile phase: MeOH =100%. Peak 1: 8.2-9.5 min; peak 2: 12.3-14.2 min.

Second step: (S)-7-(4-chloro-3,5-difluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine-3- Carboxylic acid and (R)-7-(4-chloro-3,5-difluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate acid

93a-1 (380 mg, 1.04 mmol) was dissolved in 5 mL of tetrahydrofuran and 2 mL of water, and then LiOH·H ₂ O (217.41 mg, 5.18 mmol) was added and allowed to react at room temperature for 2 h. After the completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl. After the solvent was removed, the solid was precipitated and filtered, filtered, washed with a small amount of water and dried under reduced pressure to give compound 94 (275 mg).

MS (ESI, m/z): 339.1 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.55 (s, 1H), 7.90 (s, 1H), 6.95 (t, J = 8.3 Hz, 2H), 5.30 (q, J = 6.5 Hz, 1H) , 3.85 (dt, J = 13.2, 4.6 Hz, 1H), 3.36 (dd, J = 8.3, 5.3 Hz, 1H), 2.98 (dd, J = 9.0, 5.2 Hz, 2H), 1.41 (d, J = 6.6) Hz, 3H).

93a-2 (400 mg, 1.09 mmol) was dissolved in 6 mL of tetrahydrofuran and 2 mL of water, and then LiOH·H ₂ O (229.01 mg, 5.45 mmol) was added and allowed to react at room temperature for 2 h. After the completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl. After the solvent was removed, the solid was separated and filtered, filtered, washed with a small amount of water and dried under reduced pressure to give compound 95 (350 mg).

MS (ESI, m/z): 339.1 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.58 (s, 1H), 7.97 (s, 1H), 6.96 (s, 1H), 6.93 (s, 1H), 5.33 (q, J = 6.5Hz, 1H), 3.87 (dt, J = 13.2, 4.5 Hz, 1H), 3.45 - 3.33 (m, 1H), 3.00 (d, J = 5.0 Hz, 2H), 1.42 (d, J = 6.6 Hz, 3H).

Example 75: 7-(4-Chloro-3-fluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (96)

First step: ethyl 7-(4-chloro-3-fluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (96a)

Compound 87f (80 mg, 363.20 μmol), 4-bromo-1-chloro-2-fluorobenzene (114.10 mg, 544.79 μmol), Pd(OAc) ₂ (5.71 mg, 25.42 μmol), BINAP (31.66 mg, 50.85 μmol) And Cs ₂ CO ₃ (259.84 mg, 907.99 μmol) were dissolved in 5 mL of toluene and heated to 90 ° C for 5 h under N ₂ protection. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 349.8 [M+H] ⁺ .

Second step: 7-(4-chloro-3-fluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (96)

Compound 96a (50 mg, 143.35 μmol) was dissolved in 3 mL of tetrahydrofuran and 1 mL of water, and then LiOH·H ₂ O (60.21 mg, 1.43 mmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and the compound 96 (25 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

MS (ESI, m/z): 321.7 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.57 (s, 1H), 7.88 (s, 1H), 7.35 (t, J = 9.0 Hz, 1H), 7.04 (dd, J = 13.5, 2.7 Hz, 1H), 6.85 (dd, J = 9.1, 2.5 Hz, 1H), 5.26 (q, J = 6.5 Hz, 1H), 3.80 (dt, J = 13.0, 4.6 Hz, 1H), 3.40 - 3.35 (m, 1H) ), 3.00–2.92 (m, 2H), 1.39 (d, J = 6.6 Hz, 3H).

Examples 76 and 77: (S)-7-(4-chloro-3-fluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate Acid and (R)-7-(4-chloro-3-fluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylic acid

First step: ethyl 7-(4-chloro-3-fluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (96a) Chiral separation

The chiral separation of 96a (1.835 g, 5.26 mmol) gave peaks 1 - 96a-1 ( 790 mg, 2.26 mmol) and peaks 2 - 96a-2 (730 mg, 2.09 mmol).

Chiral separation method: Instrument: YMC-K preparation system, column: CHIRALPAK IC 5.0 cm ID × 25 cm L × 10 μm; column temperature: 35 ° C; flow rate: 30.0 mL / min; detection wavelength: 214 nm; mobile phase: MeOH =100%. Peak 1: 8.0-9.1 min; peak 2: 11.0-13.0 min.

Second step: (S)-7-(4-chloro-3-fluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid and (R)-7-(4-chloro-3-fluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid 96a-1 ( 790 mg, 2.26 mmol) was dissolved in 10 mL of tetrahydrofuran and 5 mL of water, then LiOH·H ₂ O (475.18 mg, 11.32 mmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl. After the solvent was removed, the solid was separated and filtered, filtered, and filtered.

MS (ESI, m/z): 321.7 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.57 (s, 1H), 7.90 (s, 1H), 7.35 (t, J = 9.0Hz, 1H), 7.03 (dd, J = 13.5,2.8Hz, 1H), 6.85 (dd, J = 9.0, 2.6 Hz, 1H), 5.27 (q, J = 6.6 Hz, 1H), 3.81 (dt, J = 13.1, 4.7 Hz, 1H), 3.39 - 3.32 (m, 1H) ), 2.97 (dd, J = 10.3, 6.2 Hz, 2H), 1.39 (d, J = 6.6 Hz, 3H).

96a-2 (730 mg, 2.09 mmol) was dissolved in 6 mL of tetrahydrofuran and 2 mL of water, and then LiOH·H ₂ O (439.51 mg, 10.46 mmol) was added and allowed to react at room temperature for 2 h. After the completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl. After the solvent was removed, the solid was separated and filtered, filtered, washed with a small amount of water, and dried under reduced pressure to give compound 98 (660 mg).

MS (ESI, m/z): 321.7 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.64 (s, 1H), 8.02 (s, 1H), 7.37 (t, J = 8.9 Hz, 1H), 7.04 (d, J = 13.4 Hz, 1H) , 6.85 (d, J = 8.8 Hz, 1H), 5.33 (d, J = 6.5 Hz, 1H), 3.84 (d, J = 13.1 Hz, 1H), 3.43 - 3.32 (m, 1H), 3.04 (s, 2H), 1.40 (d, J = 6.5 Hz, 3H).

Example 78: 7-(3-Ethoxy-5-fluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (99)

First step: ethyl 7-(3-ethoxy-5-fluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylate ( 99a)

Compound 87f (1.2 g, 5.45 mmol), 1-bromo-3-ethoxy-5-fluorobenzene (2.15 g, 9.81 mmol), Pd(OAc) ₂ (122.03 mg, 544.79 μmol), BINAP (678.45 mg) , 1.09 mmol) and Cs ₂ CO ₃ (4.44 g, 13.62 mmol) were dissolved in 30 mL of toluene and heated to 90 ° C under N ₂ for 16 h. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 359.2 [M+H] ⁺ .

Second step: 7-(3-ethoxy-5-fluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (99)

Compound 99a (36 mg, 100.44 μmol) was dissolved in 3 mL of tetrahydrofuran and 1 mL of water, and then LiOH·H ₂ O (21.05 mg, 500 μmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and Compound 99 (25 mg) was obtained by Prep-HPLC.

Prep-HPLC conditions:

Instrument model: Agilent 1260, column: Waters SunFire Prep C ₁₈ OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 ° C; flow rate: 28.0 mL / min; detection wavelength: 214 nm; elution gradient: (0 min: 10% A, 90% B; 16 min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous formic acid.

MS (ESI, m/z): 331.1 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.56 (s, 1H), 7.88 (s, 1H), 6.41 (d, J = 12.9 Hz, 1H), 6.32 (s, 1H), 6.14 (dd, J = 10.9, 2.0 Hz, 1H), 5.24 (q, J = 6.4 Hz, 1H), 4.00 (q, J = 7.0 Hz, 2H), 3.83 - 3.72 (m, 1H), 3.00 - 2.92 (m, 2H) ), 1.38 (d, J = 6.6 Hz, 3H), 1.31 (t, J = 7.0 Hz, 3H).

Examples 79 and 80: (S)-7-(3-ethoxy-5-fluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine-3 -carboxylic acid and (R)-7-(3-ethoxy-5-fluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate acid

First step: ethyl 7-(3-ethoxy-5-fluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylate ( Chiral separation of 99a)

99a (0.862 g, 2.41 mmol) was isolated by chiral to afford peaks 1 - 99a-1 (320 mg, 892.9 mmol) and peaks 2 - 99a-2 (380 mg, 1.06 mmol).

Chiral separation method: Instrument: YMC-K preparation system, column: CHIRALPAK IC 5.0 cm ID × 25 cm L × 10 μm; column temperature: 35 ° C; flow rate: 30.0 mL / min; detection wavelength: 254 nm; mobile phase: MeOH =100%. Peak 1: 8.0-9.5 min; peak 2: 11.0-13.0 min.

Second step: (S)-7-(3-ethoxy-5-fluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate Acid and (R)-7-(3-ethoxy-5-fluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylic acid

99a-1 (320 mg, 892.9 mmol) was dissolved in 8 mL of tetrahydrofuran and 2 mL of water, and then LiOH·H ₂ O (188.8 mg, 4.5 mmol) was added and allowed to react at room temperature for 2 h. After the completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl. After the solvent was removed, the solid was precipitated, filtered, and filtered, washed with a small amount of water and dried under reduced pressure to give compound 100 (195 mg).

MS (ESI, m/z): 331.1 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.56 (s, 1H), 7.88 (s, 1H), 6.43 - 6.39 (m, 1H), 6.32 (s, 1H), 6.16 - 6.12 (m, 1H) ), 5.26–5.22 (m, 1H), 4.03–3.98 (m, 2H), 3.80–3.75 (m, 1H), 3.36–3.29 (m, 1H), 2.98–2.93 (m, 2H), 1.84–1.37 (m, 3H), 1.32–1.29 (m, 3H).

99a-2 (380 mg, 1.06 mmol) was dissolved in 8 mL of tetrahydrofuran and 2 mL of water, then LiOH·H ₂ O (222.44 mg, 5.30 mmol) was added and allowed to react at room temperature for 2 h. After the completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl. After the solvent was removed, the solid was separated and filtered, filtered, washed with a small amount of water, and dried under reduced pressure to give compound 101 (195 mg).

MS (ESI, m/z): 331.1 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.56 (s, 1H), 7.88 (s, 1H), 6.42 (d, J = 12.8 Hz, 1H), 6.32 (s, 1H), 6.14 (d, J = 10.9 Hz, 1H), 5.24 (dd, J = 13.2, 6.5 Hz, 1H), 4.00 (q, J = 7.0 Hz, 2H), 3.82 - 3.73 (m, 1H), 3.02 - 2.89 (m, 3H) ), 1.37 (d, J = 6.6 Hz, 3H), 1.30 (t, J = 7.0 Hz, 3H).

Example 81: 7-(3-Fluoro-5-methylphenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (102)

First step: 7-(3-Fluoro-5-methylphenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylic acid ethyl ester (102a )

Compound 87f (2 g, 9.08 mmol), 1-bromo-3-fluoro-5-methylbenzene (4.3 g, 22.7 mmol), Pd ₂ (dba) ₃ (830 mg, 0.91 mmol), BINAP (1.1 g, 1.8) Methyl) and Cs ₂ CO ₃ (8.8 g, 27.2 mmol) were added to 60 mL of toluene and heated to 80 ° C under N ₂ for 24 h. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 329.2 [M+H] ⁺ .

Second step: 7-(3-Fluoro-5-methylphenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (102)

Compound 102a (15 mg, 45.68 μmol) was added to 1 mL of ethanol and 2 mL of water, then NaOH (9 mg, 228.4 μmol) was added and allowed to react at room temperature for 1 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl. The solid was precipitated, filtered, and dried to give Compound 102 (10 mg).

MS (ESI, m/z): 301.1 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.64 (s, 1H), 8.00 (s, 1H), 7.33 (s, 1H), 6.66 - 6.60 (m, 2H), 6.36 - 6.34 (m, 1H) ), 5.31–5.29 (m, 1H), 3.39–3.32 (m, 2H), 3.02–3.01 (m, 2H), 2.26 (s, 3H), 1.39–1.38 (m, 3H).

Examples 82 and 83: (S)-7-(3-Fluoro-5-methylphenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine-3- Carboxylic acid and (R)-7-(3-fluoro-5-methylphenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid

First step: 7-(3-Fluoro-5-methylphenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylic acid ethyl ester (102a Chiral separation

102a (1.280 g, 3.90 mmol) was isolated by chiral to afford peaks 1 - 102a-1 (600 mg, 1.83 mmol) and peaks 2 - 102a-2 (620 mg, 1.89 mmol).

Chiral separation method: Instrument: YMC-K preparation system, column: CHIRALPAK AY 5.0 cm ID × 25 cm L × 10 μm; column temperature: 35 ° C; flow rate: 60.0 mL / min; detection wavelength: 254 nm; mobile phase: EtOH /ACN=90%/10%. Peak 1:12.5-13.5min; peak 2: 16.5-17.5min.

Second step: (S)-7-(3-Fluoro-5-methylphenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylic acid And (R)-7-(3-fluoro-5-methylphenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylic acid

102a-1 (600 mg, 1.83 mmol) was dissolved in 20 mL of tetrahydrofuran and 4 mL of water, and then LiOH·H ₂ O (383.3 mg, 9.14 mmol) was added and allowed to react at room temperature for 2 h. After the completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl. After the solvent was removed, the solid was separated and filtered, filtered, washed with a small amount of water, and dried under reduced pressure to give compound 103 (450 mg).

MS (ESI, m/z): 301.3 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.57 (s, 1H), 7.88 (s, 1H), 6.65 (s, 1H), 6.61 (d, J = 13.1Hz, 1H), 6.33 (d, J=9.4 Hz, 1H), 5.24 (q, J=6.1 Hz, 1H), 3.84–3.73 (m, 1H), 3.41–3.28 (m, 1H), 3.04–2.89 (m, 2H), 2.26 (s) , 3H), 1.38 (d, J = 6.6 Hz, 3H).

102a-2 (620 mg, 1.89 mmol) was dissolved in 8 mL of tetrahydrofuran and 2 mL water, and then LiOH·H ₂ O (396.4 mg, 9.44 mmol) was added and allowed to react at room temperature for 2 h. After the end of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and the solvent was evaporated to give a crude material. The crude product was isolated by Prep-HPLC to afford Compound 104 (428 mg).

Prep-HPLC conditions:

Instrument model: Agilent 1260, column: Waters SunFire Prep C ₁₈ OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 ° C; flow rate: 28.0 mL / min; detection wavelength: 254 nm; retention time: 3.6-5.1 min , elution gradient: (0 min: 30% A, 70% B; 16 min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous formic acid.

MS (ESI, m/z): 301.3 [M+H] ⁺ .

^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ8.57 (s, 1H), 7.88 (s, 1H), 6.65 (s, 1H), 6.61 (d, J = 13.0Hz, 1H), 6.33 (d, J=9.4 Hz, 1H), 5.24 (q, J=6.6 Hz, 1H), 3.89–3.73 (m, 1H), 3.37–3.31 (m, 1H), 3.01–2.84 (m, 2H), 2.26 (s) , 3H), 1.38 (d, J = 6.7 Hz, 3H).

Example 84: 7-(3,4-Dichloro-5-fluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylic acid (105 )

First step: ethyl 7-(3,4-dichloro-5-fluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylate (105a)

Compound 87f (100 mg, 454 μmol), 5-bromo-1,2-dichloro-3-fluorobenzene (221.5 mg, 908 μmol), Pd ₂ (dba) ₃ (10 mg, 45 μmol), SPHos (37 mg, 91 μmol) and Cs ₂ CO ₃ (370 mg, 101 μmol) was dissolved in 5 mL of xylene, and heated to 150 ° C for 6 h under N ₂ protection. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated to dryness.

MS (ESI, m/z): 383.1 [M+H] ⁺ .

Second step: ethyl 7-(3,4-dichloro-5-fluorophenyl)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-carboxylate (105)

Compound 105a (20 mg, 52.2 μmol) was added to 1 mL of ethanol and 2 mL of water, and then NaOH (10.5 mg, 261 μmol) was added and allowed to react at room temperature for 1 h. After completion of the reaction, the pH of the system was adjusted to about 3 with 1N HCl, and the solid was precipitated, filtered, and dried to give compound 105 (6 mg).

MS (ESI, m/z): 355.1 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.49 (s, 1H), 7.83 (s, 1H), 7.10 - 7.05 (m, 2H), 5.31 - 5.27 (m, 1H), 3.86 - 3.81 (m) , 1H), 3.35–3.33 (m, 1H), 2.97–2.95 (m, 2H), 1.41–1.38 (m, 3H).

Biological evaluation

The invention is further described and illustrated in the following experiments, but these experiments are not intended to limit the scope of the invention.

1.HBsAg secretion inhibition and cytotoxicity test

Purpose:

The purpose of this assay was to test the effect of the compounds of the invention on the secretion of hepatitis B virus surface antigen HBsAg and toxicity to cells.

Experimental principle:

HepG2.2.15 cells are capable of secreting mature hepatitis B virus particles, HBsAg and HBeAg into the culture medium. The HBsAg secreted by the cells can be quantified by an ELISA method, and thereby the effect of the compound on the secretion of the viral HBsAg is detected, and the cytotoxicity of the compound is detected.

experimental method:

Reagent

HepG2.2.15 cell growth medium: DMEM (Invitrogen 11960-044) + 10% FBS (Biosera FB-1280);

HepG2.2.15 assay medium: 2% FBS + DMEM

HBV HBsAg diagnostic ELISA kit (Shanghai Kehua Bioengineering Co., Ltd., S10910113);

CellTiter-Glo Luminescent Cell Viability Assay kit (Promega G7572)

Experimental steps and results:

The 96-well cell culture plate was inoculated with HepG2.2.15 cells at 15,000 cells/well, and cultured for 3 days at 37 ° C in a 5% CO ₂ cell incubator until the cells were long to full. The medium containing different concentrations of the drug was replaced and culture was continued for 7 days. Change the fluid every other day. On the 7th day, the supernatant was taken to determine the HBsAg content in the cell supernatant according to the hepatitis B virus surface antigen detection ELISA kit, and the half-inhibitory concentration (IC ₅₀ ) of HBsAg was calculated, and the above cell line was used, and CellTiter was used. Methods The cytotoxicity (CC ₅₀ ) of the compounds was determined and the number of measurements was 2 times. The experimental results are shown in Table 1.

Table IC inventive compound present HBsAg 1. ₅₀ secretion inhibition or inhibition of cytotoxicity and the CC ₅₀

化合物Compound	IC ₅₀(nM) IC ₅₀ (nM)	CC ₅₀(μM) CC ₅₀ (μM)	100nM抑制率(％)100nM inhibition rate (%)
11	24.47±3.8024.47±3.80	>150>150	NANA
22	5.46±1.795.46±1.79	102.90±10.25102.90±10.25	NANA
33	185.15±7.57185.15±7.57	>150>150	NANA
66	17.55±3.0517.55±3.05	63.98±4.5363.98±4.53	NANA
77	135.15±23.26135.15±23.26	71.14±0.1971.14±0.19	NANA
1414	45.81±7.3845.81±7.38	71.26±5.0671.26±5.06	NANA
1515	15.89±0.4015.89±0.40	84.72±4.7984.72±4.79	NANA
1717	NANA	NANA	53.58±3.4653.58±3.46
3636	82.39±0.6582.39±0.65	58.37±1.6158.37±1.61	NANA
3737	60.06±5.6960.06±5.69	69.63±0.1369.63±0.13	NANA
4242	53.51±0.2853.51±0.28	51.13±1.1551.13±1.15	NANA
4343	42.88±2.8542.88±2.85	27.47±1.3127.47±1.31	NANA
4646	107.3±1.56107.3±1.56	29.22±1.2929.22±1.29	NANA
4747	58.11±4.3758.11±4.37	48.68±5.3648.68±5.36	NANA
5050	34.07±2.1434.07±2.14	38.81±1.0038.81±1.00	NANA
5151	84.19±23.6484.19±23.64	74.67±0.4874.67±0.48	NANA
5252	36.40±0.6736.40±0.67	43.13±1.2943.13±1.29	NANA
5454	NANA	NANA	80.08±1.1580.08±1.15
5555	NANA	NANA	74.43±5.0874.43±5.08
5656	141.55±32.31141.55±32.31	76.63±1.6876.63±1.68	NANA
5757	8.20±0.978.20±0.97	95.30±5.9595.30±5.95	NANA
5959	NANA	NANA	70.96±1.0970.96±1.09
6060	22.17±1.6822.17±1.68	146.55±0.78146.55±0.78	NANA
6161	11.72±4.3811.72±4.38	79.05±4.3179.05±4.31	NANA
6262	NANA	NANA	96.13±0.8396.13±0.83
6363	NANA	NANA	65.24±2.2965.24±2.29
6464	12.92±3.1312.92±3.13	88.13±5.1588.13±5.15	NANA
6565	NANA	NANA	81.87±1.6781.87±1.67
6666	2.89±0.172.89±0.17	65.28±3.2065.28±3.20	NANA
6767	3.14±0.633.14±0.63	98.99±1.9998.99±1.99	NANA
6868	6.36±0.416.36±0.41	65.38±2.6365.38±2.63	NANA
6969	NANA	NANA	94.78±0.7694.78±0.76
7070	NANA	NANA	87.05±1.8687.05±1.86
7171	NANA	NANA	96.60±0.2996.60±0.29
7272	NANA	NANA	58.84±0.4458.84±0.44
7474	NANA	NANA	73.88±0.3573.88±0.35

7575	NANA	NANA	63.87±2.7163.87±2.71
7676	NANA	NANA	53.88±2.1853.88±2.18
7979	NANA	NANA	77.98±1.1277.98±1.12
8080	NANA	NANA	81.89±1.5281.89±1.52
8181	NANA	NANA	91.37±0.2191.37±0.21
8383	NANA	NANA	72.05±0.0172.05±0.01
8484	NANA	NANA	90.46±0.5090.46±0.50
8585	NANA	NANA	78.00±1.2278.00±1.22
8686	NANA	NANA	91.43±0.5391.43±0.53
8787	NANA	NANA	95.11±0.0695.11±0.06
8989	0.69±0.080.69±0.08	65.26±0.9065.26±0.90	NANA
9090	NANA	NANA	100.93±0.06100.93±0.06
9292	0.33±0.040.33±0.04	40.41±3.1740.41±3.17	NANA
9393	NANA	NANA	99.81±0.8999.81±0.89
9595	0.45±0.090.45±0.09	53.25±0.3853.25±0.38	NANA
9696	NANA	NANA	97.94±1.6597.94±1.65
9999	NANA	NANA	101.63±0.47101.63±0.47
101101	0.23±0.050.23±0.05	65.85±7.6265.85±7.62	NANA
102102	NANA	NANA	100.18±0.28100.18±0.28
104104	0.58±0.010.58±0.01	64.21±2.7864.21±2.78	NANA
105105	NANA	NANA	103.63±0.86103.63±0.86

Note: NA means not determined.

The results indicate that the compound of the present invention has high inhibitory activity against HBsAg secretion and has low cytotoxicity.

2. Safety assessment

(1) hERG experiment

Using ^{Predictor TM hERG Fluorescence Polarization Assay Kit (} ThermoFisher), according to kit instructions inhibition test compounds, the concentration of the test hERG potassium ion channel is 10 M, the test results in Table 2.

Table 2 Inhibition of hERG by the compounds of the invention

化合物Compound	hERG IC ₅₀(μM) hERG IC ₅₀ (μM)
11	>10>10
22	>10>10
33	>10>10
1414	>10>10
1515	>10>10
3636	>10>10
3737	>10>10
5757	>10>10
6060	>10>10
8989	>10>10
9292	>10>10
101101	>10>10
104104	>10>10

The results indicate that the compound of the present invention has no hERG inhibitory effect, resulting in a small possibility of prolonging the QT interval of the heart.

(2) CYP enzyme inhibition test

CYP450 is the most important enzyme system in drug metabolism, the most important of which are CYP1A2, CYP2D6 and CYP3A4. In the inhibition test of CYP450 enzyme, P450-Glo ^TM CYP1A2Screening System,

CYP2D6 Cyan Screening Kit and

For the CYP3A4 Red Screening Kit, the inhibitory activities of the compounds against CYP1A2, CYP2D6 and CYP3A4 were determined according to the kit instructions. The test results are shown in Table 3.

Table 3. Results of inhibition test of CYP enzyme by the compound of the present invention

The results showed that the compound of the present invention had no significant inhibitory effect on CYP1A2, CYP2D6, and CYP3A4 enzymes.

3. Pharmacokinetics (PK) study in rats

Drugs and Reagents: For intravenous (IV), the test compound was formulated into a solution with 5% DMSO: 5% solutol: 90% physiological saline; for oral (PO), the test compound was formulated into a suspension with 0.5% MC.

Test animals: Male SPF grade SD rats (3 each of IV and PO) were purchased from Chengdu Dashuo Experimental Animal Co., Ltd., and all animals were fasted for 10-14 hours before administration and returned to food 4 hours after administration.

Dosage: IV is 0.5 mg/kg or 1 mg/kg; PO is 5 mg/kg.

Pharmacokinetic test: The test compounds were administered to rats by IV and PO, respectively, and blood samples were collected through the tail vein, and about 0.30 mL of each sample was collected, and EDTA-K _{2 was} anticoagulated. The timing of IV blood collection was as follows: 0 min before administration, 5 min after administration, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h; PO blood collection time points were as follows: 0 min before administration, 0.25 h after administration , 0.5h, 1h, 2h, 4h, 6h, 8h, 24h, and centrifuged (4000 rev / min, 10min, 4 ° C) for plasma within 30min, plasma samples were stored at -80 ° C before analysis, plasma samples were precipitated protein LC-MS/MS analysis was performed after the treatment. Mass spectrometry using API 5500, liquid chromatography using Waters ACQUITY I CLASS system; column using Agela HILIC column (2.1 × 50 mm, 3.0 μm); mobile phase: phase B is water + 0.5% formic acid + 5 mM ammonium acetate, phase A is acetonitrile The flow rate is 0.5 mL/min, the column temperature is 40 ° C; the ion source is the ESI source positive ion mode, and the scanning mode is multiple reaction monitoring (MRM). The pharmacokinetic parameters of the compounds were calculated using the non-compartmental model of the pharmacokinetic software WinNonlin 6.3. The results are shown in Table 4 below:

Table 4 Pharmacokinetic parameters of the compounds of the invention in rats

* indicates that IV and PO experiments were performed on different dates and bioavailability was not calculated.

The results indicate that the compounds of the present invention have good PK properties in SD rats.

4. Pharmacokinetics (PK) study in Beagle dogs

Test animals: Male Beagle dogs (3 each for IV and PO) were purchased from Beijing Max Biotechnology Co., Ltd. All animals were fasted for 10-14 hours before administration and returned to food 4 hours after administration.

Dosage: IV was 0.5 mg/kg; PO was 2.5 mg/kg.

Pharmacokinetic test: The test compounds were administered to dogs by IV and PO, respectively. The blood samples were collected by venous blood from the extremities, and about 0.50 mL of each sample was collected, and EDTA-K _{2 was} anticoagulated. The timing of IV blood collection was as follows: 0 min before administration, 5 min after administration, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h; PO blood collection time points were as follows: 0 min before administration, 0.25 h after administration , 0.5h, 1h, 2h, 4h, 6h, 8h, 24h, and centrifuged (4000 rev / min, 10min, 4 ° C) for plasma within 30min, plasma samples were stored at -80 ° C before analysis, plasma samples were precipitated protein LC-MS/MS analysis was performed after the treatment. Mass spectrometry using API 5500, liquid chromatography using Waters ACQUITY I CLASS system; column using Agela HILIC column (2.1 × 50 mm, 3.0 μm); mobile phase: phase B is water + 0.5% formic acid + 5 mM ammonium acetate, phase A is acetonitrile The flow rate is 0.5 mL/min, the column temperature is 40 ° C; the ion source is the ESI source positive ion mode, and the scanning mode is multiple reaction monitoring (MRM). The pharmacokinetic parameters of the compounds were calculated using the non-compartmental model of the pharmacokinetic software WinNonlin 6.3. The results are shown in Table 5 below:

Table 5 Pharmacokinetic parameters of the compounds of the invention in Beagle dogs

The results indicate that the compound of the present invention (e.g., Compound 92) has excellent PK properties in Beagle dogs.

5. Pharmacokinetics (PK) study in cynomolgus monkeys

Test animals: Female cynomolgus monkeys (three of IV and PO) were purchased from Hainan Jingang Biotechnology Co., Ltd., and all animals were fasted for 10-14 hours before administration and returned to food 4 hours after administration.

Dosage: IV was 0.5 mg/kg; PO was 2.5 mg/kg.

Pharmacokinetic test: The test compounds were administered to the monkeys by IV and PO, respectively. The blood samples were collected by venous blood from the extremities, and about 0.50 mL of each sample was collected, and EDTA-K _{2 was} anticoagulated. The timing of IV blood collection was as follows: 0 min before administration, 5 min after administration, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h; PO blood collection time points were as follows: 0 min before administration, 0.25 h after administration , 0.5h, 1h, 2h, 4h, 6h, 8h, 24h, and centrifuged (4000 rev / min, 10min, 4 ° C) for plasma within 30min, plasma samples were stored at -80 ° C before analysis, plasma samples were precipitated protein LC-MS/MS analysis was performed after the treatment. Mass spectrometry using API 5500, liquid chromatography using Waters ACQUITY I CLASS system; column using Agela HILIC column (2.1 × 50 mm, 3.0 μm); mobile phase: phase B is water + 0.5% formic acid + 5 mM ammonium acetate, phase A is acetonitrile The flow rate is 0.5 mL/min, the column temperature is 40 ° C; the ion source is the ESI source positive ion mode, and the scanning mode is multiple reaction monitoring (MRM). The pharmacokinetic parameters of the compounds were calculated using the non-compartmental model of the pharmacokinetic software WinNonlin 6.3. The results are shown in Table 6 below:

Table 6 Pharmacokinetic parameters of the compounds of the invention in cynomolgus monkeys

The results indicate that the compound of the present invention (e.g., compound 92) has excellent PK properties in cynomolgus monkeys.

In addition to those described herein, various modifications of the invention are intended to come within the scope of the appended claims. Each of the references (including all patents, patent applications, journal articles, books, and any other publications) cited in this application are hereby incorporated by reference in their entirety.

Claims

a compound of formula I or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite or prodrug thereof:

among them:

R 1 is selected from a C 6 -C 14 aryl group and a 5-14 membered heteroaryl group, and the C 6 -C 14 aryl group and the 5-14 membered heteroaryl group may be optionally substituted with a substituent;

R 2 and R 3 are each independently selected from hydrogen and unsubstituted C 1 -C 6 alkyl, or R 2 and R 3 together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl;

R 4 is selected from -C(O)R 5 , -CO 2 R 6 , -C(O)NR 7 SO 2 R 8 , -C(O)NR 9 R 10 , optionally substituted by a substituent 5 Metaheteroaryl, and

Wherein: R 5 and R 8 are each independently selected from a C 1 -C 6 alkyl group and a C 3 -C 7 cycloalkyl group, and the C 1 -C 6 alkyl group and the C 3 -C 7 cycloalkyl group are optionally selected. The ground is replaced by a substituent;

R 6 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 3 -C 7 cycloalkyl, and the C 1 -C 6 alkyl and C 3 -C 7 cycloalkyl may be optionally substituted with a substituent;

R 7 , R 9 and R 10 are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl-OC 1 -C 6 alkyl and 4- a 7-membered heterocyclic group, or R 9 and R 10 together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic group, said C 1 -C 6 alkyl group, C 3 -C 7 cycloalkyl group, C 1 a -C 6 alkyl-OC 1 -C 6 alkyl group and a 4-7 membered heterocyclic group may be optionally substituted with a substituent;

R 11 and R 16 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl-OC 1 -C 6 alkyl, C 6 -C 14 Aryl, 5-14 membered heteroaryl and 4-10 membered heterocyclyl, said C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl-OC 1 -C a 6 alkyl group, a C 6 -C 14 aryl group, a 5-14 membered heteroaryl group, and a 4-10 membered heterocyclic group may be optionally substituted with a substituent;

R 12 , R 13 , R 14 and R 15 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkane a base-OC 1 -C 6 alkyl group and a 4-7 membered heterocyclic group, said C 1 -C 6 alkyl group, C 3 -C 7 cycloalkyl group, C 1 -C 6 alkoxy group, C 1 -C a 6- alkyl-OC 1 -C 6 alkyl group and a 4-7 membered heterocyclic group may be optionally substituted with a substituent;

One of X and Y is N and the other is selected from CH and N;

The "substituted substituent" means optionally substituted by one or more substituents independently selected from the group consisting of hydroxy, halo, C 1 -C 6 alkyl, halo C 1 -C 6 alkane , C 1 -C 6 alkoxy, -OC 1 -C 6 alkyl-OH, halogenated C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, cyano, nitro, -C (O)R 5 , -C(O)OR 6 , -NR 7 SO 2 R 8 , -SO 2 R 8 , -C(O)NR 9 R 10 , -SO 2 NR 9 R 10 , -NR 9 R 10 , -NR 9 C(O)R 10 , -C 1 -C 6 alkyl-OC 1 -C 6 alkyl, -OC 1 -C 6 alkyl-OC 1 -C 6 alkyl, substituted by hydroxy -OC 1 -C 6 alkyl-OC 1 -C 6 alkyl, hydroxyalkyl, C 1 -C 6 alkyl-NR 9 R 10 , C 1 -C 6 alkyl-C(O)NR 9 R 10 , C 1 -C 6 alkyl-NR 9 C(O)R 10 , aryl, heteroaryl and heterocyclic;

Provided that when R 4 is a 5-membered heteroaryl group which may be optionally substituted with a substituent, X and Y are not N at the same time.
A compound of claim 1 or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite or prodrug thereof, wherein:

R 1 is selected from a C 6 -C 14 aryl group and a 5-14 membered heteroaryl group, and the C 6 -C 14 aryl group and the 5-14 membered heteroaryl group may be optionally substituted with a substituent;

R 2 and R 3 are each independently selected from hydrogen and unsubstituted C 1 -C 6 alkyl, or R 2 and R 3 together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl;

R 4 is selected from -C(O)R 5 , -CO 2 R 6 , -C(O)NR 7 SO 2 R 8 , -C(O)NR 9 R 10 , optionally substituted by a substituent 5 Metaheteroaryl, and

Wherein: R 5 and R 8 are each independently selected from a C 1 -C 6 alkyl group and a C 3 -C 7 cycloalkyl group, and the C 1 -C 6 alkyl group and the C 3 -C 7 cycloalkyl group are optionally selected. The ground is replaced by a substituent;

R 6 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 3 -C 7 cycloalkyl, and the C 1 -C 6 alkyl and C 3 -C 7 cycloalkyl may be optionally substituted with a substituent;

R 7 , R 9 and R 10 are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl-OC 1 -C 6 alkyl and 4- a 7-membered heterocyclic group, or R 9 and R 10 together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic group, said C 1 -C 6 alkyl group, C 3 -C 7 cycloalkyl group, C 1 a -C 6 alkyl-OC 1 -C 6 alkyl group and a 4-7 membered heterocyclic group may be optionally substituted with a substituent;

R 11 and R 16 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl-OC 1 -C 6 alkyl, C 6 -C 14 Aryl, 5-14 membered heteroaryl and 4-10 membered heterocyclyl, said C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl-OC 1 -C a 6 alkyl group, a C 6 -C 14 aryl group, a 5-14 membered heteroaryl group, and a 4-10 membered heterocyclic group may be optionally substituted with a substituent;

R 12 , R 13 , R 14 and R 15 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkane a base-OC 1 -C 6 alkyl group and a 4-7 membered heterocyclic group, said C 1 -C 6 alkyl group, C 3 -C 7 cycloalkyl group, C 1 -C 6 alkoxy group, C 1 -C a 6- alkyl-OC 1 -C 6 alkyl group and a 4-7 membered heterocyclic group may be optionally substituted with a substituent;

One of X and Y is N and the other is selected from CH and N;

The "substituted substituent" means optionally substituted by one or more substituents independently selected from the group consisting of hydroxy, halo, C 1 -C 6 alkyl, halo C 1 -C 6 alkane Base, C 3 -C 7 cycloalkyl, cyano, nitro, -C(O)R 5 , -C(O)OR 6 , -NR 7 SO 2 R 8 , -SO 2 R 8 , -C( O) NR 9 R 10 , -SO 2 NR 9 R 10 , -NR 9 R 10 , -NR 9 C(O)R 10 , -OC 1 -C 6 alkyl-OC 1 -C 6 alkyl, by hydroxyl group Substituted -OC 1 -C 6 alkyl-OC 1 -C 6 alkyl, hydroxyalkyl, C 1 -C 6 alkyl-NR 9 R 10 , C 1 -C 6 alkyl-C(O)NR 9 R 10 , C 1 -C 6 alkyl-NR 9 C(O)R 10 , aryl, heteroaryl and heterocyclic.
A compound of claim 1 or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite or prodrug thereof, wherein:

R 1 is selected from a C 6 -C 10 aryl group and a 5-10 membered heteroaryl group, and the C 6 -C 10 aryl group and the 5-10 membered heteroaryl group may be optionally one or more (for example, 2) Or 3 substituents selected from the group consisting of cyano, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogenated C 1 -C 3 alkoxy, -SO 2 R 8 , -C(O)NR 9 R 10 , -OC 1 -C 6 alkyl-OC 1 -C 6 alkyl, -OC 1 -C 6 alkyl-OH , -NR 9 R 10 and a heterocyclic group;

Preferably, R 1 is selected from the group consisting of phenyl and pyridyl, and the phenyl and pyridyl groups may be optionally substituted by one or more (for example 2 or 3) substituents independently selected from the group consisting of cyanogens: Base, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogenated C 1 -C 3 alkoxy, -C(O)NH 2 , -SO 2 CH 3 , -OC 1 -C 3 alkyl-OC 1 -C 3 alkyl, -OC 1 -C 3 alkyl-OH, -NR 9 R 10 and heterocyclic group;

Preferably, R 1 is selected from the group consisting of phenyl and pyridyl, and the phenyl and pyridyl groups may be optionally substituted by one or more (for example 2 or 3) substituents independently selected from the group consisting of fluorine: , chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl, ethyl, propyl, isopropyl Base, cyano, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, -C(O)NH 2 , -SO 2 CH 3 , -NR 9 R 10 and 5 to 10 membered spiroheterocyclyl;

Preferably, R 1 is selected from the group consisting of phenyl and pyridyl, which may be optionally substituted by one or more substituents independently selected from the group of groups:

Fluorine, chlorine, bromine, methoxy, ethoxy, isopropoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl, cyano, trifluoromethyl, 2-hydroxy Ethoxy, 2-methoxyethoxy, -C(O)NH 2 and -SO 2 CH 3 ;

-NR 9 R 10 , wherein R 9 and R 10 together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group which may be optionally substituted by a substituent, wherein:

Preferably, the 4-6 membered heterocyclic group is selected from the group consisting of one or more (e.g., 2 or 3) substituents independently selected from the group consisting of the following:
Hydroxy, halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -OC 1 -C 6 alkyl-OH, halogenated C 1 -C 6 alkane Oxyl, cyano, nitro, -NH 2 , -C 1 -C 6 alkyl-OC 1 -C 6 alkyl, -OC 1 -C 6 alkyl-OC 1 -C 6 alkyl, substituted by hydroxy -OC 1 -C 6 alkyl-OC 1 -C 6 alkyl and hydroxy C 1 -C 10 alkyl;

More preferably, the 4-6 membered heterocyclyl is selected from the group consisting of optionally substituted by one or more (e.g., 2 or 3) substituents independently selected from the group consisting of
Hydroxy, fluorine, chlorine, bromine, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, -C 1 -C 3 alkyl-OC 1 -C 3 alkyl and hydroxy C 1 -C 3 alkyl -;

More preferably, the 4-6 membered heterocyclyl is selected from the group consisting of optionally substituted by one or more (e.g., 2 or 3) substituents independently selected from the group consisting of
Hydroxy, fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, hydroxymethyl and hydroxyethyl;

More preferably, the 4-6 membered heterocyclic group is selected from

And a 9 to 10 membered nitrogen-containing spiroheterocyclyl group, preferably
More preferred
A compound according to any one of claims 1 to 3, or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite or prodrug thereof, among them:

R 1 is selected from C 6 -C 10 aryl and 5-10 membered heteroaryl, and the C 6 -C 10 aryl and 5-10 membered heteroaryl may be optionally substituted by one or more of the following groups : cyano, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy, -SO 2 R 8 , -C(O)NR 9 R 10 ,- OC 1 -C 6 alkyl-OC 1 -C 6 alkyl or -OC 1 -C 6 alkyl-OH;

Preferably, R 1 is selected from the group consisting of phenyl and pyridyl, which may be optionally substituted by one or more of the following groups: cyano, halogen, C 1 -C 3 alkyl, halogen C 1- C 3 alkyl, C 1 -C 3 alkoxy, -C(O)NH 2 , -SO 2 CH 3 , -OC 1 -C 3 alkyl-OC 1 -C 3 alkyl or -OC 1 -C 3 alkyl-OH;

Preferably, R 1 is selected from the group consisting of phenyl and pyridyl, which may be optionally substituted by one or more of the following groups: cyano, halogen, C 1 -C 3 alkyl, halogen C 1- C 3 alkyl, C 1 -C 3 alkoxy, -C(O)NH 2 , -SO 2 CH 3 , -OC 1 -C 3 alkyl-OC 1 -C 3 alkyl or -OC 1 -C 3 alkyl-OH;

Preferably, R 1 is selected from the group consisting of phenyl and pyridyl, which may be optionally substituted by one or more of the following groups: fluorine, chlorine, bromine, methoxy, ethoxy, isopropyl Oxy, methyl, cyano, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, -C (O) NH 2 or -SO 2 CH 3 ;

Preferably, R 1 is selected from the group consisting of phenyl and pyridyl, which may be optionally substituted by one or more of the following groups: fluorine, methoxy, methyl, cyano, trifluoromethyl , 2-hydroxyethoxy, 2-methoxyethoxy, -C(O)NH 2 or -SO 2 CH 3 .
A compound according to any one of claims 1 to 4, or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite or prodrug thereof, among them:

R 2 and R 3 are each independently selected from hydrogen and C 1 -C 3 alkyl, or R 2 and R 3 together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl;

Preferably, R 2 and R 3 are each independently selected from hydrogen, methyl and ethyl, or R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl group;

More preferably, R 2 and R 3 are each independently selected from hydrogen and methyl, or R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl group;

Particularly preferably, R 2 and R 3 are each independently selected from the group consisting of hydrogen and methyl.
A compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite or prodrug thereof, among them:

R 4 is selected from -C(O)C 1 -C 6 alkyl, -C(O)OC 1 -C 6 alkyl, -C(O)OH, -C(O)NH 2 , -C(O) NH(C 1 -C 6 alkyl), -C(O)NH-SO 2 -C 1 -C 6 alkyl, -C(O)N(C 1 -C 6 alkyl)-SO 2 -C 1 a C 6 alkyl group, optionally substituted by one or more substituents independently selected from C 1 -C 6 alkyl (for example, tetrazolyl, thiazolyl, imidazolyl, triazolyl) And oxazolyl), and

Preferably, R 4 is selected from -C(O)C 1 -C 3 alkyl, -C(O)OC 1 -C 3 alkyl, -C(O)OH, -C(O)NH 2 , -C (O) NH-SO 2 -C 1 -C 3 alkyl,

Preferably, R 4 is selected from the group consisting of -C(O)OCH 3 , -C(O)OEt, -C(O)OH, -C(O)NH 2 , -C(O)CH 3 , -C(O) Et, -C(O)NH-SO 2 -CH 3 , -C(O)NH-SO 2 -Et,

Preferably, R 4 is selected from the group consisting of -C(O)OEt, -C(O)OH, -C(O)NH 2 , -C(O)CH 3 , -C(O)NH-SO 2 -CH 3 ,

Preferably, R 4 is selected from the group consisting of -C(O)OEt, -C(O)OH, -C(O)NH 2 , -C(O)CH 3 and -C(O)NH-SO 2 -CH 3 ;

Preferably, R 4 is selected from the group consisting of -C(O)OEt and -C(O)OH;

More preferably, R 4 is -C(O)OH.
A compound according to any one of claims 1 to 6, or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite or prodrug thereof, among them:

R 5 and R 8 are selected from C 1 -C 3 alkyl and C 3 -C 5 cycloalkyl, and the C 1 -C 3 alkyl and C 3 -C 5 cycloalkyl may be optionally substituted by a substituent ;

Preferably, R 5 and R 8 are methyl.
A compound according to any one of claims 1 to 7, or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite or prodrug thereof, among them:

R 6 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, and C 3 -C 5 cycloalkyl, and the C 1 -C 3 alkyl and C 3 -C 5 cycloalkyl may be optionally substituted with a substituent;

Preferably, R 6 is hydrogen, methyl or ethyl;

More preferably, R 6 is hydrogen or ethyl;

Particularly preferably, R 6 is hydrogen.
A compound according to any one of claims 1 to 8, or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite or prodrug thereof, among them:

R 7 , R 9 and R 10 are each independently selected from the group consisting of hydrogen, C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, C 1 -C 3 alkyl-OC 1 -C 3 alkyl and 4- a 6-membered heterocyclic group, or R 9 and R 10 together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group, said C 1 -C 3 alkyl group, C 3 -C 5 cycloalkyl group, C 1 a -C 3 alkyl-OC 1 -C 3 alkyl group or a 4-6 membered heterocyclic group may be optionally substituted with a substituent;

Preferably, R 7 , R 9 and R 10 are hydrogen.
A compound according to any one of claims 1 to 8, or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite or prodrug thereof, among them:

R 9 and R 10 together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group which may be optionally substituted with a substituent, wherein:

Preferably, the 4-6 membered heterocyclic group is selected from the group consisting of one or more (e.g., 2 or 3) substituents independently selected from the group consisting of the following:
Hydroxy, halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -OC 1 -C 6 alkyl-OH, halogenated C 1 -C 6 alkane Oxyl, cyano, nitro, -NH 2 , -C 1 -C 6 alkyl-OC 1 -C 6 alkyl, -OC 1 -C 6 alkyl-OC 1 -C 6 alkyl, substituted by hydroxy -OC 1 -C 6 alkyl-OC 1 -C 6 alkyl and hydroxy C 1 -C 10 alkyl;

More preferably, the 4-6 membered heterocyclyl is selected from the group consisting of optionally substituted by one or more (e.g., 2 or 3) substituents independently selected from the group consisting of
Hydroxy, fluorine, chlorine, bromine, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, -C 1 -C 3 alkyl-OC 1 -C 3 alkyl and OH-C 1 -C 3 alkane base-;

More preferably, the 4-6 membered heterocyclyl is selected from the group consisting of optionally substituted by one or more (e.g., 2 or 3) substituents independently selected from the group consisting of
Hydroxy, fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, hydroxymethyl and hydroxyethyl;

More preferably, the 4-6 membered heterocyclic group is selected from
A compound according to any one of claims 1 to 10, or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite or prodrug thereof, among them:

R 11 and R 16 are each independently selected from hydrogen, C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, C 1 -C 3 alkyl-OC 1 -C 3 alkyl, C 6 -C 14 Aryl, 5-14 membered heteroaryl and 4-6 membered heterocyclyl, said C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, C 1 -C 3 alkyl-OC 1 -C a 3- alkyl group, a C 6 -C 14 aryl group, a 5-14 membered heteroaryl group, and a 4-6 membered heterocyclic group may be optionally substituted with a substituent;

Preferably, R 11 and R 16 are each independently selected from the group consisting of hydrogen, C 1 -C 3 alkyl, 5-10 membered heteroaryl, and 4-6 membered heterocyclyl;

Preferably, R 11 and R 16 are each independently selected from the group consisting of hydrogen and methyl.
A compound according to any one of claims 1 to 11, or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite or prodrug thereof, among them:

R 12 , R 13 , R 14 and R 15 are each independently selected from the group consisting of hydrogen, C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkane a base-OC 1 -C 3 alkyl group and a 4-6 membered heterocyclic group, said C 1 -C 3 alkyl group, C 3 -C 5 cycloalkyl group, C 1 -C 3 alkoxy group, C 1 -C The 3- alkyl-OC 1 -C 3 alkyl group and the 4-6 membered heterocyclic group may be optionally substituted with a substituent;

Preferably, R 12 , R 13 , R 14 and R 15 are all hydrogen.
A compound according to any one of claims 1 to 12, or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite or prodrug thereof, among them:

X is N and Y is CH; or

X is CH and Y is N; or

X is N and Y is N.
A compound according to any one of claims 1 to 13 or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite or prodrug thereof, among them:

The "substituted substituent" means optionally substituted by one or more substituents independently selected from the group consisting of hydroxy, halo, C 1 -C 6 alkyl, halo C 1 -C 6 alkane , C 1 -C 6 alkoxy, -OC 1 -C 6 alkyl-OH, halogenated C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, cyano, nitro, -C (O) C 1 -C 6 alkyl, -C(O)OH, -C(O)OC 1 -C 6 alkyl, -NHSO 2 C 1 -C 6 alkyl, -N(C 1 -C 6 Alkyl)SO 2 C 1 -C 6 alkyl, -SO 2 C 1 -C 6 alkyl, -C(O)NH 2 , -C(O)NH(C 1 -C 6 alkyl), -SO 2 NH 2 , -SO 2 NH(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), as defined in claim 1 or 2 with respect to R 9 and R 10 4-7 membered heterocyclic group, -NHC(O)C 1 -C 6 alkyl, -N(C 1 -C 6 alkyl)C(O)C 1 -C 6 alkyl, -C 1 -C 6 alkyl -OC 1 -C 6 alkyl, -OC 1 -C 6 alkyl group -OC 1 -C 6 alkyl, hydroxyl substituted -OC 1 -C 6 alkyl group -OC 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkyl-NH 2 , C 1 -C 6 alkyl-NH(C 1 -C 6 alkyl), C 1 -C 6 alkyl-C(O) NH 2 , C 1 -C 6 alkyl-C(O)NH(C 1 -C 6 alkyl), C 1 -C 6 alkyl-NHC(O)C 1 -C 6 alkyl, C 1 -C 6 alkyl -N (C 1 -C 6 alkyl ) C (O) C 1 -C 6 alkyl, aryl, heteroaryl and 5-10 membered spiro-heterocyclyl;

Preferably, the "substituted with" means optionally substituted with one or more substituents independently selected from the group consisting of substituted: hydroxy, halo, C 1 -C 3 alkyl, halo C 1 - C 3 alkyl, C 1 -C 3 alkoxy, -OC 1 -C 3 alkyl-OH, halogenated C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl, cyano, nitro , -C(O)C 1 -C 3 alkyl, -C(O)OH, -C(O)OC 1 -C 3 alkyl, -NHSO 2 C 1 -C 3 alkyl, -N (C 1 -C 3 alkyl)SO 2 C 1 -C 3 alkyl, -SO 2 C 1 -C 3 alkyl, -C(O)NH 2 , -C(O)NH(C 1 -C 3 alkyl) , -SO 2 NH 2 , -SO 2 NH(C 1 -C 3 alkyl), -NH 2 , -NH(C 1 -C 3 alkyl), as defined in claim 10 with respect to R 9 and R 10 4-6 membered heterocyclic group, -NHC(O)C 1 -C 3 alkyl, -N(C 1 -C 3 alkyl)C(O)C 1 -C 3 alkyl, -C 1 -C alkyl -OC 1 -C 3 alkyl, -OC 1 -C 3 alkyl group -OC 1 -C 3 alkyl, substituted hydroxyl group -OC 1 -C 3 alkyl group -OC 1 -C 3 alkyl, Hydroxy C 1 -C 3 alkyl, C 1 -C 3 alkyl-NH 2 , C 1 -C 3 alkyl-NH(C 1 -C 3 alkyl), C 1 -C 3 alkyl-C(O NH 2 , C 1 -C 3 alkyl-C(O)NH(C 1 -C 3 alkyl), C 1 -C 3 alkyl-NHC(O)C 1 -C 3 alkyl, C 1 - C 3 alkyl-N (C 1 -C 3 alkyl)C(O)C 1 -C 3 alkyl and 9 to 10 membered nitrogen-containing spiroheterocyclyl;

Preferably, the "substituted substituent" means optionally substituted by one or more substituents independently selected from the group consisting of: hydroxy; fluoro, chloro, bromo; methyl, ethyl, isopropyl Fluoromethyl, difluoromethyl, trifluoromethyl; methoxy, ethoxy, isopropoxy; -OCH 2 OH, -OCH 2 CH 3 OH; fluoromethoxy, difluoromethoxy , trifluoromethoxy; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; cyano; nitro; -C(O)CH 3 , -C(O)CH 2 CH 3 ;-C(O ) OH, -C(O)OCH 3 , -C(O)OCH 2 CH 3 ; -NHSO 2 CH 3 , -NHSO 2 CH 2 CH 3 , -N(CH 3 )SO 2 CH 3 , -N(CH 3 ) SO 2 CH 2 CH 3 ; -SO 2 CH 3 , -SO 2 CH 2 CH 3 ; -C(O)NH 2 , -C(O)NHCH 3 , -C(O)NHCH 2 CH 3 ;- SO 2 NH 2 , -SO 2 NHCH 3 , -SO 2 NHCH 2 CH 3 ; -NH 2 , -NHCH 3 , -NHCH 2 CH 3 ; 4-6 as defined in claim 10 for R 9 and R 10 Heterocyclyl; -NHC(O)CH 3 , -NHC(O)CH 2 CH 3 , -N(CH 3 )C(O)CH 3 , -N(CH 3 )C(O)CH 2 CH 3 ; -CH 2 -OCH 3 , -CH 2 CH 2 -OCH 3 , -CH 2 -OCH 2 CH 3 , -CH 2 CH 2 -OCH 2 CH 3 ; -OCH 2 -OCH 3 , -OCH 2 -OCH 2 CH 3 , -OCH 2 CH 2 -OCH 3 ; -OCH 2 -OCH 3 , -OCH 2 -OCH 2 CH 3 or -OCH 2 CH 2 -OCH 3 substituted by hydroxy; -CH 2 OH, -CH 2 CH 2 OH ;-CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 -NH(CH 3 ), -CH 2 -NH(CH 2 CH 3 ), -CH 2 CH 2 -NH(CH 3 ), - CH 2 CH 2 -NH(CH 2 CH 3 ); -CH 2 C(O)NH 2 , -CH 2 C(O)NH(CH 3 ), -CH 2 C(O)NH(CH 2 CH 3 ) , -CH 2 CH 2 C(O)NH(CH 3 ), -CH 2 CH 2 C(O)NH(CH 2 CH 3 ); -CH 2 -NHC(O)CH 3 , -CH 2 -N ( CH 3 )C(O)CH 3 , -CH 2 -N(CH 3 )C(O)CH 2 CH 3 ; and 9 to 10 membered nitrogen-containing spiroheterocyclyl;

Preferably, the "substituted substituent" means optionally substituted by one or more substituents independently selected from the group consisting of fluorine, chlorine, bromine; methyl, ethyl, isopropyl; Methyl, difluoromethyl, trifluoromethyl; methoxy, ethoxy, isopropoxy; -OCH 2 OH, -OCH 2 CH 3 OH; fluoromethoxy, difluoromethoxy, three Fluoromethoxy; cyano; -SO 2 CH 3 , -SO 2 CH 2 CH 3 ; -C(O)NH 2 , -C(O)NHCH 3 , -C(O)NHCH 2 CH 3 ; Relating to the 4-6 membered heterocyclic group defined by R 9 and R 10 ; -CH 2 -OCH 3 , -CH 2 CH 2 -OCH 3 , -CH 2 -OCH 2 CH 3 , -CH 2 CH 2 -OCH 2 CH 3 ; -OCH 2 -OCH 3 , -OCH 2 -OCH 2 CH 3 , -OCH 2 CH 2 -OCH 3 ; -CH 2 OH, -CH 2 CH 2 OH;

Preferably, the "substituted substituent" means optionally substituted by one or more substituents independently selected from the group consisting of fluorine, chlorine, bromine; methyl; trifluoromethyl; methoxy , ethoxy, isopropoxy; -OCH 2 CH 3 OH; fluoromethoxy, difluoromethoxy, trifluoromethoxy; cyano; -SO 2 CH 3 ; -C(O)NH 2 a 4-6 membered heterocyclic group as defined in claim 10 for R 9 and R 10 ; -CH 2 -OCH 3 ; -OCH 2 CH 2 -OCH 3 ; -CH 2 OH;
A compound according to any one of claims 1 to 14, or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite or prodrug thereof, Wherein the compound is a compound of formula II:

Wherein X, Y, R 1 and R 4 are as defined in any one of claims 1 to 14.
A compound according to any one of claims 1 to 14, or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite or prodrug thereof, Wherein the compound is a compound of formula III:

Wherein R 1 and R 4 are as defined in any one of claims 1 to 14.
A compound according to any one of claims 1 to 14, or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite or prodrug thereof, Wherein the compound is a compound of formula IV:

among them:

R 1 and R 4 are as defined in any one of claims 1 to 14;

R 2 is an unsubstituted C 1 -C 6 alkyl group, preferably an unsubstituted C 1 -C 3 alkyl group, more preferably a methyl group or an ethyl group, more preferably a methyl group;

R 3 is hydrogen or unsubstituted C 1 -C 6 alkyl (preferably unsubstituted C 1 -C 3 alkyl, more preferably methyl or ethyl); preferably H or methyl;

or

R 2 and R 3 together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl group, preferably a 3-6 membered cycloalkyl group, such as a cyclopropyl group;

In particular, the compound is a compound of formula V or VI:
A compound according to any one of claims 1 to 14, or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite or prodrug thereof, Wherein the compound is a compound of formula VII:

among them:

R 4 is as defined in any one of claims 1 to 14;

One of W 1 , W 2 and W 3 is N, and the other two are CR 17 ;

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

R 17 is each independently selected from the group consisting of:

(1) hydrogen, halogen (e.g., fluorine, chlorine, and bromine), C 1 -C 6 alkyl, and C 1 -C 6 alkoxy;

(2) -NR 9 R 10 , wherein R 9 and R 10 are as defined in claim 10;

(3) a 5- to 10-membered spiroheterocyclyl group, preferably a 9- to 10-membered nitrogen-containing spiroheterocyclyl group, more preferably
Particularly preferred
A compound according to claim 18, or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite or prodrug thereof, wherein:

R 4 is selected from the group consisting of -C(O)OEt, -C(O)OH, -C(O)NH 2 , -C(O)CH 3 and -C(O)NH-SO 2 -CH 3 ;

R 17 is each independently selected from the group consisting of:

(1) hydrogen, halogen (such as fluorine, chlorine and bromine), C 1 -C 3 alkyl (such as methyl, ethyl and propyl) and C 1 -C 3 alkoxy (such as methoxy and ethoxy) base);

(2) -NR 9 R 10 , wherein R 9 and R 10 are as defined in claim 10;

(3)
Optimal
A compound according to claim 18 or 19, or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite or prodrug thereof, wherein:

R 4 is -C(O)OH;

R 17 is each independently selected from the group consisting of hydrogen, methyl, methoxy, and fluorine.
A compound according to any one of claims 1 to 14, or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite or prodrug thereof, Wherein the compound is a compound of formula VIII:

among them:

R 3 is hydrogen or unsubstituted C 1 -C 6 alkyl (preferably unsubstituted C 1 -C 3 alkyl, more preferably methyl or ethyl); preferably H or methyl;

R 4 is as defined in any one of claims 1 to 14;

R 18 , R 19 , R 20 and R 21 are each independently selected from H, halogen, cyano, halo C 1 -C 6 alkyl, C 1 -C 6 alkyl, -OC 1 -C 6 alkyl, -OC 1 -C 6 alkyl-OC 1 -C 6 alkyl, -OC 1 -C 6 alkyl-OH, halogenated C 1 -C 6 alkoxy, -C(O)R 5 , -C( O) OR 6 , -NR 7 SO 2 R 8 , -SO 2 R 8 , -C(O)NR 9 R 10 , -SO 2 NR 9 R 10 , -NR 9 R 10 and -NR 9 C(O) R 10 ; and

R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each as defined in any one of claims 1 to 14.
A compound of claim 21 or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite or prodrug thereof, wherein:

R 18 , R 19 , R 20 and R 21 are each independently selected from H, halogen, cyano, halo C 1 -C 3 alkyl, C 1 -C 3 alkyl, -OC 1 -C 3 alkyl, -OC 1 -C 3 alkyl-OC 1 -C 3 alkyl, -OC 1 -C 3 alkyl-OH, halogenated C 1 -C 3 alkoxy and -S(O) 2 C 1 -C 3 alkyl;

Preferably, R 18 , R 19 , R 20 and R 21 are each independently selected from the group consisting of H, fluorine, chlorine, bromine, cyano, trifluoromethyl, methyl, methoxy, ethoxy, isopropoxy , -O-CH 2 -CH 2 -OMe, -O-CH 2 CH 2 -OH, trifluoromethoxy, fluoromethoxy, difluoromethoxy and -S(O) 2 CH 3 .
A compound according to claim 21 or 22, or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite or prodrug thereof, wherein:

R 4 is selected from the group consisting of -C(O)OEt and -C(O)OH;

R 18 is selected from the group consisting of H, fluorine, chlorine, methyl, cyano and trifluoromethyl;

R 19 is selected from the group consisting of H, fluorine, chlorine, methoxy and methyl;

R 20 is selected from the group consisting of H, fluorine, chlorine, trifluoromethyl, methyl, cyano and -S(O) 2 CH 3 ;

R 21 is selected from the group consisting of H, fluorine, chlorine, bromine, methoxy, ethoxy, -O-CH 2 -CH 2 -OMe, trifluoromethyl, -O-CH 2 -CH 2 -OH, cyano, -C(O)NH 2 , trifluoromethoxy, isopropoxy, difluoromethoxy, fluoromethoxy and methyl.
A compound according to claim 1 or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite or prodrug thereof, wherein said compound is selected from the group consisting of :
A pharmaceutical composition comprising a compound according to any one of claims 1 to 24 or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate thereof, A metabolite or prodrug, and one or more pharmaceutically acceptable carriers.
A pharmaceutical preparation comprising a compound according to any one of claims 1 to 24 or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolism thereof Or prodrug, or the pharmaceutical composition of claim 25.
A compound according to any one of claims 1 to 24, or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite or prodrug thereof, Use of the pharmaceutical composition of claim 25 or the pharmaceutical preparation of claim 26 in the manufacture of a medicament for the treatment of a disease associated with excessive secretion of HBsAg, preferably the disease is hepatitis B.
The use of claim 27, wherein the medicament further comprises other agents for treating a disease or condition associated with excessive secretion of HBsAg.
Method of preparing a compound of formula II:

among them:

R 4 is selected from the group consisting of -C(O)R 5 , -CO 2 R 6 , -C(O)NR 7 SO 2 R 8 and -C(O)NR 9 R 10 ;

X, Y, R 1 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are as defined in any one of claims 1 to 14;

The method includes the following steps:

The first step: the compound II-1 is reduced to give the compound II-2, wherein R a is a C 1 -C 4 alkyl group, such as a methyl group, an ethyl group or an isopropyl group, preferably an ethyl group;

The second step: compound II-2 and R 1 -L are coupled or nucleophilic substituted to form compound II-3, wherein L is a leaving group such as halogen (eg F, Cl, Br or I) or trifluoro Methanesulfonyloxy;

The third step: the compound II-3 is converted into the target compound of the formula II by a suitable reaction.
Method of preparing a compound of formula II:

among them:

R 4 is selected from a 5-membered heteroaryl group optionally substituted with a substituent
The definition of R 4 as set forth in any one of claims 1, 2 and 6;

X, Y, R 1 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are as defined in any one of claims 1 to 14;

The method includes the following steps:

Step 1: Compound II-4 is reduced to give compound II-5, wherein PG 1 is a suitable hydroxy protecting group (for example C 1 -C 3 alkyl, such as methyl, ethyl or isopropyl, preferably methyl );

Step 2: Compound II-5 and R 1 -L are reacted or nucleophilically substituted to form compound II-6, wherein L is a leaving group such as halogen (eg F, Cl, Br or I) or trifluoro Methanesulfonyloxy;

The third step: compound II-6 is deprotected to form compound II-7;

Step 4: Conversion of compound II-7 to compound II-8, wherein PG 2 is a suitable hydroxy protecting group (eg, trifluoromethanesulfonyl);

Step 5: Compound II-8 is coupled with R 4 -boric acid or R 4 -borate to form a compound of formula II.
Method for preparing a compound of formula V:

among them:

R 4 is selected from the group consisting of -C(O)R 5 , -CO 2 R 6 , -C(O)NR 7 SO 2 R 8 and -C(O)NR 9 R 10 ;

R 1 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are as defined in any one of claims 1 to 14;

The method includes the following steps:

First step: Compound V-1 is coupled with a suitable organotin compound to form compound V-2, wherein each occurrence of R a is independently selected from a C 1 -C 4 alkyl group, such as methyl or ethyl. Or isopropyl, preferably ethyl; R b is a leaving group such as halogen (eg Cl, Br or I) or trifluoromethanesulfonyloxy;

The second step: the compound V-2 is cyclized to form the compound V-3;

The third step: conversion of compound V-3 to compound V-4, wherein PG 3 is a suitable amino protecting group, such as benzyl, p-toluenesulfonyl, benzoyl, benzyloxycarbonyl, allyloxycarbonyl, methoxy a carbonyl group, an ethoxycarbonyl group or a tert-butoxycarbonyl group;

The fourth step: Compound V-4 is reacted by Kulinkovich to form compound V-5;

Step 5: Compound V-5 is deprotected to form compound V-6;

Step 6: Compound V-6 and R 1 -L are coupled or nucleophilic substituted to form compound V-7, wherein L is a leaving group such as halogen (eg F, Cl, Br or I) or trifluoro Methanesulfonyloxy;

Step 7: Compound V-7 is converted to the target compound of formula V by a suitable reaction.
Method of preparing a compound of formula VI:

among them:

R 4 is selected from the group consisting of -C(O)R 5 , -CO 2 R 6 , -C(O)NR 7 SO 2 R 8 and -C(O)NR 9 R 10 ;

R 1 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are as defined in any one of claims 1 to 14;

The method includes the following steps:

The first step: compound VI-1 and NC-C(O)OR a undergo a [2+2+2] cycloaddition reaction to form compound VI-2, wherein PG 3 is an amino protecting group, such as benzyl or p-toluene. Acyl, benzoyl, benzyloxycarbonyl, allyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl, especially p-toluenesulfonyl; R a is C 1 -C 4 alkyl, such as methyl, Ethyl or isopropyl, preferably methyl or ethyl;

The second step: compound VI-2 is deprotected to form compound VI-3;

Step 3: Compound VI-3 undergoes a coupling reaction or nucleophilic substitution reaction with R 1 -L to form compound VI-4, wherein L is a leaving group such as a halogen (for example, F, Cl, Br or I) or OTf ;

Fourth step: Compound VI-4 is converted to the target compound of formula VI by a suitable reaction.
The method of any one of claims 29, 31 and 32, wherein the suitable reaction is selected from the group consisting of:

(1) by hydrolysis to form a target compound in which R 4 is -CO 2 H,

(2) transesterification with an alcohol R 6 OH to form a target compound wherein R 4 is -CO 2 R 6 and R 6 is not H;

(3) reacting with HN(OMe)Me to form Weinreb amide, and then reacting the obtained Weinreb amide with Grignard reagent R 5 MgBr to form a target compound wherein R 4 is -C(O)R 5 ;

(4) was hydrolyzed to the acid, and the resulting acid with HNR 7 SO 2 R 8 wherein R 4 is generated -C (O) NR title compound 7 SO 2 R 8 is a condensation reaction; and

(5) an amine hydrolysis reaction with HNR 9 R 10 to form a target compound in which R 4 is -C(O)NR 9 R 10 , or a hydrolysis reaction occurs to form an acid, and then the resulting acid is condensed with an amine HNR 9 R 10 to form R 4 is a target compound of -C(O)NR 9 R 10 .
A compound according to any one of claims 1 to 24, or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, eutectic, solvate, metabolite or prodrug thereof, The pharmaceutical composition according to claim 25 or the pharmaceutical preparation according to claim 26 for use in the treatment of a disease associated with excessive secretion of HBsAg, preferably the disease is hepatitis B.
A method of treating a disease associated with excessive secretion of HBsAg, the method comprising administering to an individual in need thereof an effective amount of a compound according to any one of claims 1 to 24, or a stereoisomer, tautomer, pharmacy thereof An acceptable salt, polymorph, eutectic, solvate, metabolite or prodrug, pharmaceutical composition of claim 25, or pharmaceutical formulation of claim 26, and optionally including co-administered other An agent for treating a disease or condition associated with excessive secretion of HBsAg; preferably, the disease is hepatitis B.